Cholera

Cholera
Classification and external resources

Scanning electron microscope image of Vibrio cholerae

ICD-10

A00

ICD-9

001

DiseasesDB

29089

MedlinePlus

000303

eMedicine

med/351

MeSH

D002771

Cholera is an infection in the small intestine caused by the bacterium Vibrio cholerae. The main
symptoms are profuse, watery diarrhea and vomiting. Transmission occurs primarily by drinking
water or eating food that has been contaminated by the feces of an infected person, including one
with no apparent symptoms. The severity of the diarrhea and vomiting can lead to rapid
dehydration and electrolyte imbalance, and death in some cases. The primary treatment is oral
rehydration therapy, typically with oral rehydration solution (ORS), to replace water and
electrolytes. If this is not tolerated or does not provide improvement fast enough, intravenous
fluids can also be used. Antibacterial drugs are beneficial in those with severe disease to shorten

its duration and severity. Worldwide, it affects 35 million people and causes 100,000130,000
deaths a year as of 2010. Cholera was one of the earliest infections to be studied by
epidemiological methods.

Contents
[hide]

1 Signs and symptoms

2 Cause
o 2.1 Susceptibility
o 2.2 Transmission

3 Mechanism
o 3.1 Genetic structure

4 Diagnosis
o 4.1 Enrichment media
o 4.2 Plating media

5 Prevention
o 5.1 Surveillance
o 5.2 Vaccine

6 Treatment
o 6.1 Fluids
o 6.2 Electrolytes
o 6.3 Antibiotics
o 6.4 Sari filtration

7 Prognosis

8 Epidemiology

9 History
o 9.1 Cholera morbus
o 9.2 Research

10 Notable cases

11 References

12 Further reading

13 External links

Signs and symptoms

A person with severe dehydration due to cholera - note the sunken eyes and decreased skin turgor
which produces wrinkled hands.
The primary symptoms of cholera are profuse, painless diarrhea and vomiting of clear fluid.[1]
These symptoms usually start suddenly, one to five days after ingestion of the bacteria.[1] The
diarrhea is frequently described as "rice water" in nature and may have a fishy odor.[1] An
untreated person with cholera may produce 1020 litres of diarrhea a day[1] with fatal results. For
every symptomatic person, 3 to 100 people get the infection but remain asymptomatic.[2] Cholera
has been nicknamed the "blue death" due to a patient's skin turning a bluish-gray hue from
extreme loss of fluids.[3]
If the severe diarrheoea is not treated with intravenous rehydration, it can result in lifethreatening dehydration and electrolyte imbalances.[1] The typical symptoms of dehydration
include low blood pressure, poor skin turgor (wrinkled hands), sunken eyes, and a rapid pulse.[1]

Cause
Main article: Vibrio cholerae

Vibrio cholerae, the bacterium that causes cholera

Transmission is primarily by the fecal contamination of food and water caused by poor
sanitation.[4] This bacterium can, however, live naturally in any environment.[5]

Susceptibility
About 100 million bacteria must typically be ingested to cause cholera in a normal healthy adult.
[1]
This dose, however, is less in those with lowered gastric acidity (for instance those using
proton pump inhibitors).[1] Children are also more susceptible, with two- to four-year-olds having
the highest rates of infection.[1] Individuals' susceptibility to cholera is also affected by their
blood type, with those with type O blood being the most susceptible.[1][6] Persons with lowered
immunity, such as persons with AIDS or children who are malnourished, are more likely to
experience a severe case if they become infected.[7] However, it should be noted that any
individual, even a healthy adult in middle age, can experience a severe case, and each person's
case should be measured by the loss of fluids, preferably in consultation with a doctor or other
health worker.

The cystic fibrosis genetic mutation in humans has been said to maintain a selective advantage:
heterozygous carriers of the mutation (who are thus not affected by cystic fibrosis) are more
resistant to V. cholerae infections.[8] In this model, the genetic deficiency in the cystic fibrosis
transmembrane conductance regulator channel proteins interferes with bacteria binding to the
gastrointestinal epithelium, thus reducing the effects of an infection.

Transmission
Cholera is typically transmitted by either contaminated food or water. In the developed world,
seafood is the usual cause, while in the developing world it is more often water.[1] Cholera has
been found in only two other animal populations: shellfish and plankton.[1]

People infected with cholera often have diarrhea, and if this highly liquid stool, colloquially
referred to as "rice-water" or "faucet butt", contaminates water used by others, disease
transmission may occur.[9] The source of the contamination is typically other cholera sufferers
when their untreated diarrheal discharge is allowed to get into waterways, groundwater or
drinking water supplies. Drinking any infected water and eating any foods washed in the water,
as well as shellfish living in the affected waterway, can cause a person to contract an infection.
Cholera is rarely spread directly from person to person. Both toxic and nontoxic strains exist.
Nontoxic strains can acquire toxicity through a temperate bacteriophage.[10] Coastal cholera
outbreaks typically follow zooplankton blooms, thus making cholera a zoonotic disease.

Mechanism
Most bacteria, when consumed, do not survive the acidic conditions of the human stomach.[11]
The few surviving bacteria conserve their energy and stored nutrients during the passage through
the stomach by shutting down much protein production. When the surviving bacteria exit the
stomach and reach the small intestine, they need to propel themselves through the thick mucus
that lines the small intestine to get to the intestinal walls, where they can thrive. V. cholerae
bacteria start up production of the hollow cylindrical protein flagellin to make flagella, the corkscrew helical fibers they rotate to propel themselves through the mucus of the small intestine.
Once the cholera bacteria reach the intestinal wall, they no longer need the flagella to move. The
bacteria stop producing the protein flagellin, thus again conserving energy and nutrients by
changing the mix of proteins which they manufacture in response to the changed chemical
surroundings. On reaching the intestinal wall, V. cholerae start producing the toxic proteins that
give the infected person a watery diarrhea. This carries the multiplying new generations of V.
cholerae bacteria out into the drinking water of the next host if proper sanitation measures are
not in place.
The cholera toxin (CTX or CT) is an oligomeric complex made up of six protein subunits: a
single copy of the A subunit (part A), and five copies of the B subunit (part B), connected by a
disulfide bond. The five B subunits form a five-membered ring that binds to GM1 gangliosides
on the surface of the intestinal epithelium cells. The A1 portion of the A subunit is an enzyme
that ADP-ribosylates G proteins, while the A2 chain fits into the central pore of the B subunit
ring. Upon binding, the complex is taken into the cell via receptor-mediated endocytosis. Once
inside the cell, the disulfide bond is reduced, and the A1 subunit is freed to bind with a human
partner protein called ADP-ribosylation factor 6 (Arf6).[12] Binding exposes its active site,
allowing it to permanently ribosylate the Gs alpha subunit of the heterotrimeric G protein. This
results in constitutive cAMP production, which in turn leads to secretion of H2O, Na+, K+, Cl,
and HCO3 into the lumen of the small intestine and rapid dehydration. The gene encoding the
cholera toxin is introduced into V. cholerae by horizontal gene transfer. Virulent strains of V.
cholerae carry a variant of temperate bacteriophage called CTXf or CTX.
Microbiologists have studied the genetic mechanisms by which the V. cholerae bacteria turn off
the production of some proteins and turn on the production of other proteins as they respond to
the series of chemical environments they encounter, passing through the stomach, through the
mucous layer of the small intestine, and on to the intestinal wall.[13] Of particular interest have

been the genetic mechanisms by which cholera bacteria turn on the protein production of the
toxins that interact with host cell mechanisms to pump chloride ions into the small intestine,
creating an ionic pressure which prevents sodium ions from entering the cell. The chloride and
sodium ions create a salt-water environment in the small intestines, which through osmosis can
pull up to six litres of water per day through the intestinal cells, creating the massive amounts of
diarrhea. The host can become rapidly dehydrated if an appropriate mixture of dilute salt water
and sugar is not taken to replace the blood's water and salts lost in the diarrhea.
By inserting separate, successive sections of V. cholerae DNA into the DNA of other bacteria,
such as E. coli that would not naturally produce the protein toxins, researchers have investigated
the mechanisms by which V. cholerae responds to the changing chemical environments of the
stomach, mucous layers, and intestinal wall. Researchers have discovered a complex cascade of
regulatory proteins controls expression of V. cholerae virulence determinants. In responding to
the chemical environment at the intestinal wall, the V. cholerae bacteria produce the TcpP/TcpH
proteins, which, together with the ToxR/ToxS proteins, activate the expression of the ToxT
regulatory protein. ToxT then directly activates expression of virulence genes that produce the
toxins, causing diarrhea in the infected person and allowing the bacteria to colonize the intestine.
[13]
Current research aims at discovering "the signal that makes the cholera bacteria stop
swimming and start to colonize (that is, adhere to the cells of) the small intestine."[13]

Genetic structure
Amplified fragment length polymorphism fingerprinting of the pandemic isolates of V. cholerae
has revealed variation in the genetic structure. Two clusters have been identified: Cluster I and
Cluster II. For the most part, Cluster I consists of strains from the 1960s and 1970s, while Cluster
II largely contains strains from the 1980s and 1990s, based on the change in the clone structure.
This grouping of strains is best seen in the strains from the African continent.[14]

[edit] Diagnosis
A rapid dip-stick test is available to determine the presence of V. cholerae.[5] In those samples
that test positive, further testing should be done to determine antibiotic resistance.[5] In epidemic
situations, a clinical diagnosis may be made by taking a patient history and doing a brief
examination. Treatment is usually started without or before confirmation by laboratory analysis.
Stool and swab samples collected in the acute stage of the disease, before antibiotics have been
administered, are the most useful specimens for laboratory diagnosis. If an epidemic of cholera is
suspected, the most common causative agent is V. cholerae O1. If V. cholerae serogroup O1 is
not isolated, the laboratory should test for V. cholerae O139. However, if neither of these
organisms is isolated, it is necessary to send stool specimens to a reference laboratory. Infection
with V. cholerae O139 should be reported and handled in the same manner as that caused by V.
cholerae O1. The associated diarrheal illness should be referred to as cholera and must be
reported in the United States.[15]
A number of special media have been employed for the cultivation for cholera vibrios. They are
classified as follows:

[edit] Enrichment media

1. Alkaline peptone water at pH 8.6
2. Monsur's taurocholate tellurite peptone water at pH 9.2

[edit] Plating media

1. Alkaline bile salt agar (BSA): The colonies are very similar to those on nutrient agar.
2. Monsur's gelatin Tauro cholate trypticase tellurite agar (GTTA) medium: Cholera vibrios
produce small, translucent colonies with a greyish-black center.
3. TCBS medium: This is the mostly widely used medium; it contains thiosulphate, citrate,
bile salts and sucrose. Cholera vibrios produce flat, 23-mm-diameter, yellow-nucleated
colonies.
Direct microscopy of stool is not recommended, as it is unreliable. Microscopy is preferred only
after enrichment, as this process reveals the characteristic motility of Vibrio and its inhibition by
appropriate antisera. Diagnosis can be confirmed, as well as serotyping done by agglutination
with specific sera.

