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Bacterial pathogenicity

Parasite versus host defence

Microorganisms evolution
The

tendency of the living organisms to seize new environments. The microorganisms succeeded. The bacteria have been trying for almost 2 milliard years to become two from one, in the shortest possible period of time, the most economical possible and in varied conditions. (Franois Jacob)

Microorganisms evolution
We have appeared, evolved and survived in a world dominated by microorganisms. Microorganisms, biological factor of our environment. A continuos history: microbial virulence & antimicrobial defense mechanisms of the host.

Characteristics of the parasitism

Loss

of structures that ensure independent life. Auxotrophs versus prototrophs. Some microorganisms can synthesize by themselves all the aminoacids and they are called prototrophs. Auxotrophs have lost, by mutation, a biosynthetic ability.

Appearance and development of structures and functions that ensure: penetration in the host; maintenance, survival and multiplication; invasion of the host; survival of the parasite in nature: between two hosts, under the pressure of the immune response of the host.

Microbial pathogenicity

Virulence

factors are characteristics that enable bacteria to cause disease. Pathogenic bacteria may have one or several virulence factors. They may be common to all bacteria of a given genus or species, or they may be a characteristic of special pathogenic strains.

Microbial pathogenicity

Virulence factors that are common to the genus or species appear to give the organism a survival advantage; they may be selected during evolution. Those that are unique to some strains are usually acquired through mechanisms of genetic exchange (generally conjugation and transduction) and are not associated with specific survival advantage for the bacterium.

Virulence

Expresses the pathogenicity degree of a microorganism and is expressed in MLD (minimum letal dose) and, more precise, in LD50 (letal dose 50% - amount of Ag that kill 50% of inoculated animals). The precise measurement of virulence and the cloning of bacterial DNA allowed identification of virulence factors and their codifying genes.

The molecular Kochs postulates

The investigated phenotype (property, structure, function) has to be associated to pathogenic strains of a species or to pathogenic species of a genus. The specific inactivation of the gene(s) that codify the suspected pathogenic phenotype has to lead to quantifiable loss of virulence. Reversion or allelic substitution of the mutant gene has to restore virulence. Def: different forms of a new gene that appeared after mutation = allel and they have the some place as first (original) gene

Virulence by genetic mutation

Penetration in the host

Through breaks in the covering mucus of secretor epithelia. Translocation through digestive epithelium the role of M cells from the intestinal lymphatic epithelium minimum resistance place (bacteria pass through the epithelium and reach blood) ; favorable conditions in new-born: immaturity of covering mucus and of the digestive flora (to see, formation of climax populations and the role of anaerobic bacteria). The role of bacterial and viral neuraminidases.

Penetration in the host

Through breaks in the covering mucus of secretor epithelia. Through breaks in the ecological barrier created by bacteriocins. By motility: e.g., spirochete, Proteus.

Maintenance on surfaces through ligands:

Fimbriae Capsule Proteins

(common pili)

of the external membrane Capsomers (viruses structure) Glycoproteins

Fimbriae (common pili)

E. Colis pilli - adherence

"Capsule-swelling reaction"

Attachment receptor specific

Survival

Protection against phagocytes and complement, by: capsule; the capsulated variants of bacteria are virulent and the encapsulated are harmless; antigen O (surface structure of LPS). agressins: leucocidins, hemolysins (e.g., pyogenic streptococci) kill leucocytes and erythrocytes respectivelly.

Survival

Neutralization

of the acid gastric barrier by production of urease (e.g., Helicobacter). Resistance to microbicidal mechanisms in the phagocytes: obligate intracellular (Richettsiia, Clamydia, Coxiella ) or facultative intracellular organisms (Salmonella, Shigella, Yersinia).

Multiplication in the host

Bacterial iron chelators; siderophores are iron-binding factors that allow some bacteria to compete with the host for iron, which is bound to hemoglobin, transferrin, and lactoferrin. Selective advantages of the capsule (channel of bacterial enzymes and nutrients resulted from the aggressed cell).

Host invasion

Invasines: hialuronidase, colagenase. Enzymes that break down collagen (i.e., collagenases, hyaluronidases) and fibrin (i.e., fibrinolysins) allow better penetration of bacteria into tissues. Motility- help bacteria to pass through epithelial cells layer.

Shigella inavasine and invasion

Salmonella penetration mechanism

Avoidance of hosts immune response

Localization of the microorganism in privileged sites latent infections with facultative or obligate intracellular bacteria; persistent viral infections (viruses are obligate intracellular microorganisms). Immune response suppression mumps virus stimulates Tsupressor lymphocytes; HIV destroys T4 lymphocytes (T helper) less frequent in bacteria (tuberculosis, activate T supressor cells) than viruses.

