Bacterial pathogenesis

Microbiology Lecture 4

Dr Adrian Harrison
Learning outcomes

By the end of this lecture you should:

• Be aware of how humans interact with bacteria, the normal flora of the
human body and what makes a pathogen.

• Understand the basis of bacterial pathogenesis in terms of colonization,

routes of entry and categories of diseases

• Be familiar with the molecular mechanisms underpinning pathogenesis

including invasiveness and toxigenicity

• Understand how antibiotics work and the development of antibiotic

resistance
A human is an ecosystem
Mouth
Streptococcus, Lactobacillus,
Fusobacterium, Veillonella,
Corynebacterium, Neisseria,
Actinomyces
Skin
Staphylococcus, Corynebacterium,
Acinetobacter, Propionibacterium,
Micrococcus

Respiratory tract
Streptococcus, Staphylococcus,
Corynebacterium, Neisseria

Gastrointestinal tract
Lactobacillus, Streptococcus,
Bacteriodes, Bifidobacterium,
Eubacterium, Ruminococcus,
Clostridium, Escherichia,
Klebsiella, Proteus, Enterococcus,
Staphylococcus
Urogenital tract
Escherichia, Klebsiella, Proteus,
Neisseria, Lactobacillus,
Corynebacterium, Staphylococcus,
Clostridium, Peptostreptococcus
3D Map of skin microbes Low diversity
High diversity

Amina Bouslimani et al. PNAS 2015;112:E2120-E2129

Normal flora or indigenous microbiota

• Normal flora includes >200 species.

• Beneficial or at least harmless to the host:

– protection against colonization by harmful bacteria;
– production of antimicrobial compounds;
– synthesis of vitamins
– stimulation of the production of natural antibodies

False-coloured electron micrograph

of Streptococcus mutans (pink) in
dental plaque. Manfred Kage, Peter
Arnold Inc./Science Photo Library.
Normal flora or indigenous microbiota

• Members of the normal flora can turn from harmless to

harmful:
– in immunocompromised hosts (HIV, cancer patients)

– when they move from their site of colonization to adjacent

areas of normally sterile tissues, often as a result of surgery
or intestinal perforation.

False-coloured electron micrograph

of Streptococcus mutans (pink) in
dental plaque. Manfred Kage, Peter
Arnold Inc./Science Photo Library.
What makes a pathogen?

• A microorganism that is able to cause disease in an animal,

plant or insect.

• More than 100 bacterial species cause disease in humans.

• Two mechanisms underpinning pathogenesis are:

– Invasiveness
– Toxigenicity

• These two factors determine the virulence (capacity to cause

disease) of a pathogen.
Invasiveness

• The ability of a pathogen to invade the body, spread into it and

to establish an infection.

• It involves mechanisms for:

– colonization (adherence and initial proliferation)
– production of extracellular substances which facilitate
invasion (invasins)
– evasion of the host defences
Invasiveness - Routes of entry
The routes of entry define the four large classes of bacterial diseases:

1. Inhalation of contaminated air respiratory diseases

2. Ingestion of contaminated food or water intestinal

diseases

3. Contact with another infected host sexually transmitted

diseases

4. Bite by an infected organism vector-borne diseases

Invasiveness - Colonization
Bacterium

Adhesin
Receptor

Epithelial cells

E. coli adhesins: pili and fimbriae

-Type-I fimbriae bind mannose on the surface of
eukaryotic cells
- ability to encode different fimbriae to associate
with different host cell types

Tip protein (containing the binding site for the receptor)

Toxigenicity – Exotoxins

• The ability to damage the host by producing toxic

chemicals.
• Proteins that are secreted by the pathogen.
• Usually enzymes.
• Destroy cellular structures.
• Classified as:
- cytotoxins
- neurotoxins
- enterotoxins
Cytotoxin example

• Diphtheria toxin (Corynebacterium

diphtheriae)

• Prevents protein synthesis in

eukaryotic cells

• Causes Diphtheria
Neurotoxin example
• Botulinum toxin (Clostridium
botulinum)

• Prevents the release of acetylcholine

in synapses leading to paralysis

• Most acutely lethal toxin known

(LD50 of 1.3–2.1 ng/kg)
Neurotoxin example 2
• Tetanus toxin (Clostridium tetani)
• Causes Tetanus (Lock Jaw)
• Blocks the release of inhibitory neurotransmitters at
synaptic cleft

Painting by Sir Charles Bell, 1809

Many exotoxins consist of two subunits
Endotoxins
• Lipopolysaccharides of the cell envelope of Gram-
negative bacteria
• Attached to the bacterial cell
Microbes are ruthless killers
Bacterial pathogens: Vibrio cholerae
• Causes Cholera

• Lives in surface waters around the world. Eye of Science/Science Photo Library.

