Bacterial Pathogenesis
The plague doctor in clothing worn to protect from contagion, circa
1656. We are haunted by images of the horrors of disease and death.
Very short introduction to Bacteria: worth to see
http://www.youtube.com/watch?v=qCn92mbWxd4
楊倍昌
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Learning Objectives
After reading this section, students will be able to...
• Explain how to identify a disease pathogen.
• Describe the modes of infectious disease
transmission.
• Describe how bacteria damage host cells.
• Explain the mechanisms used by bacteria to
evade host defense system.
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共存
共生
+ Trichonympha
(protozoan)
 Commensalism and symbiosis are presented as part of a
continuum, distinguished by the identification of specific
benefits derived by one or both members of a host-bacterial
partnership.
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
Most human infections are caused by
opportunistic pathogen.

The function of commensal microbe.

Probiotics are defined as live cultures of microorganisms administered orally and acting
beneficially on host health.
H. Tlaskalov´a-Hogenov´a et al. 2004,
Commensal bacteria (normal microflora), mucosal immunity and chronic
inflammatory and autoimmune diseases. Immunol Letters 93 97–108.
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Some facts
Death per 100,000,
1952 versus 2007 (WHO 2008)
Gastritis, enteritis, and colitis 135
Pneumonia 134.5
Tuberculosis, all forms 91.6
Heart disease 49.0
Vascular lesions affecting central nervous system 48.8
Cause of perinatal mortality 44.1
Nephritis and nephrosis 36.3
Malignant neoplams 30.7
Bronchitis 28.1
Malaria 27.5
175.9
56.7
56.2
44.6
31.1
25.7
22.5
22.2
17.2
8.6
Malignant neoplasms:
Heart diseases
Cerebrovascular diseases
Diabetes mellitus
Accidents
Pneumonia
Chronic liver disease and cirrhosis
Nephritis, nephrotic syndrome, and nephrosis
Suicide
Hypertensive disease
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Some facts
2001
low- and middle-income countries: high-income countries:
1.
2.
3.
4.
5.
Heart disease
Stroke
Lower respiratory infections
HIV/AIDS
Fetus/newborn (perinatal)
conditions
6. Chronic obstructive pulmonary
disease (COPD)
7. Diarrhea
8. Tuberculosis
9. Malaria
10.Road traffic accidents
1.
2.
3.
4.
5.
Heart disease
Stroke
Lung cancer
Lower respiratory infections
Chronic obstructive pulmonary
disease (COPD)
6. Colon and rectum cancers
7. Alzheimer's disease
8. Type 2 diabetes
9. Breast cancer
10.Stomach cancer
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Innocent or Murder?
Who is to be blamed?
Not decided. Until…
Robert Koch,1843-1910,
Germany
Koch’s postulates:
1. Suspected pathogen must be present
2. Pathogen must be isolated and grown in pure culture
3. Cultured pathogen must cause the disease
4. Same pathogen must be re-isolated from the subject
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Human and microbes

Normal flora (beneficial or
ignored):


GI track, skin, upper respiratory track
Virulent bacteria (actively cause
disease): pathogenic islands
Opportunistic bacteria (when host
with underline problem):



Pseudomonas aeruginosa: cystic fibrosis/ burn
TB, Kaposi’s sarcoma (herpesvirus): AIDS
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Why we do not get ill?
(i) the entire invading population is killed
by phagocytic cells, such as neutrophils, or
circulating bacteriocidal compounds, such
as complement, (ii) the density of bacteria
traversing the integument is collectively too
low to condition the tissue to allow their
population to grow, or (iii) the mutations
or phase shifts required to get across the
mucosa or survive in the blood do not
occur.
It is complex and strong stochastic
How Microbs Cause Disease: http://www.youtube.com/watch?v=fNaAisFiPdU
It takes about 1 hr 30 min.
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Bacterial pathogenesis

Infection/entry
 Virulence factors
 Pathogenesis
 Escape of immune
surveillance
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Infection/entry







Ingestion (fecal-oral)
Inhalation (respiratory)
Trauma (burn)
Arthropod bite
(zoonoses: mosquito,
flea, tick, Tsetse fly)
Sexual transmission
Needle stick (blood
transfusion)
Maternal-neonatal
http://nihroadmap.nih.gov/hmp/
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Modes of infectious disease transmission




Ingestion: Salmonella, Shigella, Vibrio,
Clostridium etc..
Inhalation: Mycobacterium, Mycoplasma,
Chlamydia etc..
Trauma: Clostridium tetani

Arthropod bite: Rickettsia, Yersinia pestis, etc.
Sexual transmission: Neisseria gonorrboeae,