Avoidance of hosts immune response

Identity

between bacterial structures and hosts structures: e.g., antigen K1 of Escherichia coli and cerebral polysialosilglycopeptides severe meningitis in neonate (K1 antigen it is nor recognized as nonself) Masking of the parasite with hosts antigens: e.g., schistosomas.

Avoidance of hosts immune response


Antigenic

variation of the parasite (ex., gonococci: the immune dominant domain of piline is hypervariable and protects the functional domain against the hosts immune response: antibodies against the hypervariable domain select a new antigenic variant before the appearance of the immune response against the ligand).

Strategies of survival in the host

Multitude of serovars defined by virulence antigens (e.g., Streptococcus pyogenes, rhinoviruses). Antigenic variation (e.g., influenza virus and its antigenic shift and antigenic drift) help viruses to change their antigenic structure (they elude the immune system: the previous Ab are efficient only for the previous Ag).

Virulence by genetic mutation

Survival strategies between two successive hosts

a. Sporulation b. Resistance in the environment resistance to dryness (e.g., mycobacteria, staphylococci); selective advantages in minimally nutritive, watery media (e.g., opportunistic gram-negative bacilli). c. Very fragile microorganisms - adaptation to biological vectors (arthropode borne viruses, Rickettsiia); - sexual transmission (syphilis).

Virulence Factors - conclusions


(2) (3) (4)

Virulence factors help bacteria to invade the host, cause disease, and evade host defenses.

Harming of the hosts structures:


direct

mechanisms (toxins) indirect mechanisms (hypersensitivity reactions I IV)

Direct mechanisms.

Bacterial toxins: proteic toxins (exotoxins) lipopolysaccharidic (LPS) toxins (endotoxins) Thermal stability: proteic toxins are heat labile, LPS toxins are heat stable. Toxicity: MLD (minimum letal dose) ng/kg proteic toxins; mg/kg LPS toxins.

Specificity and mechanism of action:

High

specificity of proteic toxins, which have a structural AB model: B = ligand polypeptides; A = ADP ribose transferase (active domain). The high specificity of the effect depends on the receptors for B and the molecular target, with modified function, by fixation of ADPribose. E.g., the elongation factor (diphtheria toxin) - inhibition of the proteic synthesis.

Cytolytic proteic toxins:


pores -

formation because of intramembranary oligomerisation: hemolysins of streptococci, staphylococci etc., phospholipases (e.g., clostridial hemolysins).

Unspecific effects of LPS toxins:


fever, leukopenia, shock, necrosis

by activation of chemical mediators and interleukins from macrophages, complement activation on alternative pathway.

LPS of Gram (-) bacteria

Antigenicity versus toxicity.


Toxoids

and anti-toxins. Toxoids = bacterial toxine without toxigenic capacity but still immunogenic (induce antibodies appearance). Can be produce from toxins after heat treatment and phormol. Can be used as vaccines. Anti-toxins serum with Ab against toxin (can be used in serotherapy).

Indirect mechanisms.

Hypersensitivity reactions: Type I, anaphylactic; Type II, cytolitic - cytotoxic; Type III, by immune complex; Type IV, cell-mediated or delayed.

Type I, anaphylactic:
possible

in viral infections (e.g., respiratory syncytial virus), asthma, tissue phase of helminthes infections (e.g., echinococcosis, ascaridiosis). It is frequent associated with allergens inoculation (ex. Penicillin).

Type II, cytotoxic:

antibodies

+ complement, as in hemolytic anemia in Mycoplasma pneumoniae infection ; antibodies + complement and natural killer (NK) cells, cytotoxic T lymphocytes, as in hepatitis B virus infection and hepatitis C virus infection ;

Type III, immune complex:

circulating

complexes (serum disease type); e.g., post-streptococcal acute glomerulonephritis, hepatitis B etc. tissue complexes (Arthus reaction type); e.g., measles after inefficient vaccination, possibly in some severe forms of influenza.

S pyogenes : type III hypersensitivity reaction by immune complexes and C activtation

Type IV, cell-mediated or delayed


Ex.:

infections with facultative intracellular microorganisms (as Mycobacterium tuberculosis).