Prevention

Cholera hospital in Dhaka, showing typical "cholera beds"

Although cholera may be life-threatening, prevention of the disease is normally straightforward
if proper sanitation practices are followed. In developed countries, due to nearly universal
advanced water treatment and sanitation practices, cholera is no longer a major health threat. The

last major outbreak of cholera in the United States occurred in 19101911.[16][17] Effective
sanitation practices, if instituted and adhered to in time, are usually sufficient to stop an
epidemic. There are several points along the cholera transmission path at which its spread may
be halted:

Sterilization: Proper disposal and treatment of infected fecal waste water produced by
cholera victims and all contaminated materials (e.g. clothing, bedding, etc.) are essential.
All materials that come in contact with cholera patients should be sanitized by washing in
hot water, using chlorine bleach if possible. Hands that touch cholera patients or their
clothing, bedding, etc., should be thoroughly cleaned and disinfected with chlorinated
water or other effective antimicrobial agents.

Sewage: antibacterial treatment of general sewage by chlorine, ozone, ultraviolet light or

other effective treatment before it enters the waterways or underground water supplies
helps prevent undiagnosed patients from inadvertently spreading the disease.

Sources: Warnings about possible cholera contamination should be posted around

contaminated water sources with directions on how to decontaminate the water (boiling,
chlorination etc.) for possible use.

Water purification: All water used for drinking, washing, or cooking should be sterilized
by either boiling, chlorination, ozone water treatment, ultraviolet light sterilization (e.g.
by solar water disinfection), or antimicrobial filtration in any area where cholera may be
present. Chlorination and boiling are often the least expensive and most effective means
of halting transmission. Cloth filters or sari filtration, though very basic, have
significantly reduced the occurrence of cholera when used in poor villages in Bangladesh
that rely on untreated surface water. Better antimicrobial filters, like those present in
advanced individual water treatment hiking kits, are most effective. Public health
education and adherence to appropriate sanitation practices are of primary importance to
help prevent and control transmission of cholera and other diseases.

Surveillance
Surveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists
as a seasonal disease in many endemic countries, occurring annually mostly during rainy
seasons. Surveillance systems can provide early alerts to outbreaks, therefore leading to
coordinated response and assist in preparation of preparedness plans. Efficient surveillance
systems can also improve the risk assessment for potential cholera outbreaks. Understanding the
seasonality and location of outbreaks provide guidance for improving cholera control activities
for the most vulnerable.[18] For prevention to be effective, it is important that cases are reported to
national health authorities.[1]

Vaccine
Main article: Cholera vaccine

A number of safe and effective oral vaccines for cholera are available.[19] Dukoral, an orally
administered, inactivated whole cell vaccine, has an overall efficacy of about 52% during the
first year after being given and 62% in the second year, with minimal side effects.[19] It is
available in over 60 countries. However, it is not currently recommended by the Centers for
Disease Control and Prevention (CDC) for most people traveling from the United States to
endemic countries.[20] One injectable vaccine was found to be effective for two to three years.
The protective efficacy was 28% lower in children less than 5 years old.[21] However, as of 2010,
it has limited availability.[4] Work is under way to investigate the role of mass vaccination.[22] The
World Health Organization (WHO) recommends immunization of high risk groups, such as
children and people with HIV, in countries where this disease is endemic.[4] If people are
immunized broadly, herd immunity results, with a decrease in the amount of contamination in the
environment.[5]

Treatment

Cholera patient being treated by medical staff in 1992

Continued eating speeds the recovery of normal intestinal function. The World Health
Organization recommends this generally for cases of diarrhea from whatever cause.[23] A CDC
training manual specifically for cholera states: Continue to breastfeed your baby if the baby has
watery diarrhea, even when traveling to get treatment. Adults and older children should continue
to eat frequently.[24]

Fluids
In most cases, cholera can be successfully treated with oral rehydration therapy (ORT), which is
highly effective, safe, and simple to administer.[5] Rice-based solutions are preferred to glucosebased ones due to greater efficiency.[5] In severe cases with significant dehydration, intravenous
rehydration may be necessary. Ringer's lactate is the preferred solution, often with added
potassium.[1][23] Large volumes and continued replacement until diarrhea has subsided may be
needed.[1] Ten percent of a person's body weight in fluid may need to be given in the first two to
four hours.[1] This method was first tried on a mass scale during the Bangladesh Liberation War,
and was found to have much success.[25]
If commercially produced oral rehydration solutions are too expensive or difficult to obtain,
solutions can be made. One such recipe calls for 1 litre of boiled water, 1/2 teaspoon of salt, 6
teaspoons of sugar, and added mashed banana for potassium and to improve taste.[26]

Electrolytes
As there frequently is initially acidosis, the potassium level may be normal, even though large
losses have occurred.[1] As the dehydration is corrected, potassium levels may decrease rapidly,
and thus need to be replaced.[1]

Antibiotics
Antibiotic treatments for one to three days shorten the course of the disease and reduce the
severity of the symptoms.[1] People will recover without them, however, if sufficient hydration is
maintained.[5] Doxycycline is typically used first line, although some strains of V. cholerae have
shown resistance.[1] Testing for resistance during an outbreak can help determine appropriate
future choices.[1] Other antibiotics proven to be effective include cotrimoxazole, erythromycin,
tetracycline, chloramphenicol, and furazolidone.[27] Fluoroquinolones, such as norfloxacin, also
may be used, but resistance has been reported.[28]
In many areas of the world, antibiotic resistance is increasing. In Bangladesh, for example, most
cases are resistant to tetracycline, trimethoprim-sulfamethoxazole, and erythromycin.[5] Rapid
diagnostic assay methods are available for the identification of multiple drug-resistant cases.[29]
New generation antimicrobials have been discovered which are effective against in in vitro
studies.[30]

Sari filtration
An effective and relatively cheap method to prevent transmission of V. cholera is the practice of
folding a sari (a long fabric garment) multiple times to create a simple filter for drinking water.[31]
Folding saris four to eight times may create a simple filter to reduce the amount of active V.
cholera in the filtered water.[32] The education of proper sari filter use is imperative, as there is a
positive correlation between sari misuse and the incidence of childhood diarrhea; soiled saris
worn by women are vectors of transmission of enteric pathogens to young children.[33] Educating
at-risk populations about the proper use of the sari filter method may decrease V. choleraassociated disease.

Prognosis
If people with cholera are treated quickly and properly, the mortality rate is less than 1%;
however, with untreated cholera, the mortality rate rises to 5060%.[1][34] For certain genetic
strains of cholera, such as the one present during the 2010 epidemic in Haiti and the 2004
outbreak in India, death can occur within two hours of the first sign of symptoms.[35]

[Malaria
From Wikipedia, the free encyclopedia
Jump to: navigation, search

Malaria
Classification and external resources

Ring-forms and gametocytes of Plasmodium

falciparum in human blood.
ICD-10

B50

ICD-9

084

OMIM

248310

DiseasesDB

7728

MedlinePlus

000621

eMedicine

med/1385 emerg/305 ped/1357

MeSH

C03.752.250.552

Malaria is a mosquito-borne infectious disease of humans and other animals caused by

eukaryotic protists (a type of microorganism) of the genus Plasmodium. The protists first infect
the liver, then act as parasites within red blood cells, causing symptoms that typically include
fever and headache, in severe cases progressing to coma or death. The disease is widespread in
tropical and subtropical regions in a broad band around the equator, including much of SubSaharan Africa, Asia, and the Americas.
Five species of Plasmodium can infect and be transmitted by humans. Severe disease is largely
caused by P. falciparum while the disease caused by P. vivax, P. ovale, and P. malariae is
generally a milder form that is rarely fatal. The zoonotic species P. knowlesi, prevalent in
Southeast Asia, causes malaria in macaques but can also cause severe infections in humans.
Malaria is prevalent in tropical regions because the significant amounts of rainfall, consistently
high temperatures and high humidity, along with stagnant waters in which mosquito larvae
readily mature, provide them with the environment they need for continuous breeding. Disease
transmission can be reduced by preventing mosquito bites by distribution of mosquito nets and
insect repellents, or with mosquito-control measures such as spraying insecticides and draining
standing water.
The World Health Organization has estimated that in 2010, there were 216 million cases of
malaria. Around 655,000 people died from the disease, most of whom were children under the
age of five.[1] The actual number of deaths may be significantly higher, as precise statistics are
unavailable in many rural areas, and many cases are undocumented. P. falciparumresponsible
for the most severe form of malariacauses the vast majority of deaths associated with the
disease. Malaria is commonly associated with poverty, and can indeed be a cause of poverty and
a major hindrance to economic development.
Despite a clear need, no vaccine offering a high level of protection currently exists. Efforts to
develop one are ongoing. Several medications are available to prevent malaria in travelers to
malaria-endemic countries (prophylaxis). A variety of antimalarial medications are available.
Severe malaria is treated with intravenous or intramuscular quinine or, since the mid-2000s, the
artemisinin derivative artesunate, which is superior to quinine in both children and adults.
Resistance has developed to several antimalarial drugs, most notably chloroquine and
artemisinin.
Contents

1 Signs and symptoms

2 Cause

2.1 Life cycle

2.2 Recurrent malaria

3 Pathogenesis
o

3.1 Genetic resistance

3.2 Malarial hepatopathy

4 Diagnosis
o

4.1 Classification

5 Prevention
o

5.1 Medications

5.2 Vector control

5.3 Indoor residual spraying

5.4 Mosquito nets

5.5 Other methods

6 Treatment
o

6.1 Uncomplicated malaria

6.2 Severe malaria

7 Prognosis

8 Epidemiology

9 History

10 Society and culture

o

10.1 Counterfeit and substandard drugs

10.2 War

10.3 Eradication efforts

11 Research
o

11.1 Immunization

12 In other animals

13 References

14 Further reading

15 External links

Signs and symptoms

Main symptoms of malaria[2]

Typical fever patterns of malaria

The signs and symptoms of malaria typically begin 825 days following infection.[3] However,
symptoms may occur later in those who have taken antimalarial medications as prevention.[4] The
presentation may include fever, shivering, arthralgia (joint pain), vomiting, hemolytic anemia,

jaundice, hemoglobinuria, retinal damage,[5] and convulsions. Approximately 30% of people

however will no longer have a fever upon presenting to a health care facility.[4]
The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and
then fever and sweating lasting about two hours or more, occurring every two days in P. vivax
and P. ovale infections, and every three days for P. malariae. P. falciparum infection can cause
recurrent fever every 3648 hours or a less pronounced and almost continuous fever.[6] For
reasons that are poorly understood, but that may be related to high intracranial pressure, children
with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage.[7]
Cerebral malaria is associated with retinal whitening, which may be a useful clinical sign in
distinguishing malaria from other causes of fever.[8]
Severe malaria is usually caused by P. falciparum, and typically arises 614 days after infection.
[9]
Non-falciparum species have however been found to be the cause of ~14% of cases of severe
malaria in some groups.[4] Consequences of severe malaria include coma and death if untreated
young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen),
severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, and
hemoglobinuria with renal failure may occur. Renal failure is a feature of blackwater fever,
where hemoglobin from lysed red blood cells leaks into the urine.[9]
Cause

A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial

cell in this false-colour electron micrograph.

Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa). In humans
malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi.[10][11] Among
those infected, P. falciparum is the most common species identified (~75%) followed by P. vivax

(~20%).[4] P. falciparum accounts for the majority of deaths.[12] P. vivax proportionally is more
common outside of Africa.[13] There have been documented human infections with several
species of Plasmodium from higher apes; however, with the exception of P. knowlesia
zoonotic species that causes malaria in macaques[11]these are mostly of limited public health
importance.[14]
Recurrent malaria

Malaria recurs after treatment for three reasons. Recrudescence occurs when parasites are not
cleared by treatment, whereas reinfection indicates complete clearance with new infection
established from a separate infective mosquito bite; both can occur with any malaria parasite
species. Relapse is specific to P. vivax and P. ovale and involves re-emergence of blood-stage
parasites from latent parasites (hypnozoites) in the liver.[4] Describing a case of malaria as cured
by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive.
The longest incubation period reported for a P. vivax infection is 30 years.[9] Approximately one
in five of P. vivax malaria cases in temperate areas involve overwintering by hypnozoites, with
relapses beginning the year after the mosquito bite.[18]

Pathogenesis
LIFE CYCLE

The life cycle of malaria parasites. A mosquito causes infection by taking a blood
meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect
liver cells, where they multiply into merozoites, rupture the liver cells, and return to
the bloodstream. Then, the merozoites infect red blood cells, where they develop
into ring forms, trophozoites and schizonts that in turn produce further merozoites.
Sexual forms are also produced, which, if taken up by a mosquito, will infect the
insect and continue the life cycle. Life cycle

The definitive hosts for malaria parasites are female mosquitoes of the Anopheles genus, which
act as transmission vectors to humans and other vertebrates, the secondary hosts. Young
mosquitoes first ingest the malaria parasite by feeding on an infected vertebrate carrier and the
infected Anopheles mosquitoes eventually carry Plasmodium sporozoites in their salivary glands.
A mosquito becomes infected when it takes a blood meal from an infected vertebrate. Once
ingested, the parasite gametocytes taken up in the blood will further differentiate into male or
female gametes and then fuse in the mosquito's gut. This produces an ookinete that penetrates the
gut lining and produces an oocyst in the gut wall. When the oocyst ruptures, it releases
sporozoites that migrate through the mosquito's body to the salivary glands, where they are then
ready to infect a new human host. The sporozoites are injected into the skin, alongside saliva,
when the mosquito takes a subsequent blood meal. This type of transmission is occasionally
referred to as anterior station transfer.[15]
Only female mosquitoes feed on blood; male mosquitoes feed on plant nectar, and thus do not
transmit the disease. The females of the Anopheles genus of mosquito prefer to feed at night.
They usually start searching for a meal at dusk, and will continue throughout the night until
taking a meal.[16] Malaria parasites can also be transmitted by blood transfusions, although this is
rare.[17]

Malaria infection develops via two phases: one that involves the liver or hepatic system
(exoerythrocytic), and one which involves red blood cells, or erythrocytes (erythrocytic). When
an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's
saliva enter the bloodstream and migrate to the liver where they infect hepatocytes, multiplying
asexually and asymptomatically for a period of 830 days.[19] After a potential dormant period in
the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture
of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage
of the life cycle.[19] The parasite escapes from the liver undetected by wrapping itself in the cell
membrane of the infected host liver cell.[20]

Within the red blood cells, the parasites multiply further, again asexually, periodically breaking
out of their hosts to invade fresh red blood cells. Several such amplification cycles occur. Thus,
classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping
and infecting red blood cells.[19]
Some P. vivax sporozoites do not immediately develop into exoerythrocytic-phase merozoites,
but instead produce hypnozoites that remain dormant for periods ranging from several months
(612 months is typical) to as long as three years. After a period of dormancy, they reactivate and
produce merozoites. Hypnozoites are responsible for long incubation and late relapses in P. vivax
infections, although their existence in P. ovale is uncertain.[21]
The parasite is relatively protected from attack by the body's immune system because for most of
its human life cycle it resides within the liver and blood cells and is relatively invisible to
immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To
avoid this fate, the P. falciparum parasite displays adhesive proteins on the surface of the infected
blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby
sequestering the parasite from passage through the general circulation and the spleen.[22] The
blockage of the microvasculature causes symptoms such as in placental and cerebral malaria. In
cerebral malaria the sequestrated red blood cells can breach the bloodbrain barrier possibly
leading to coma.[23]

Micrograph of a placenta from a stillbirth due to maternal malaria. H&E stain. Red
blood cells are anuclear; blue/black staining in bright red structures (red blood cells)
indicate foreign nuclei from the parasites

Although the red blood cell surface adhesive proteins (called PfEMP1, for P. falciparum
erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good
immune targets, because of their extreme diversity; there are at least 60 variations of the protein
within a single parasite and even more variants within whole parasite populations.[22] The parasite
switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of
the pursuing immune system.[24]

Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of an
infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual
recombination of the parasite occurs in the mosquito's gut. New sporozoites develop and travel to
the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to
the mosquitoes, and malaria in pregnant women is an important cause of stillbirths, infant
mortality and low birth weight,[25] particularly in P. falciparum infection, but also in other species
infection, such as P. vivax.[26]

Genetic resistance
Main article: Genetic resistance to malaria

Due to the high levels of mortality and morbidity caused by malariaespecially the
P. falciparum speciesit is thought to have placed the greatest selective pressure on the human
genome in recent history. Several diseases may provide some resistance to it including sickle cell
disease, thalassaemias, glucose-6-phosphate dehydrogenase deficiency as well as the presence of
Duffy antigens on the subject's red blood cells.[27][28]
The impact of sickle cell anemia on malaria immunity is of particular interest. Sickle cell anemia
causes a defect to the hemoglobin molecule in the blood. Instead of retaining the biconcave
shape of a normal red blood cell, the modified hemoglobin S molecule causes the cell to sickle or
distort into a curved shape. Due to the sickle shape, the molecule is not as effective in taking or
releasing oxygen, and therefore malaria parasites cannot complete their life cycle in the cell.
Individuals who are homozygous for sickle cell anemia seldom survive this defect, while those
who are heterozygous experience immunity to the disease. Although the potential risk of death
for those with the homozygous condition seems to be unfavorable to population survival, the trait
is preserved because of the benefits provided by the heterozygous form.[29]
Malarial hepatopathy

Hepatic dysfunction as a result of malaria is rare and is usually a result of a coexisting liver
condition such as viral hepatitis and chronic liver disease.[30] Hepatitis, which is characterized by
inflammation of the liver, is not actually present in what is called malarial hepatitis; the term as
used here invokes the reduced liver function associated with severe malaria.[30] While
traditionally considered a rare occurrence, malarial hepatopathy has seen an increase in malaria
endemic areas, particularly in Southeast Asia and India.[30] Liver compromise in people with
malaria correlates with a greater likelihood of complications and death.[30]
Diagnosis

Main article: Diagnosis of malaria

Malaria is typically diagnosed by the microscopic examination of blood using blood films or
using antigen-based rapid diagnostic tests.[31][32] Rapid diagnostic tests that detect P. vivax are not
as effective as those targeting P. falciparum.[33] They also are unable to tell how many parasites
are present.[4] Areas that cannot afford laboratory diagnostic tests often use only a history of
subjective fever as the indication to treat for malaria.[34] Polymerase chain reaction based tests
have been developed, though these are not widely implemented in malaria-endemic regions as of
2012, due to their complexity.[4]
Classification

Malaria is divided into severe and uncomplicated by the World Health Organization (WHO).[4]
Severe malaria is diagnosed when any of the following criteria are present, otherwise it is
considered uncomplicated.[35]

Decreased consciousness

Significant weakness such that the person is unable to walk

Inability to feed

Two or more convulsions

Low blood pressure (less than 70 mmHg in adults or 50 mmHg in children)

Breathing problems

Circulatory shock

Kidney failure or hemoglobin in the urine

Bleeding problems, or hemoglobin less than 5 g/dl

Pulmonary edema

Low blood glucose (less than 2.2 mmol/l / 40 mg/dl)

Acidosis or lactate levels of greater than 5 mmol/l

A parasite level in the blood of greater than 2%

Prevention

Anopheles albimanus mosquito feeding on a human arm. This mosquito is a vector

of malaria and mosquito control is an effective way of reducing the incidence of
malaria.