• Symptoms: severe diarrhea, leg cramps, vomiting and

dehydration.

• Transmission route: ingestion of faecally contaminated water.

• Molecular cause of the disease is an enterotoxin, the cholera toxin.

• Fatality rate: as high as 30-50% if left untreated. However, if

patients are given rehydration therapy, then the death rate is 1%.
Bacterial pathogens: Vibrio cholerae - toxin
A

A
B B
B B B
B

Model of cholera AB toxin

GM1

Adenylate
Epithelial cells cyclase
of the intestine
Bacterial pathogens: Vibrio cholerae -history

Soho
square

John Snow,
the 1854
epidemic
in Soho and
the Broad
Street
pump.
The Broad Street pump
Bacterial pathogens: Yersinia pestis
• Rod-shaped, Gram-negative bacterium
• Causative agent of plague
• Vector-borne disease transmitted via bite of an infected
flea
• Fleas that live on Black rats (Rattus rattus)
Bacterial pathogens: Yersinia pestis
• Haemorrhaging of the lymph nodes causes the
appearance of buboes (Bubonic plague).

• Bacteria in the blood stream cause septicaemia.

• Human to human spread by Pneumonic plague

• Bubonic plague kills 50%

• Pneumonic plague kills 90%.

Black Death - Symptoms
The Black Death – a 14th Century Catastrophe

• Worse outbreak was in the 1300’s.

• Believed to have started in central Asia and spread to Europe

• Claimed to have come to Europe via the Crimea during the

siege of Kaffa in 1346.

• Mongol army rumoured to have used an early form of

“biological warfare” by catapulting corpses into the besieged
city.
• Genoese merchants fled
the city by boat carrying
the disease to the ports
that they landed at.

• The disease then spread

throughout Europe.

• Two thirds of the

population of Europe
were infected, of which
half died. i.e. one third of
population (40 million)
Black Death – How do we know it was
Yersinia pestis

East Smithfield burial site

Genome of Yersinia pestis read from victims
of the Black Death

1 chromosome

3 plasmids
(WMD or Weapons
of Mass Distruction!)

Plasmids harbor genes that are responsible for

the virulence of the bacterium.

Bos KI et al. (2011) A draft genome of Yersinia pestis from victims of the Black Death. Nature 478: 506-510.
Black Death - Today

•There are still places where the disease is still endemic

Antibiotics
• Chemicals that kill or inhibit the growth of
microorganisms

• Used to treat microbial infections.

• Some are natural products of microbes, but many

are now chemically synthesized.
- Natural
- Semi synthetic
- Synthetic
Antibiotics
• Alexander Fleming
discovered the first
antibiotic, penicillin, by
chance
• In 1928. He isolated it from
the mould Penicillium
notatum and found it
prevented the growth of
bacteria even when it was
highly diluted.
• Developed during WW2 by
Florey, Chain and Heatley.
Antibiotics

• Work by interfering with a bacteria-specific

biological process:

- cell wall synthesis

- cell membrane structure
- protein synthesis
- nucleic acid synthesis
Antibiotics
Antibiotics - Drug resistance

• Bacteria can develop resistance to an

antibiotic that was previously effective in
killing them.

• Drug resistance is acquired by

chromosomal mutation or acquisition of a
plasmid or fragment of DNA carrying a gene
encoding for the resistance from a resistant
bacterium

•With time, they can become resistant to

multiple antibiotics.
MRSA. Biomedical Imaging Unit, Southampton General Hospital.
Learning outcomes

By the end of this lecture you should:

• Be aware of how humans interact with bacteria, the normal flora of the
human body and what makes a pathogen.

• Understand the basis of bacterial pathogenesis in terms of colonization,

routes of entry and categories of diseases

• Be familiar with the molecular mechanisms underpinning pathogenesis

including invasiveness and toxigenicity

• Understand how antibiotics work and the development of antibiotic

resistance