Virulence by microbial synergism


The alteration of the defense mechanisms by a microorganism enhances the possibility of the invasion by other microorganisms (e.g., respiratory viral infections and their bacterial complications); Easier colonization of an area by summing the virulence factors: the oxygen consume by aerobic bacteria facilitate the multiplication in the tissues of anaerobic bacteria (ex. E. coli + Bacteroides); reciprocal supply of growth factors; common use of the same ligand (e.g., capsule).

Regulation of bacterial virulence factors

Pathogenic bacteria have developed from free, saprophytic ones. Many of them have kept independent life abilities. They measure very precisely their metabolic needs and synthesize one product only when it offers a selective advantage.

Regulation of bacterial virulence factors


Extrachromosomal

codification of some virulence factors with the possibility of amplification and deamplification of this information stock: - Plasmidic codification (e.g., iron chelators, pili, hemolysins, enterotoxins); - Prophage codification (e.g., proteic toxins).

Regulation of bacterial virulence factors


Control of the essential virulence genes by a complex environmental signals system: Temperature: Bordetella pertussis expresses virulence genes at 37C, but represses them at lower growth temperatures. Yersinia enterocolitica and Listeria monocytogenes express motility only at 25C (probably significant for the life outside the human body), but represses it at 37C. Yersinia expresses yops genes that codify for antiphagocitary proteins, maximally at 37C, but represses them at 25C.

Regulation of bacterial virulence factors

Control of the essential virulence genes by a complex environmental signals system: Temperature Osmotic pressure, pH, temperature, medium composition in aminoacids control the expression of 20 genes in Vibrio cholerae. Ex: the choleric toxin is produced in higher amounts at pH 6.0 than at pH 8.5, at 30C than at 37C.

Immunity of the host


Innate

(natural) immunity - unspecific Acquired immunity - specific

Natural immunity
Present

from the first moment of life Unspecific active for all foreign antigens Eliminate (in some limits) all microorganisms

Natural immunity
Mechanical

barriers (intact skin and mucosa connective tissue) Chemical barrier (IFN, complement system, C reactive protein - CRP) Cellular barrier (inflammatory cells granulocytes, reticuloendothelial system)

Leukocytes

Leukocytes,

the main cells in the immune system, provide either innate or specific adaptive immunity. These cells are derived from myeloid or lymphoid lineage. Myeloid cells include highly phagocytic, motile neutrophils, monocytes, and macrophages that provide a first line of defense against most pathogens.

Leukocytes
The

other myeloid cells, including eosinophils, basophils, and their tissue counterparts, mast cells, are involved in defense against parasites and in the genesis of allergic reactions. In contrast, lymphocytes regulate the action of other leukocytes and generate specific immune responses that prevent chronic or recurrent infections.

Reticuloendothelial System

2) 3) 4)

Cells of the RES provide natural immunity against microorganisms by: a coupled process of phagocytosis and intracellular killing, recruiting other inflammatory cells through the production of cytokines, and presenting peptide antigens to lymphocytes for the production of antigen-specific immunity.

Reticuloendothelial System
-

The RES consists of circulating monocytes; resident macrophages in the liver, spleen, lymph nodes, thymus, submucosal tissues of the respiratory and alimentary tracts, bone marrow, and connective tissues; and macrophage-like cells including dendritic cells in lymph nodes, Langerhans cells in skin, and glial cells in the central nervous system.

Acquired Immunity- Immune Mechanisms


Antibody

and secondary biologic

activities Serum antibodies are the signal and specific component of a complex inactivation system. Serum IgM and IgG antibodies exert their protective effect directly upon bacteria whose surface polysaccharides or proteins are protective antigens.

Immune Mechanisms

For

some pathogens such as meningococci (Gram-negative), the antigen-antibody configuration will activate the serum complement protein cascade with deposition of a C8,9 peptide probe that drills itself through the outer membrane. The resultant lesion causes release of intracellular components and lysis of the meningococci.

Immune Mechanisms

In

addition to bacteriolysis, other Gramnegatives, such as Haemophilus influenzae type b, also may be inactivated by serum antibody, affixed to the polysaccharide of this pathogen, that attracts and activates serum complement proteins to form C3 and C5 complexes.

Immune Mechanisms

The

latter complexes (C3 C5) attract and activate phagocytic cells that engulf and digest the pathogen (opsonophagocytosis). This antibody-initiated, complementdependent phagocytosis and killing are required for Gram-positive bacteria whose cell wall is not susceptible to lysis by complement.