Methods used to prevent malaria include medications, mosquito eradication and the prevention
of bites. The presence of malaria in an area requires a combination of high human population
density, high mosquito population density and high rates of transmission from humans to
mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite
will eventually disappear from that area, as happened in North America, Europe and much of the
Middle East. However, unless the parasite is eliminated from the whole world, it could become
re-established if conditions revert to a combination that favours the parasite's reproduction.[36]
Many countries are seeing an increasing number of imported malaria cases owing to extensive
travel and migration.
Many researchers argue that prevention of malaria may be more cost-effective than treatment of
the disease in the long run, but the capital costs required are out of reach of many of the world's
poorest people. There is a wide disparity in the costs of control (i.e. maintenance of low
endemicity) and elimination programs between countries. For example, in Chinawhose
government in 2010 announced a strategy to pursue malaria elimination in the Chinese provinces
the required investment is a small proportion of public expenditure on health. In contrast, a
similar program in Tanzania would cost an estimated one-fifth of the public health budget.[37]
Medications
Main article: Malaria prophylaxis

Several drugs, most of which are used for treatment of malaria, can be taken preventively.
Chloroquine may be used where the parasite is still sensitive.[38] However, due to resistance one
of three medicationsmefloquine (Lariam), doxycycline (available generically), or the
combination of atovaquone and proguanil hydrochloride (Malarone)is frequently needed.[38]
Doxycycline and the atovaquone and proguanil combination are the best tolerated; mefloquine is
associated with higher rates of neurological and psychiatric symptoms.[38]

The prophylactic effect does not begin immediately upon starting the drugs, so people
temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks
before arriving and should continue taking them for four weeks after leaving (with the exception
of atovaquone proguanil that only needs to be started two days prior and continued for seven
days afterwards). Generally, these drugs are taken daily or weekly, at a lower dose than is used
for treatment of a person who contracts the disease. Use of prophylactic drugs is seldom practical
for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term
visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative
adverse effects from long-term use, and because some effective anti-malarial drugs are difficult
to obtain outside of wealthy nations.[39] The use of prophylactic drugs where malaria-bearing
mosquitoes are present may encourage the development of partial immunity.[40]
Vector control
Further information: Mosquito control

Man spraying kerosene oil to protect against mosquitoes carrying malaria, Panama
Canal Zone 1912

Efforts to eradicate malaria by eliminating mosquitoes have been successful in some areas.
Malaria was once common in the United States and southern Europe, but vector control
programs, in conjunction with the monitoring and treatment of infected humans, eliminated it
from those regions. In some areas, the draining of wetland breeding grounds and better sanitation
were adequate. Malaria was eliminated from most parts of the USA in the early 20th century by
such methods, and the use of the pesticide DDT and other means eliminated it from the
remaining pockets in the South by 1951.[41] (see National Malaria Eradication Program)

Before DDT, malaria was successfully eradicated or controlled in tropical areas like Brazil and
Egypt by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats
of the larva stages, for example by applying the highly toxic arsenic compound Paris Green to
places with standing water. This method has seen little application in Africa for more than half a
century.[42]
A more targeted and ecologically friendly vector control strategy involves genetic manipulation
of malaria mosquitoes. Advances in genetic engineering technologies make it possible to
introduce foreign DNA into the mosquito genome and either decrease the lifespan of the
mosquito, or make it more resistant to the malaria parasite.[43] Sterile insect technique is a genetic
control method whereby large numbers of sterile males mosquitoes are reared and released.
Mating with wild females reduces the wild population in the subsequent generation; repeated
releases eventually eradicate the target population. Progress towards transgenic, or genetically
modified, insects suggests that wild mosquito populations could be made malaria resistant.
Successful replacement of current populations with a new genetically modified population relies
upon a drive mechanism, such as transposable elements to allow for non-Mendelian inheritance
of the gene of interest. Although this approach has been used successfully to eradicate some
parasitic diseases of veterinary importance, technological problems have hindered its effective
deployment with malaria vector species.[43]
Indoor residual spraying
Further information: Indoor residual spraying and DDT and malaria

Indoor residual spraying (IRS) is the practice of spraying insecticides on the interior walls of
homes in malaria-affected areas. After feeding, many mosquito species rest on a nearby surface
while digesting the bloodmeal, so if the walls of dwellings have been coated with insecticides,
the resting mosquitos will be killed before they can bite another victim and transfer the malaria
parasite.[44]
The first pesticide used for IRS was DDT.[41] Although it was initially used exclusively to combat
malaria, its use quickly spread to agriculture. In time, pest control, rather than disease control,
came to dominate DDT use, and this large-scale agricultural use led to the evolution of resistant
mosquitoes in many regions. The DDT resistance shown by Anopheles mosquitoes can be
compared to antibiotic resistance shown by bacteria. The overuse of antibacterial soaps and
antibiotics led to antibiotic resistance in bacteria, similar to how overspraying of DDT on crops
led to DDT resistance in Anopheles mosquitoes. During the 1960s, awareness of the negative
consequences of its indiscriminate use increased, ultimately leading to bans on agricultural
applications of DDT in many countries in the 1970s. Since the use of DDT has been limited or
banned for agricultural use for some time, DDT may now be more effective as a method of
disease-control.[45]

Although DDT has never been banned for use in malaria control and there are several other
insecticides suitable for IRS,[43] Robert Gwadz of the National Institutes of Health said in 2007
that bans are responsible for tens of millions of deaths in tropical countries where DDT had once
been effective in controlling malaria.[46] Furthermore, most of the problems associated with DDT
use stem specifically from its industrial-scale application in agriculture, rather than its use in
public health.[45]
The World Health Organization currently advises the use of 12 insecticides in IRS operations,
including DDT as well as alternative insecticides (such as the pyrethroids permethrin and
deltamethrin).[47] This public health use of small amounts of DDT is permitted under the
Stockholm Convention on Persistent Organic Pollutants (POPs), which prohibits the agricultural
use of DDT.[45] However, because of its legacy, many developed countries previously
discouraged DDT use even in small quantities.[48]
One problem with all forms of IRS is insecticide resistance via evolution. Mosquito that are
affected by IRS tend to rest and live indoors, and due to the irritation caused by spraying, their
descendants tend to rest and live outdoors, meaning that they are not as affectedif affected at
allby the IRS, which greatly reduces its effectiveness as a defense mechanism.[49]
Mosquito nets
Main article: Mosquito net

Mosquito nets create a protective barrier against malaria-carrying mosquitoes that

bite at night.

Mosquito nets help keep mosquitoes away from people and significantly reduce infection rates
and transmission of malaria. The nets are not a perfect barrier and they are often treated with an
insecticide designed to kill the mosquito before it has time to search for a way past the net.
Insecticide-treated nets (ITNs) are estimated to be twice as effective as untreated nets and offer
greater than 70% protection compared with no net.[43] Although ITNs are proven to be very
effective against malaria, only about 13% of households in sub-Saharan countries own them.[50]

Since the Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net"
above the center of a bed to drape over it completely.[51]
Other methods

Community participation and health education strategies promoting awareness of malaria and the
importance of control measures have been successfully used to reduce the incidence of malaria in
some areas of the developing world.[52] Recognizing the disease in the early stages can stop the
disease from becoming fatal. Education can also inform people to cover over areas of stagnant,
still water, such as water tanks that are ideal breeding grounds for the parasite and mosquito, thus
cutting down the risk of the transmission between people. This is generally used in urban areas
where there are large centers of population in a confined space and transmission would be most
likely in these areas.[53]
Other interventions for the control of malaria include mass drug administrations[33] and
intermittent preventive therapy.[54]
Treatment

When properly treated, people with malaria can usually expect a complete recovery.[55] The
treatment depends on the severity of the disease; whether people can take oral drugs or must be
admitted depends on the assessment and the experience of the clinician.
Uncomplicated malaria

Uncomplicated malaria may be treated with oral medications. The most effective strategy for
P. falciparum infection is the use of artemisinins in combination with other antimalarials (known
as artemisinin-combination therapy).[56] This is done to reduce the risk of resistance against
artemisinin.[56] These additional antimalarials include amodiaquine, lumefantrine, mefloquine or
sulfadoxine/pyrimethamine.[35] Another recommended combination is dihydroartemisinin and
piperaquine.[35] Recently, malaria with partial resistance to artemisins has occurred in Southeast
Asia.[57][58]
Severe malaria

Severe malaria requires the parenteral administration of antimalarial drugs. Until the mid-2000s
the most used treatment for severe malaria was quinine, but artesunate has been shown to be
superior to quinine in both children[59] and adults.[60][61] Treatment of severe malaria also involves
supportive measures.[62] Infection with P. vivax, P. ovale or P. malariae is usually treated on an
outpatient basis (while a person is at home). Treatment of P. vivax requires both treatment of
blood stages (with chloroquine or ACT) as well as clearance of liver forms with primaquine.[63]
] Prognosis

Disability-adjusted life year for malaria per 100,000 inhabitants in 2004.

no data

20002500

<10

25002750

10100

27503000

100500

30003250

5001000

32503500

10001500

3500

15002000

Severe malaria can progress extremely rapidly and cause death within hours or days.[9] In the
most severe cases of the disease, fatality rates can reach 20%, even with intensive care and
treatment.[4] Over the longer term, developmental impairments have been documented in children
who have suffered episodes of severe malaria.[64] It causes widespread anemia during a period of
rapid brain development and also direct brain damage. This neurologic damage results from
cerebral malaria to which children are more vulnerable.[64]
[edit] Epidemiology

Map showing the distribution of malaria in the world. [65] :

Elevated occurence of

Occurence of chloroquine-resistant
malaria : No plasmodium falciparum or chloroquine-resistance : No malaria
chloroquine- or multi-resistant malaria :

The WHO estimates that there were 216 million cases of malaria in 2010 resulting in 655,000
deaths.[1] An estimate in The Lancet places the number of deaths in 2010 higher at 1.24 million.

[66][67]

The majority of cases occur in children under five years old;[68] pregnant women are also
especially vulnerable. Despite efforts to reduce transmission and increase treatment, there has
been little change in which areas are at risk of this disease since 1992.[69] Indeed, if the
prevalence of malaria stays on its present upwards course, the death rate could double in the next
twenty years.[70] Precise statistics are unknown because many cases occur in rural areas where
people do not have access to hospitals or the means to afford health care. As a consequence, the
majority of cases are undocumented.[70]
Although coinfection with HIV and malaria does increase mortality, this is less of a problem than
with HIV/tuberculosis coinfection, due to the two diseases usually attacking different age ranges,
with malaria being most common in the young and active tuberculosis most common in the old.
[71]
Although HIV/malaria coinfection produces less severe symptoms than the interaction
between HIV and TB, HIV and malaria do contribute to each other's spread. This effect comes
from malaria increasing viral load and HIV infection increasing a person's susceptibility to
malaria infection.[72]
Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many
parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 8590% of malaria
fatalities occur.[73] The geographic distribution of malaria within large regions is complex, and
malaria-afflicted and malaria-free areas are often found close to each other.[74] Malaria is
prevalent in tropical regions because of the significant amounts of rainfall, consistent high
temperatures and high humidity, along with stagnant waters in which mosquito larvae readily
mature, providing them with the environment they need for continuous breeding.[75] In drier
areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall.[76]
Malaria is more common in rural areas than in cities; this is in contrast to dengue fever where
urban areas present the greater risk.[77] For example, several cities in Vietnam, Laos and
Cambodia are essentially malaria-free, but the disease is present in many rural regions.[78] By
contrast, in Africa malaria is present in both rural and urban areas, though the risk is lower in the
larger cities.[79] The global endemic levels of malaria have not been mapped since the 1960s.
However, the Wellcome Trust, UK, has funded the Malaria Atlas Project to rectify this, providing
a more contemporary and robust means with which to assess current and future malaria disease
burden.[80] As of 2010, countries with the highest death rate per 100,000 population are Cote
d'Ivoire with (86.15), Angola (56.93) and Burkina Faso (50.66) all in Africa.[81] A map of
Plasmodium falciparum endemicity in 2010 has been published.[82]
History
Main article: History of malaria

Malaria has infected humans for over 50,000 years, and Plasmodium may have been a human
pathogen for the entire history of the species.[83] Close relatives of the human malaria parasites

remain common in chimpanzees. Some new evidence suggests that the most virulent strain of
human malaria may have originated in gorillas.[84]
References to the unique periodic fevers of malaria are found throughout recorded history,
beginning in 2700 BC in China.[85] Malaria may have contributed to the decline of the Roman
Empire,[86] and was so pervasive in Rome that it was known as the "Roman fever".[87] Several
regions in ancient Rome were considered at-risk for the disease because of the favorable
conditions present for malaria vectors. This included areas such as southern Italy, the island of
Sardinia, the Pontine Marshes, the lower regions of coastal Etruria and the city of Rome along
the Tiber River. The presence of stagnant water in these places was preferred by mosquitoes for
breeding grounds. Irrigated gardens, swamp-like grounds, runoff from agriculture, and drainage
problems from road construction led to the increase of standing water.[88]
The term malaria originates from Medieval Italian: mala aria "bad air"; the disease was
formerly called ague or marsh fever due to its association with swamps and marshland.[89]
Malaria was once common in most of Europe and North America,[90] where it is no longer
endemic,[91] though imported cases do occur.[92]

British doctor Ronald Ross received the Nobel Prize for Physiology or Medicine in
1902 for his work on malaria.

Malaria was the most important health hazard encountered by U.S. troops in the South Pacific
during World War II, where about 500,000 men were infected.[93] According to Joseph Patrick
Byrne, "Sixty thousand American soldiers died of malaria during the African and South Pacific

campaigns."[94] Scientific studies on malaria made their first significant advance in 1880, when a
French army doctor working in the military hospital of Constantine in Algeria named Charles
Louis Alphonse Laveran observed parasites for the first time, inside the red blood cells of people
suffering from malaria. He therefore proposed that malaria is caused by this organism, the first
time a protist was identified as causing disease.[95] For this and later discoveries, he was awarded
the 1907 Nobel Prize for Physiology or Medicine. The malarial parasite was called Plasmodium
by the Italian scientists Ettore Marchiafava and Angelo Celli.[96] A year later, Carlos Finlay, a
Cuban doctor treating people with yellow fever in Havana, provided strong evidence that
mosquitoes were transmitting disease to and from humans.[97] This work followed earlier
suggestions by Josiah C. Nott,[98] and work by Sir Patrick Manson, the "father of tropical
medicine", on the transmission of filariasis.[99]
In April 1894, a Scottish physician Sir Ronald Ross visited Sir Patrick Manson at his house on
Queen Anne Street, London. This visit was the start of four years of collaboration and fervent
research that culminated in 1898 when Ross, who was working in the Presidency General
Hospital in Calcutta, proved the complete life-cycle of the malaria parasite in mosquitoes. He
thus proved that the mosquito was the vector for malaria in humans by showing that certain
mosquito species transmit malaria to birds. He isolated malaria parasites from the salivary glands
of mosquitoes that had fed on infected birds.[100] For this work, Ross received the 1902 Nobel
Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly
established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt,
Panama, Greece and Mauritius.[101] The findings of Finlay and Ross were later confirmed by a
medical board headed by Walter Reed in 1900. Its recommendations were implemented by
William C. Gorgas in the health measures undertaken during construction of the Panama Canal.
This public-health work saved the lives of thousands of workers and helped develop the methods
used in future public-health campaigns against the disease.[102]
The first effective treatment for malaria came from the bark of cinchona tree, which contains
quinine. This tree grows on the slopes of the Andes, mainly in Peru. The indigenous peoples of
Peru made a tincture of cinchona to control malaria. The Jesuits noted the efficacy of the practice
and introduced the treatment to Europe during the 1640s, where it was rapidly accepted.[103] It
was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and
named by the French chemists Pierre Joseph Pelletier and Joseph Bienaim Caventou.[104][105]
Quinine become the predominant malarial medication until the 1920s, when other medications
began to be developed. In the 1940s, chloroquine replaced quinine as the treatment of both
uncomplicated and severe falciparum malaria until resistance supervened, first in Southeast Asia
and South America in the 1950s and then globally in the 1980s.[61] Artemisinins, discovered by
Chinese scientists in the 1970s, are now the recommended treatment for falciparum malaria,
administered in combination with other antimalarials as well as in severe disease.[106]
Society and culture

Malaria is not just a disease commonly associated with poverty but also a cause of poverty and a
major hindrance to economic development.[107] Tropical regions are affected most; however,
malarias furthest extent reaches into some temperate zones with extreme seasonal changes. The
disease has been associated with major negative economic effects on regions where it is
widespread. During the late 19th and early 20th centuries, it was a major factor in the slow
economic development of the American southern states.[108] A comparison of average per capita
GDP in 1995, adjusted for parity of purchasing power, between countries with malaria and
countries without malaria gives a fivefold difference ($1,526 USD versus $8,268 USD). In
countries where malaria is common, average per capita GDP has risen (between 1965 and 1990)
only 0.4% per year, compared to 2.4% per year in other countries.[109]
Poverty is both a cause and effect of malaria, since the poor do not have the financial capacities
to prevent or treat the disease. In its entirety, the economic impact of malaria has been estimated
to cost Africa $12 billion USD every year. The economic impact includes costs of health care,
working days lost due to sickness, days lost in education, decreased productivity due to brain
damage from cerebral malaria, and loss of investment and tourism.[68] In some countries with a
heavy malaria burden, the disease may account for as much as 40% of public health expenditure,
3050% of admissions to hospital, and up to 50% of outpatient visits.[110] The slow demographic
transition in Africa may be partly attributed to malaria. Total fertility rates were best explained
by child mortality, as measured indirectly by infant mortality, in a 2007 study.[111]
A study on the effect of malaria on IQ in a sample of Mexicans found that exposure during the
birth year to malaria eradication was associated with increases in IQ. It also increased the
probability of employment in a skilled occupation. The author suggests that this may be one
explanation for the Flynn effect and that this may be an important explanation for the link
between national malaria burden and economic development.[112] The cognitive abilities and
school performance are impaired in sub-groups of people (with either cerebral malaria or
uncomplicated malaria) when compared with healthy controls. Studies comparing cognitive
functions before and after treatment for acute malarial illness continued to show significantly
impaired school performance and cognitive abilities even after recovery. Malaria prophylaxis
was shown to improve cognitive function and school performance in clinical trials when
compared to placebo groups.[64] April 25 is World Malaria Day.[81]
Counterfeit and substandard drugs

Sophisticated counterfeits have been found in several Asian countries such as Cambodia,[113]
China,[114] Indonesia, Laos, Thailand, and Vietnam, and are an important cause of avoidable death
in those countries.[115] The WHO said that studies indicate that up to 40% of artesunate based
malaria medications are counterfeit, especially in the Greater Mekong region and have
established a rapid alert system to enable information about counterfeit drugs to be rapidly
reported to the relevant authorities in participating countries.[116] There is no reliable way for

doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are
attempting to combat the persistence of counterfeit drugs by using new technology to provide
security from source to distribution.[117]
Another clinical and public health concern is the proliferation of substandard antimalarial
medicines resulting from inappropriate concentration of ingredients, contamination with other
drugs or toxic impurities, poor quality ingredients, poor stability and inadequate packaging.[118] A
2012 study demonstrated that roughly one-third of antimalarial medications in Southeast Asia
and Sub-Saharan Africa failed chemical analysis, packaging analysis, or were falsified.[119]

Eradication efforts

Several notable attempts are being made to eliminate the parasite from sections of the world, or
to eradicate it worldwide. In 2006, the organization Malaria No More set a public goal of
eliminating malaria from Africa by 2015, and the organization plans to dissolve if that goal is
accomplished.[122] Several malaria vaccines are in clinical trials, which are intended to provide
protection for children in endemic areas and reduce the speed of transmission of the disease. As
of 2012, The Global Fund to Fight AIDS, Tuberculosis and Malaria has distributed 230 million
insecticide-treated nets intended to stop mosquito-born transmission of malaria.[123] According to
director Inder Singh, the U.S.-based Clinton Foundation has significantly reduced the cost of
drugs to treat malaria, and is working to further reduce the spread of the disease.[124] Other
efforts, such as the Malaria Atlas Project focus on analyzing climate and weather information
required to accurately predict the spread of malaria based on the availability of habitat of
malaria-carrying parasites.[80]
Malaria has been successfully eradicated in certain areas. The Republic of Mauritius, a tropical
island located in the western Indian Ocean, considered ecological connections to malaria
transmission when constructing their current plan for malaria control. To prevent mosquitoes
from breeding in aquatic areas, DDT is used in moderate amounts. Additionally, larvae-eating
fish are placed in water sources to remove the malaria vectors before they become a threat to the
human population. Obstructions are also removed from these sources to maintain water flow and
reduce stagnant water. Similarly, marsh or swamp-like environments are drained and filled to
diminish mosquito breeding grounds. These actions have produced positive results. The program
has cut infection and death rates tremendously, and is cost effective, only requiring $1USD per
head each year. This success is a clear indication that responses to adverse environmental
conditions can decrease rates of disease.[125]
Research

With the onset of drug-resistant Plasmodium parasites, new strategies are required to combat the
widespread disease. One such approach lies in the introduction of synthetic pyridoxal-amino acid
adducts, which are channeled into the parasite. Thus, trapped upon phosphorylation by
plasmodial PdxK (pyridoxine/pyridoxal kinase), the proliferation of Plasmodium parasites is
effectively hindered by a novel compound, PT3, a cyclic pyridoxyl-tryptophan methyl ester,
without harming human cells.[126]
Malaria parasites contain apicoplasts, an organelle usually found in plants, complete with their
own functioning genomes. These apicoplasts are thought to have originated through the
endosymbiosis of algae and play a crucial role in various aspects of parasite metabolism, for
example in fatty acid biosynthesis.[127] As of 2003, 466 proteins have been found to be produced
by apicoplasts[128] and these are now being investigated as possible targets for novel anti-malarial
drugs.[127]
Malaria vaccines have been an elusive goal of research. The first promising studies
demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice
with live, radiation-attenuated sporozoites, which provided significant protection to the mice
upon subsequent injection with normal, viable sporozoites.[129] Since the 1970s, there has been a
considerable effort to develop similar vaccination strategies within humans. It was determined
that an individual can be protected from a P. falciparum infection if they receive over 1,000 bites
from infected yet irradiated mosquitoes.[130]
[edit] Immunization
Main article: Malaria vaccine

Immunity (or, more accurately, tolerance) does occur naturally, but only in response to repeated
infection with multiple strains of malaria.[131] A completely effective vaccine is not yet available
for malaria, although several vaccines are under development.[132] SPf66 was tested extensively
in endemic areas in the 1990s, but clinical trials showed it to be insufficiently effective.[133] Other
vaccine candidates, targeting the blood-stage of the parasite's life cycle, have also been
insufficient on their own.[134] Several potential vaccines targeting the pre-erythrocytic stage are
being developed, with RTS,S showing the most promising results so far.[130]
In other animals

Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents.