Immune Mechanisms

Serum

antibodies may confer immunity by binding directly to viral pathogens. The effect of this simple interaction is neutralization or inactivation of the virus. In many cases, antibody binding renders the viral pathogen incapable of infecting a host cell by preventing penetration of cells.

Immune Mechanisms

As

an example, antibodies to the fusion (F) protein of measles prevent the integration of virus with the cell membrane of the host. Some larger viral pathogens, coated with specific antibody, may be phagocytized and digested

Immune Mechanisms

Antibodies

that neutralize bacterial toxins (antitoxins), such as tetanus, diphtheria and pertussis toxins, are protective and therapeutic. The protective effects of antitoxins are varied.

Immune Mechanisms

Antitoxin

does not exert antibacterial action upon Clostridium tetani. Rather, antitoxin inactivates the functions of tetanus toxin that facilitates its migration up the neural sheath to the synapse, and antibodies to the enzymatic region inhibit its alteration of the synapse.

Tetanus toxin

Immune Mechanisms

The

neutralizing activities of diphtheria and pertussis antitoxins, in contrast, exert secondary antibacterial actions upon their respective pathogens.

Immune Mechanisms

Both

toxins serve to condition the respiratory epithelium to permit colonization by Corynebacterium diphtheriae toxine and Bordetella pertussis: the former by its cytotoxicity and the latter by its inactivation of the function of phagocytic cells. Antitoxins block these actions and facilitate the function of phagocytic cells.

Cell-mediated immunity
Antigen-specific activation of T cells The targets for activated T cells are parasitized host cells. The secondary or inactivation mechanisms invoked by activated T cell phagocytic host cell complexes are not clearly understood. One important mechanism is the release of nitrous oxide that results in killing of the host cell and of the pathogen. Cell-mediated immunity is largely, if not exclusively, a curative mechanism.

Infection
Is

penetration and multiplication in the body of an infectious agent: virus, bacterium, fungus, and protozoa. Multiplication, invasion of the tissues, toxin production by the etiological agent produces lesions translated into clinical signs and symptoms of infectious disease.

Infection
When

the only detectable reaction of the host is the immune response, the process is called subclinical infection. The importance of subclinical infection: induces immunization; the patient is source of infection.

Infection
The

latent infection is characterized by the prolonged and asymptomatic persistence, in deep sites, of the microbes that dont multiply (dormant microbes). E.g., rickettsiosis, primary tuberculosis, syphilis. Latent infection can reactivate.

Infection
Spontaneous

microbiological cure of the latent infection is possible. The dormant microbes: are not susceptible to antimicrobial drugs; cant be detected by direct methods; stimulate the hosts immunity (immunity disappears after the microbiological cure of the infection).

From the origin of the microbe point of view, there are:

4) 5) 6)

Endogenous infections, produced by opportunists that belong to the normal flora; Exogenous infections, produced by pathogens from an external source. Exogenous infections appear when there coexist: a source of infection; a way of transmission; a susceptible host.

Exogenous infections
Transmissible

diseases are the diseases corresponding to exogenous infections. The highly transmissible ones are called contagious diseases.

Source of infection

Man Animals Inanimate

Source of infection

Man

infections for which man is the only source of infection are called anthroponoses. Patients with infectious diseases - patients with acute infections; - patients with chronic infections. Healthy carriers (they are often unknown, so, they are dangerous sources of infection).

Source of infection
- persons with subclinical infections; - convalescent carriers (after many infections of mucosae, the microorganism can persist, after clinical cure, for weeks or months). - contact carriers (medical staff, the family can contaminate with microbes that survive in the nose, pharynx or intestine and are eliminated with the secretions); - non-contact carriers (these persons become carriers after contact with other categories of carriers).

Source of infection

Animals they are sources of infection for zooanthroponoses. Inanimate sources of infection: soil, water, organic material deposits.

Transmission of infection
It is ensured by: elimination of microbes from the source; contamination with these microbes of parts of the environment, which transform into vehicle of the infection; access of the microbes in the susceptible host.

Transmission of infection

Ways of transmission of the infection: direct contact; transmission mediated by: air, soil, water, food, contaminated hands, contaminated objects; arthropods:mechanical vectors flies, cockroach; biological vector hematophage arthropods (microbes can multiply).

Cycle of eyes infection

Portals of entrance

Transplacental (congenital) infections. E.g., Treponema pallidum, Listeria monocytogenes, rubella virus,cytomegalovirus etc. Respiratory portal of entrance. E.g., Streptococcus pyogenes, pneumococci, Haemophilus, meningococci, tuberculosis bacilli, diphtheria bacilli, influenza viruses, common cold viruses, measles virus etc.