DEFENCE SYSTEMS pg 77

Immune system
From Wikipedia, the free encyclopedia
Jump to: navigation, search

A scanning electron microscope image of a single neutrophil (yellow), engulfing

anthrax bacteria (orange).

The immune system is a system of biological structures and processes within an organism that
protects against disease. To function properly, an immune system must detect a wide variety of
agents, from viruses to parasitic worms, and distinguish them from the organism's own healthy
tissue.
Pathogens can rapidly evolve and adapt to avoid detection and neutralization by the immune
system. As a result, multiple defense mechanisms have also evolved to recognize and neutralize
pathogens. Even simple unicellular organisms such as bacteria possess a rudimentary immune
system, in the form of enzymes that protect against bacteriophage infections. Other basic
immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants,
such as plants and insects. These mechanisms include phagocytosis, antimicrobial peptides called
defensins, and the complement system. Jawed vertebrates, including humans, have even more
sophisticated defense mechanisms,[1] including the ability to adapt over time to recognize specific
pathogens more efficiently. Adaptive (or acquired) immunity creates immunological memory
after an initial response to a specific pathogen, leading to an enhanced response to subsequent
encounters with that same pathogen. This process of acquired immunity is the basis of
vaccination.

Disorders of the immune system can result in autoimmune diseases, inflammatory diseases and
cancer.[2][3] Immunodeficiency occurs when the immune system is less active than normal,
resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be
the result of a genetic disease, such as severe combined immunodeficiency, or acquired
conditions such as HIV/AIDS or the use of immunosuppressive medication. In contrast,
autoimmunity results from a hyperactive immune system attacking normal tissues as if they were
foreign organisms. Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid
arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immunology covers the
study of all aspects of the immune system.
Contents
[hide]

1 History of immunology

2 Layered defense

3 Surface barriers

4 Innate immune system

o

4.1 Humoral and chemical barriers

4.1.1 Inflammation

4.1.2 Complement system

4.2 Cellular barriers

5 Adaptive immune system

o

5.1 Lymphocytes

5.1.1 Killer T cells

5.1.2 Helper T cells

5.1.3 T cells

5.1.4 B lymphocytes and antibodies

5.1.5 Alternative adaptive immune system

5.2 Immunological memory

5.2.1 Passive memory

5.2.2 Active memory and immunization

6 Disorders of human immunity

o

6.1 Immunodeficiencies

6.2 Autoimmunity

6.3 Hypersensitivity

7 Other mechanisms

8 Tumor immunology

9 Physiological regulation
o

9.1 Nutrition and diet

10 Manipulation in medicine

11 Manipulation by pathogens

12 See also

13 References

14 External links

History of immunology
For more details on this topic, see History of immunology.

Paul Ehrlich

Immunology is a science that examines the structure and function of the immune system. It
originates from medicine and early studies on the causes of immunity to disease. The earliest
known reference to immunity was during the plague of Athens in 430 BC. Thucydides noted that
people who had recovered from a previous bout of the disease could nurse the sick without
contracting the illness a second time.[4] In the 18th century, Pierre-Louis Moreau de Maupertuis
made experiments with scorpion venom and observed that certain dogs and mice were immune
to this venom.[5] This and other observations of acquired immunity were later exploited by Louis
Pasteur in his development of vaccination and his proposed germ theory of disease.[6] Pasteur's
theory was in direct opposition to contemporary theories of disease, such as the miasma theory.
It was not until Robert Koch's 1891 proofs, for which he was awarded a Nobel Prize in 1905,
that microorganisms were confirmed as the cause of infectious disease.[7] Viruses were confirmed
as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.[8]
Immunology made a great advance towards the end of the 19th century, through rapid
developments, in the study of humoral immunity and cellular immunity.[9] Particularly important
was the work of Paul Ehrlich, who proposed the side-chain theory to explain the specificity of
the antigen-antibody reaction; his contributions to the understanding of humoral immunity were
recognized by the award of a Nobel Prize in 1908, which was jointly awarded to the founder of
cellular immunology, Elie Metchnikoff.[10]
Layered defense

The immune system protects organisms from infection with layered defenses of increasing
specificity. In simple terms, physical barriers prevent pathogens such as bacteria and viruses
from entering the organism. If a pathogen breaches these barriers, the innate immune system
provides an immediate, but non-specific response. Innate immune systems are found in all plants

and animals.[11] If pathogens successfully evade the innate response, vertebrates possess a second
layer of protection, the adaptive immune system, which is activated by the innate response. Here,
the immune system adapts its response during an infection to improve its recognition of the
pathogen. This improved response is then retained after the pathogen has been eliminated, in the
form of an immunological memory, and allows the adaptive immune system to mount faster and
stronger attacks each time this pathogen is encountered.[12]
Components of the immune system
Innate immune system

Adaptive immune system

Response is non-specific

Pathogen and antigen specific response

Exposure leads to immediate maximal

response

Lag time between exposure and maximal

response

Cell-mediated and humoral components Cell-mediated and humoral components

No immunological memory

Exposure leads to immunological memory

Found in nearly all forms of life

Found only in jawed vertebrates

Both innate and adaptive immunity depend on the ability of the immune system to distinguish
between self and non-self molecules. In immunology, self molecules are those components of an
organism's body that can be distinguished from foreign substances by the immune system.[13]
Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self
molecules are called antigens (short for antibody generators) and are defined as substances that
bind to specific immune receptors and elicit an immune response.[14]
Surface barriers

Several barriers protect organisms from infection, including mechanical, chemical, and
biological barriers. The waxy cuticle of many leaves, the exoskeleton of insects, the shells and
membranes of externally deposited eggs, and skin are examples of mechanical barriers that are
the first line of defense against infection.[14] However, as organisms cannot be completely sealed
against their environments, other systems act to protect body openings such as the lungs,
intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject
pathogens and other irritants from the respiratory tract. The flushing action of tears and urine
also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal
tract serves to trap and entangle microorganisms.[15]
Chemical barriers also protect against infection. The skin and respiratory tract secrete
antimicrobial peptides such as the -defensins.[16] Enzymes such as lysozyme and phospholipase
A2 in saliva, tears, and breast milk are also antibacterials.[17][18] Vaginal secretions serve as a
chemical barrier following menarche, when they become slightly acidic, while semen contains

defensins and zinc to kill pathogens.[19][20] In the stomach, gastric acid and proteases serve as
powerful chemical defenses against ingested pathogens.
Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers
by competing with pathogenic bacteria for food and space and, in some cases, by changing the
conditions in their environment, such as pH or available iron.[21] This reduces the probability that
pathogens will reach sufficient numbers to cause illness. However, since most antibiotics nonspecifically target bacteria and do not affect fungi, oral antibiotics can lead to an "overgrowth" of
fungi and cause conditions such as a vaginal candidiasis (a yeast infection).[22] There is good
evidence that re-introduction of probiotic flora, such as pure cultures of the lactobacilli normally
found in unpasteurized yogurt, helps restore a healthy balance of microbial populations in
intestinal infections in children and encouraging preliminary data in studies on bacterial
gastroenteritis, inflammatory bowel diseases, urinary tract infection and post-surgical infections.
[23][24][25]

Innate immune system

For more details on this topic, see Innate immune system.

Microorganisms or toxins that successfully enter an organism encounter the cells and
mechanisms of the innate immune system. The innate response is usually triggered when
microbes are identified by pattern recognition receptors, which recognize components that are
conserved among broad groups of microorganisms,[26] or when damaged, injured or stressed cells
send out alarm signals, many of which (but not all) are recognized by the same receptors as those
that recognize pathogens.[27] Innate immune defenses are non-specific, meaning these systems
respond to pathogens in a generic way.[14] This system does not confer long-lasting immunity
against a pathogen. The innate immune system is the dominant system of host defense in most
organisms.[11]
[edit] Humoral and chemical barriers
For more details on this topic, see Humoral immunity.
Inflammation
For more details on this topic, see Inflammation.

Inflammation is one of the first responses of the immune system to infection.[28] The symptoms of
inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow
into tissue. Inflammation is produced by eicosanoids and cytokines, which are released by
injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation
of blood vessels associated with inflammation, and leukotrienes that attract certain white blood
cells (leukocytes).[29][30] Common cytokines include interleukins that are responsible for
communication between white blood cells; chemokines that promote chemotaxis; and interferons

that have anti-viral effects, such as shutting down protein synthesis in the host cell.[31] Growth
factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit
immune cells to the site of infection and promote healing of any damaged tissue following the
removal of pathogens.[32]
Complement system
For more details on this topic, see Complement system.

The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It
contains over 20 different proteins and is named for its ability to "complement" the killing of
pathogens by antibodies. Complement is the major humoral component of the innate immune
response.[33][34] Many species have complement systems, including non-mammals like plants,
fish, and some invertebrates.[35]
In humans, this response is activated by complement binding to antibodies that have attached to
these microbes or the binding of complement proteins to carbohydrates on the surfaces of
microbes. This recognition signal triggers a rapid killing response.[36] The speed of the response
is a result of signal amplification that occurs following sequential proteolytic activation of
complement molecules, which are also proteases. After complement proteins initially bind to the
microbe, they activate their protease activity, which in turn activates other complement
proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by
controlled positive feedback.[37] The cascade results in the production of peptides that attract
immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen,
marking it for destruction. This deposition of complement can also kill cells directly by
disrupting their plasma membrane.[33]
Cellular barriers

A scanning electron microscope image of normal circulating human blood. One can
see red blood cells, several knobby white blood cells including lymphocytes, a
monocyte, a neutrophil, and many small disc-shaped platelets.