Portals of entrance

Digestive portal of entrance. They may produce diarrhea (Vibrio cholerae, non typhoid Salmonella, dysentery bacilli, viruses, protozoa etc.), or systemic infections (typhoid Salmonella, enteroviruses etc.). Only a few of them are capable to infect the stomach (Helicobacter pylori). Lesions of the skin or mucosae: traumatical or surgical wounds, bitten wounds. Friction and scratching introduces in the deep layers of the skin or mucosae microbes deposed on the surface.

Portals of entrance
Injection

^ hematophage insects inject microorganisms from the blood sucked from the previous person. ^ syringes,

Viral local infections

Invasion and lesions of tissues and organs:

dissemination

in the neighborhood; dissemination by the lymphatic vessels; dissemination by blood; dissemination by nerves.

Spread of picornaviruses

Dissemination by blood
Bacteremia

is an occasional penetration of a low number of bacteria in blood. Repeated or continuos penetration of bacteria and their toxins in high amounts in blood is called septicemia.

Spread of infection through blood

Spread of infection through the central nervous system

Dissemination by blood

Septicemia is accompanied by numerous secondary localizations of bacteria in organs and skin. During bacteremia, secondary localizations are occasional. Bacteremia has no clinical symptoms or it produces only fever and chills. Septicemia produces high fever, through alteration of the general status, clinical signs connected to the secondary localizations.

Stages of the infection:

Incubation lasts from the moment the microbe penetrates the host until the first signs of disease appear. Onset corresponds to the first clinical symptoms, generally non-specific. State phase characteristic signs for different infections appear, as a consequence of the lesions in target organs and tissues. Complications may appear because of the worsening of the lesions or because new lesions appear at distance. Terminal phase

Evolution of enteric fever

Terminal phase
a. cure = disappearance of the clinical symptoms, disappearance of the infective microbe from the lesions and their healing; Sequels may remain after severe lesions. Spontaneous cure of an Infection is a consequence of immunity. Clinical cure is not always accompanied by microbiological cure. After clinical cure some patients remain healthy carriers; sometimes, a latent infection persists.

Terminal phase
b. chronicization of the infection = prolonged persistence of the microbe in the tissues and the persistence of the lesions; c. death.

Primary and secondary infections


Pathogens

are virulent enough to produce an infection even in an immune-competent person (primary infection). Sometimes the primary infection alters the defense mechanisms of the host, facilitating a secondary infection, produced by opportunists.

Manifestations of the infections in communities:


Sporadic Endemic Epidemic Pandemic

Manifestations of the infections in communities:


Sporadic

infections appear occasionally, at irregular intervals of time, in a low number, disseminated in the territory and without connection between cases. Endemic infections are characterized by a constant presence of an infection in a community, with a frequency that varies very little from year to year.

Manifestations of the infections in communities:


Epidemic

is characterized by a sudden rise of the frequency of an infection in a community, over the estimated one, with demonstrated connections among them. Epidemic in a small community is called epidemic outbreak;

Manifestations of the infections in communities:


Epidemic

at an international scale is called pandemic.

Hospital infection

Hospital

(nosocomial) infection is the infection caught in the hospital, in the conditions created by hospitalization and by the medical or surgical act. Hospital infection is produced by microbes from the hospital.

Hospital infection

The

hospital microbial fund includes: infecting or carriage microorganisms of the hospitalized patients, the normal flora and carriage microorganisms of the medical staff, microorganisms spread by the hospital environment (air, food, objects, hands, contaminated instruments or drugs).

Hospital infection

Some -

bacteria are more often transmitted: Staphylococcus aureus, Escherichia coli and related gram-negative bacilli, Pseudomonas aeruginosa.

Hospital infection

Out

of these strains have been selected dangerous hospital strains: - they have multiple resistance to antibiotics and disinfectants; - they have great colonization abilities of the surfaces of the host; - they are more virulent than the communitary strains of the same species.

Aggressive medical and surgical acts:

Punctions,

endoscopy, assisted breathing, surgery, prolonged catheterizing create breaks in the outlays of the organism, pass through normally colonized areas, with a possible transport of the organisms in normally sterile areas. Frequent transfusions rise the risk of transmission of HBV, HCV, HIV;

Aggressive medical and surgical acts:


Perfusions

may produce severe infections with bacteria that accidentally contaminate and multiply in perfusion solutions. Immune suppressive and immune depressive medication enhances susceptibility to opportunistic infections.

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