Leukocytes (white blood cells) act like independent, single-celled organisms and are the second
arm of the innate immune system.[14] The innate leukocytes include the phagocytes
(macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural
killer cells. These cells identify and eliminate pathogens, either by attacking larger pathogens
through contact or by engulfing and then killing microorganisms.[35] Innate cells are also
important mediators in the activation of the adaptive immune system.[12]
Phagocytosis is an important feature of cellular innate immunity performed by cells called
'phagocytes' that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body
searching for pathogens, but can be called to specific locations by cytokines.[14] Once a pathogen
has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a
phagosome, which subsequently fuses with another vesicle called a lysosome to form a
phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a
respiratory burst that releases free radicals into the phagolysosome.[38][39] Phagocytosis evolved as
a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of
pathogens as a defense mechanism.[40] Phagocytosis probably represents the oldest form of host
defense, as phagocytes have been identified in both vertebrate and invertebrate animals.[41]
Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of
invading pathogens.[42] Neutrophils are normally found in the bloodstream and are the most
abundant type of phagocyte, normally representing 50% to 60% of the total circulating
leukocytes.[43] During the acute phase of inflammation, particularly as a result of bacterial
infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis,
and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells
that reside within tissues and produce a wide array of chemicals including enzymes, complement
proteins, and regulatory factors such as interleukin 1.[44] Macrophages also act as scavengers,
ridding the body of worn-out cells and other debris, and as antigen-presenting cells that activate
the adaptive immune system.[12]
Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment;
therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines.[45] They are
named for their resemblance to neuronal dendrites, as both have many spine-like projections, but
dendritic cells are in no way connected to the nervous system. Dendritic cells serve as a link
between the bodily tissues and the innate and adaptive immune systems, as they present antigen
to T cells, one of the key cell types of the adaptive immune system.[45]

Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory
response.[46] They are most often associated with allergy and anaphylaxis.[43] Basophils and
eosinophils are related to neutrophils. They secrete chemical mediators that are involved in
defending against parasites and play a role in allergic reactions, such as asthma.[47] Natural killer
(NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have been
infected by viruses.[48]
Adaptive immune system
For more details on this topic, see Adaptive immune system.

The adaptive immune system evolved in early vertebrates and allows for a stronger immune
response as well as immunological memory, where each pathogen is "remembered" by a
signature antigen.[49] The adaptive immune response is antigen-specific and requires the
recognition of specific "non-self" antigens during a process called antigen presentation. Antigen
specificity allows for the generation of responses that are tailored to specific pathogens or
pathogen-infected cells. The ability to mount these tailored responses is maintained in the body
by "memory cells". Should a pathogen infect the body more than once, these specific memory
cells are used to quickly eliminate it.
Lymphocytes

The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B
cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem
cells in the bone marrow.[35] B cells are involved in the humoral immune response, whereas T
cells are involved in cell-mediated immune response.
Both B cells and T cells carry receptor molecules that recognize specific targets. T cells
recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the
pathogen) have been processed and presented in combination with a "self" receptor called a
major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the
killer T cell and the helper T cell. Killer T cells only recognize antigens coupled to Class I MHC
molecules, while helper T cells only recognize antigens coupled to Class II MHC molecules.
These two mechanisms of antigen presentation reflect the different roles of the two types of T
cell. A third, minor subtype are the T cells that recognize intact antigens that are not bound to
MHC receptors.[50]
In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and
recognizes whole pathogens without any need for antigen processing. Each lineage of B cell
expresses a different antibody, so the complete set of B cell antigen receptors represent all the
antibodies that the body can manufacture.[35]

Killer T cells

Killer T cells directly attack other cells carrying foreign or abnormal antigens on
their surfaces.[51]

Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other
pathogens), or are otherwise damaged or dysfunctional.[52] As with B cells, each type of T cell
recognises a different antigen. Killer T cells are activated when their T cell receptor (TCR) binds
to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition
of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then
travels throughout the body in search of cells where the MHC I receptors bear this antigen. When
an activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores
in the target cell's plasma membrane, allowing ions, water and toxins to enter. The entry of
another toxin called granulysin (a protease) induces the target cell to undergo apoptosis.[53] T cell
killing of host cells is particularly important in preventing the replication of viruses. T cell
activation is tightly controlled and generally requires a very strong MHC/antigen activation
signal, or additional activation signals provided by "helper" T cells (see below).[53]
Helper T cells

Function of T helper cells: Antigen-presenting cells (APCs) present antigen on their

Class II MHC molecules (MHC2). Helper T cells recognize these, with the help of their
expression of CD4 co-receptor (CD4+). The activation of a resting helper T cell
causes it to release cytokines and other stimulatory signals (green arrows) that
stimulate the activity of macrophages, killer T cells and B cells, the latter producing
antibodies. The stimulation of B cells and macrophages succeeds a proliferation of T
helper cells.

Helper T cells regulate both the innate and adaptive immune responses and help determine which
immune responses the body makes to a particular pathogen.[54][55] These cells have no cytotoxic
activity and do not kill infected cells or clear pathogens directly. They instead control the
immune response by directing other cells to perform these tasks.
Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC
molecules. The MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor,
which recruits molecules inside the T cell (e.g., Lck) that are responsible for the T cell's
activation. Helper T cells have a weaker association with the MHC:antigen complex than
observed for killer T cells, meaning many receptors (around 200300) on the helper T cell must
be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be
activated by engagement of a single MHC:antigen molecule. Helper T cell activation also
requires longer duration of engagement with an antigen-presenting cell.[56] The activation of a
resting helper T cell causes it to release cytokines that influence the activity of many cell types.
Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages
and the activity of killer T cells.[14] In addition, helper T cell activation causes an upregulation of
molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which
provide extra stimulatory signals typically required to activate antibody-producing B cells.[57]
T cells

T cells possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ () T
cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The

conditions that produce responses from T cells are not fully understood. Like other
'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T
cells, T cells straddle the border between innate and adaptive immunity.[58] On one hand, T
cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor
diversity and can also develop a memory phenotype. On the other hand, the various subsets are
also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern
recognition receptors. For example, large numbers of human V9/V2 T cells respond within
hours to common molecules produced by microbes, and highly restricted V1+ T cells in
epithelia respond to stressed epithelial cells.[50]

An antibody is made up of two heavy chains and two light chains. The unique
variable region allows an antibody to recognize its matching antigen. [51]
[edit] B lymphocytes and antibodies

A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen.[59]
This antigen/antibody complex is taken up by the B cell and processed by proteolysis into
peptides. The B cell then displays these antigenic peptides on its surface MHC class II
molecules. This combination of MHC and antigen attracts a matching helper T cell, which
releases lymphokines and activates the B cell.[60] As the activated B cell then begins to divide, its
offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen.
These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen
and mark them for destruction by complement activation or for uptake and destruction by
phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or
by interfering with the receptors that viruses and bacteria use to infect cells.[61]
Alternative adaptive immune system

Although the classical molecules of the adaptive immune system (e.g., antibodies and T cell
receptors) exist only in jawed vertebrates, a distinct lymphocyte-derived molecule has been

discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals
possess a large array of molecules called variable lymphocyte receptors (VLRs) that, like the
antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of
genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies,
and with the same degree of specificity.[62]
[edit] Immunological memory
For more details on this topic, see Immunity (medical).

When B cells and T cells are activated and begin to replicate, some of their offspring become
long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember
each specific pathogen encountered and can mount a strong response if the pathogen is detected
again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to
infection with that pathogen and prepares the immune system for future challenges.
Immunological memory can be in the form of either passive short-term memory or active longterm memory.
Passive memory

Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection.
Several layers of passive protection are provided by the mother. During pregnancy, a particular
type of antibody, called IgG, is transported from mother to baby directly across the placenta, so
human babies have high levels of antibodies even at birth, with the same range of antigen
specificities as their mother.[63] Breast milk or colostrum also contains antibodies that are
transferred to the gut of the infant and protect against bacterial infections until the newborn can
synthesize its own antibodies.[64] This is passive immunity because the fetus does not actually
make any memory cells or antibodiesit only borrows them. This passive immunity is usually
short-term, lasting from a few days up to several months. In medicine, protective passive
immunity can also be transferred artificially from one individual to another via antibody-rich
serum.[65]

The time-course of an immune response begins with the initial pathogen encounter,
(or initial vaccination) and leads to the formation and maintenance of active
immunological memory.
Active memory and immunization

Long-term active memory is acquired following infection by activation of B and T cells. Active
immunity can also be generated artificially, through vaccination. The principle behind
vaccination (also called immunization) is to introduce an antigen from a pathogen in order to
stimulate the immune system and develop specific immunity against that particular pathogen
without causing disease associated with that organism.[14] This deliberate induction of an immune
response is successful because it exploits the natural specificity of the immune system, as well as
its inducibility. With infectious disease remaining one of the leading causes of death in the
human population, vaccination represents the most effective manipulation of the immune system
mankind has developed.[35][66]
Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based
on acellular components of micro-organisms, including harmless toxin components.[14] Since
many antigens derived from acellular vaccines do not strongly induce the adaptive response,
most bacterial vaccines are provided with additional adjuvants that activate the antigenpresenting cells of the innate immune system and maximize immunogenicity.[67]
Disorders of human immunity

The immune system is a remarkably effective structure that incorporates specificity, inducibility
and adaptation. Failures of host defense do occur, however, and fall into three broad categories:
immunodeficiencies, autoimmunity, and hypersensitivities.
Immunodeficiencies
For more details on this topic, see Immunodeficiency.

Immunodeficiencies occur when one or more of the components of the immune system are
inactive. The ability of the immune system to respond to pathogens is diminished in both the
young and the elderly, with immune responses beginning to decline at around 50 years of age
due to immunosenescence.[68][69] In developed countries, obesity, alcoholism, and drug use are
common causes of poor immune function.[69] However, malnutrition is the most common cause
of immunodeficiency in developing countries.[69] Diets lacking sufficient protein are associated
with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody
concentrations, and cytokine production. Additionally, the loss of the thymus at an early age
through genetic mutation or surgical removal results in severe immunodeficiency and a high
susceptibility to infection.[70]

Immunodeficiencies can also be inherited or 'acquired'.[14] Chronic granulomatous disease, where

phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or
congenital, immunodeficiency. AIDS and some types of cancer cause acquired
immunodeficiency.[71][72]
Autoimmunity
For more details on this topic, see Autoimmunity.

Overactive immune responses comprise the other end of immune dysfunction, particularly the
autoimmune disorders. Here, the immune system fails to properly distinguish between self and
non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies
react with "self" peptides.[73] One of the functions of specialized cells (located in the thymus and
bone marrow) is to present young lymphocytes with self antigens produced throughout the body
and to eliminate those cells that recognize self-antigens, preventing autoimmunity.[59]
Hypersensitivity
For more details on this topic, see Hypersensitivity.

Hypersensitivity is an immune response that damages the body's own tissues. They are divided
into four classes (Type I IV) based on the mechanisms involved and the time course of the
hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often
associated with allergy. Symptoms can range from mild discomfort to death. Type I
hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils
when cross-linked by antigen.[74] Type II hypersensitivity occurs when antibodies bind to
antigens on the patient's own cells, marking them for destruction. This is also called antibodydependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies.[74]
Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM
antibodies) deposited in various tissues trigger Type III hypersensitivity reactions.[74] Type IV
hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes
between two and three days to develop. Type IV reactions are involved in many autoimmune and
infectious diseases, but may also involve contact dermatitis (poison ivy). These reactions are
mediated by T cells, monocytes, and macrophages.[74]
Other mechanisms
For more details on this topic, see Innate immune system#Other forms of innate
immunity.

It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as
invertebrates do not generate lymphocytes or an antibody-based humoral response.[1] Many
species, however, utilize mechanisms that appear to be precursors of these aspects of vertebrate
immunity. Immune systems appear even in the structurally most simple forms of life, with

bacteria using a unique defense mechanism, called the restriction modification system to protect
themselves from viral pathogens, called bacteriophages.[75] Prokaryotes also possess acquired
immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of
phage that they have come into contact with in the past, which allows them to block virus
replication through a form of RNA interference.[76][77]
Pattern recognition receptors are proteins used by nearly all organisms to identify molecules
associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily
conserved component of the innate immune response found in all animals and plants, and
represent the main form of invertebrate systemic immunity.[1] The complement system and
phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA
interference pathway are conserved across all eukaryotes, and are thought to play a role in the
immune response to viruses.[78]
Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic
chemical signals that are sent through a plant.[79] Individual plant cells respond to molecules
associated with pathogens known as Pathogen-associated molecular patterns or PAMPs.[80] When
a part of a plant becomes infected, the plant produces a localized hypersensitive response,
whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease
to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response
used by plants that renders the entire plant resistant to a particular infectious agent.[79] RNA
silencing mechanisms are particularly important in this systemic response as they can block virus
replication.[81]
Tumor immunology
Further information: Cancer immunology

Macrophages have identified a cancer cell (the large, spiky mass). Upon fusing with
the cancer cell, the macrophages (smaller white cells) inject toxins that kill the

tumor cell. Immunotherapy for the treatment of cancer is an active area of medical
research.[82]

Another important role of the immune system is to identify and eliminate tumors. The
transformed cells of tumors express antigens that are not found on normal cells. To the immune
system, these antigens appear foreign, and their presence causes immune cells to attack the
transformed tumor cells. The antigens expressed by tumors have several sources;[83] some are
derived from oncogenic viruses like human papillomavirus, which causes cervical cancer,[84]
while others are the organism's own proteins that occur at low levels in normal cells but reach
high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at
high levels, transforms certain skin cells (e.g. melanocytes) into tumors called melanomas.[85][86]
A third possible source of tumor antigens are proteins normally important for regulating cell
growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.[83]
[87][88]

The main response of the immune system to tumors is to destroy the abnormal cells using killer
T cells, sometimes with the assistance of helper T cells.[86][89] Tumor antigens are presented on
MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize
the tumor cell as abnormal.[90] NK cells also kill tumorous cells in a similar way, especially if the
tumor cells have fewer MHC class I molecules on their surface than normal; this is a common
phenomenon with tumors.[91] Sometimes antibodies are generated against tumor cells allowing
for their destruction by the complement system.[87]
Clearly, some tumors evade the immune system and go on to become cancers.[92] Tumor cells
often have a reduced number of MHC class I molecules on their surface, thus avoiding detection
by killer T cells.[90] Some tumor cells also release products that inhibit the immune response; for
example by secreting the cytokine TGF-, which suppresses the activity of macrophages and
lymphocytes.[93] In addition, immunological tolerance may develop against tumor antigens, so the
immune system no longer attacks the tumor cells.[92]
Paradoxically, macrophages can promote tumor growth [94] when tumor cells send out cytokines
that attract macrophages, which then generate cytokines and growth factors that nurture tumor
development. In addition, a combination of hypoxia in the tumor and a cytokine produced by
macrophages induces tumor cells to decrease production of a protein that blocks metastasis and
thereby assists spread of cancer cells.
Physiological regulation

Hormones can act as immunomodulators, altering the sensitivity of the immune system. For
example, female sex hormones are known immunostimulators of both adaptive[95] and innate
immune responses.[96] Some autoimmune diseases such as lupus erythematosus strike women
preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such

as testosterone seem to be immunosuppressive.[97] Other hormones appear to regulate the immune

system as well, most notably prolactin, growth hormone and vitamin D.[98][99]
When a T-cell encounters a foreign pathogen, it extends a vitamin D receptor. This is essentially
a signaling device that allows the T-cell to bind to the active form of vitamin D, the steroid
hormone calcitriol. T-cells have a symbiotic relationship with vitamin D. Not only does the T-cell
extend a vitamin D receptor, in essence asking to bind to the steroid hormone version of vitamin
D, calcitriol, but the T-cell expresses the gene CYP27B1, which is the gene responsible for
converting the pre-hormone version of vitamin D, calcidiol into the steroid hormone version,
calcitriol. Only after binding to calcitriol can T-cells perform their intended function. Other
immune system cells that are known to express CYP27B1 and thus activate vitamin D calcidiol,
are dendritic cells, keratinocytes and macrophages.[100][101]
It is conjectured that a progressive decline in hormone levels with age is partially responsible for
weakened immune responses in aging individuals.[102] Conversely, some hormones are regulated
by the immune system, notably thyroid hormone activity.[103] The age-related decline in immune
function is also related to dropping vitamin D levels in the elderly. As people age, two things
happen that negatively affect their vitamin D levels. First, they stay indoors more due to
decreased activity levels. This means that they get less sun and therefore produce less
cholecalciferol via UVB radiation. Second, as a person ages the skin becomes less adept at
producing vitamin D.[104]
The immune system is affected by sleep and rest,[105] and sleep deprivation is detrimental to
immune function.[106] Complex feedback loops involving cytokines, such as interleukin-1 and
tumor necrosis factor- produced in response to infection, appear to also play a role in the
regulation of non-rapid eye movement (REM) sleep.[107] Thus the immune response to infection
may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to
REM sleep.[108]
Nutrition and diet

The function of the immune system, like most systems in the body, is dependent on proper
nutrition. It has been long known that severe malnutrition leads to immunodeficiency.[citation needed]
Overnutrition is also associated with diseases such as diabetes and obesity, which are known to
affect immune function. More moderate malnutrition, as well as certain specific trace mineral
and nutrient deficiencies, can also compromise the immune response.[109]
Specific foods may also affect the immune system; for example, fresh fruits, vegetables, and
foods rich in certain fatty acids may foster a healthy immune system[110] while an excess of proinflammatory fatty acids can cause an imbalance in the immune system.[citation needed] Likewise, fetal
undernourishment can cause a lifelong impairment of the immune system.[111] In traditional

medicine, some herbs are believed to stimulate the immune system,[112] such as echinacea,
licorice, ginseng, astragalus, sage, garlic, elderberry, and hyssop, as well as honey.
Manipulation in medicine

The immunosuppressive drug dexamethasone

The immune response can be manipulated to suppress unwanted responses resulting from
autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against
pathogens that largely elude the immune system (see immunization). Immunosuppressive drugs
are used to control autoimmune disorders or inflammation when excessive tissue damage occurs,
and to prevent transplant rejection after an organ transplant.[35][113]
Anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoids
are the most powerful of these drugs; however, these drugs can have many undesirable side
effects, such as central obesity, hyperglycemia, osteoporosis, and their use must be tightly
controlled.[114] Lower doses of anti-inflammatory drugs are often used in conjunction with
cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine. Cytotoxic drugs
inhibit the immune response by killing dividing cells such as activated T cells. However, the
killing is indiscriminate and other constantly dividing cells and their organs are affected, which
causes toxic side effects.[113] Immunosuppressive drugs such as ciclosporin prevent T cells from
responding to signals correctly by inhibiting signal transduction pathways.[115]
Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs
are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on
larger peptides and proteins (which are typically larger than 6000 Da). In some cases, the drug
itself is not immunogenic, but may be co-administered with an immunogenic compound, as is
sometimes the case for Taxol. Computational methods have been developed to predict the
immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic
antibodies, assessing likely virulence of mutations in viral coat particles, and validation of
proposed peptide-based drug treatments. Early techniques relied mainly on the observation that
hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids;

[116]

however, more recent developments rely on machine learning techniques using databases of
existing known epitopes, usually on well-studied virus proteins, as a training set.[117] A publicly
accessible database has been established for the cataloguing of epitopes from pathogens known
to be recognizable by B cells.[118] The emerging field of bioinformatics-based studies of
immunogenicity is referred to as immunoinformatics.[119] Immunoproteomics is a term used to
describe the study of large sets of proteins (proteomics) involved in the immune response.
Manipulation by pathogens

The success of any pathogen depends on its ability to elude host immune responses. Therefore,
pathogens evolved several methods that allow them to successfully infect a host, while evading
detection or destruction by the immune system.[120] Bacteria often overcome physical barriers by
secreting enzymes that digest the barrier, for example, by using a type II secretion system.[121]
Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell,
providing a direct route for proteins to move from the pathogen to the host. These proteins are
often used to shut down host defenses.[122]
An evasion strategy used by several pathogens to avoid the innate immune system is to hide
within the cells of their host (also called intracellular pathogenesis). Here, a pathogen spends
most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells,
antibodies and complement. Some examples of intracellular pathogens include viruses, the food
poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium
falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium
tuberculosis, live inside a protective capsule that prevents lysis by complement.[123] Many
pathogens secrete compounds that diminish or misdirect the host's immune response.[120] Some
bacteria form biofilms to protect themselves from the cells and proteins of the immune system.
Such biofilms are present in many successful infections, e.g., the chronic Pseudomonas
aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.[124] Other
bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples
include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus
magnus (protein L).[125]
The mechanisms used to evade the adaptive immune system are more complicated. The simplest
approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface
of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation.
An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential
for entry into its host target cell are constantly changing. These frequent changes in antigens may
explain the failures of vaccines directed at this virus.[126] The parasite Trypanosoma brucei uses a
similar strategy, constantly switching one type of surface protein for another, allowing it to stay
one step ahead of the antibody response.[127] Masking antigens with host molecules is another
common strategy for avoiding detection by the immune system. In HIV, the envelope that covers

the viron is formed from the outermost membrane of the host cell; such "self-cloaked" viruses
make it difficult for the immune system to identify them as "non-self" structures.[128]