HIV, chlamydia, etc
Needle stick: Staphylococcus, HIV, HBV

Maternal-neonatal: HIV, HBV, Neisseria, etc.
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另外一種分類法
Modes of infectious disease transmission
• Contact transmission
– Direct contact (person-to-person): syphilis, gonorrhear, herpes
– Indirect contact: enterovirus infection, measles
– Droplet (less than 1 meter): whooping cough, strep throat
• Vehicle transmission
– Airborne: influenza, tuberculoses, chickenpox
– Water-borne (fecal-oral infection): cholera, diarrhea
– Food-borne: hepatitis, food poisoning, typhoid fever
• Vector transmission
– Biological vectors: malaria, plaque, yellow fever
– Mechanical vectors: E. coli diarrhea, salmonellosis
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Where to find the pathogen?
Extracellular versus Intracellular Parasitism
 Extracellular parasites
 destroyed when phagocytosed.
 damaging tissues as they remain outside cells.
 inducing the production of opsonizing antibodies, they
usually produce acute diseases of relatively short
duration.
 Intracellular parasites
 can multiply within phagocytes.
 frequently cause chronic disease.
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 Extracellular parasites
 Respiratory, cutaneous, tract infections:
Streptococcus spp, Staphylococcus spp.
 Digestion tract infections: Salmonella spp.,
Shigella spp.
 Intracellular parasites
 Respiratory (pneumopathies: immunosuppresive;
children): Chlamydia, Legionella, Mycobateria.
 Sex-transmitted: Chlamydia trachomatis
 CNS + other sites: Listeria monocytogenes;
Pregnant women; immunosuppressive patients
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The environment in a cell
 Cytosol: pH=7
 Phagosome: pH=6
 Phagolysosome: pH=5
http://bio.winona.msus.edu/bates/Bio241/images/figure-04-13b.jpg
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Intracellular bacteria
Listeria
Shigella
Endosomes
Phagolysosomes
Legionella
Chlamydia
Sammonella
Mycobacteria
lysosomes
Phagosomes
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Infection cycle of Listeria monocytogenes.
The bacteria mediate their own internalisation into the cell (1). Cellular
vacuoles are then lysed by the pore forming toxin listeriolysin O and
phospholipase C (2). Once in the cytoplasm the bacteria multiply (5) and
rapidly move around the cell by polar polymerisation of host actin: comet-like
structure (3). On collision with the cell membrane the bacterium forces its way
into the neighboring cell where it lyses the double membrane compartment
and the cycle is complete (4)
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Barrier systems
Host cell
membrane
Taken up by
phagocyte
and resist killing
Inhibitory
molecule
Mycobacterium
Production
Of antibody
Degrade
antibody
IgA protease
Streptococcus
Antimicrobia
cell-mediated
response
Activate T cells
non-specifically
and
Productively
Superantigen
Staphylococcus
Antimicrobial
immune
response
Vary presenting
Switch on
microbial antigen production of
different
antigens
Genetic
recombination
Borrelia
Streptococcus
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Virulence factors
• Factors enhance the ability of bacteria to
cause disease
An example of Pseudomonas aeruginosa

Adhesins: attachment

Alginate production: mucoid layer

Exotoxin A: inhibits host protein synthesis

Exoenzyme S: interferes with phagocytic killing

Elastolytic activity: degrades elastin

Phospholipase C: damages tissue

Pyocyanin: damages tissue by ROS

Antibiotic resistance: complicates therapy
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Pathogenic action of bacteria

Tissue destruction: flesh-eating
bacteria: Necrotizing fasciitis


Obstruction: Cytic fibrosis
Toxins: bacterial components that directly
harm tissue or trigger disease symptoms



Endotoxin: lipopolysaccharides
Exotoxin: A-B toxins
Immunopathogenesis


Excess immune responses
Autoimmunity
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Endotoxins: heat stable
IL-6 induced in monocytes
exposed to LPS and PM102.5 extracts from indoor
and outdoor air. Cytokines
were measured after
exposure of monocytes to
particle extracts for six
hours.
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Endotoxin: lipopolysaccharide
IL-1
TNF
Pseudomonas aeruginosa
Fever
Disseminated intravascular coagulation
Septic shock
death
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Some exotoxins: heat labile





Diphtheria
Cholera toxin
Tetanus
Botulinum
Superantigens
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Toxins: Inhibition of protein synthesis
Subunit A
Corynebacterium diphtheriae
Beta-phage: lysogenic
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Development of
vaccine for toxins
Diphtheria antitoxin
1901 Nobel prize
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Toxins: cause hyperactivation
Vibrio cholerae
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Botulinum neutotoxin type B 肉毒素

Clostridium botulinum causes Botulism is a
severe type of food poisoning caused by the
ingestion of foods containing the
neurotoxin formed during growth of the
bacteria.

can be destroyed if heated to 80ºC for at
least 10 minutes.

weakness and vertigo, followed by double
vision, difficulty in speaking, swallowing
and breathing, muscle weakness,
abdominal distention, and constipation.
Paralysis and death may follow.
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Toxins: affect on nerve-muscle transmission
Block the release of ACH
Ästhetik-Forum Berlin
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Tetanus 破傷風
Tetanus toxin:
Patient number in Canada
After antitoxin vaccine
1941-1995
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Toxins: affect on nerve-muscle transmission
The x-ray crystal structure for the tetanus toxin showing how
the amino acid chain is folded.
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Superantigens
Polyclonal T cell activation
Aberrant cytokines,
cell death
Antigen/
MHC-1
Specific T cell
activation
Anti-microbes
immunity
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Known and suspected association of
superantigens with human disease (1)

Acute diseases
 Food
poisoning: SEs
 Staph TSS
Menstrual:
TSST-1
Nonmenstrual: SEB, SEC, TSST-1
 StrepTSS:SPe’s
 Sudden
infant death syndrome: SEs?, SPe,s
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Known and suspected association of
superantigens with human disease (2)

Autoimmune diseases
 Rheumatic
fever, rheumatic hart disease:
M proteins, SPe’s?
 Kawasaki disease: TSST-1?, SPe’s?
 Lyme disease
 Reumatoid arthritis
 Multiple sclerosis
 Sjögren’s syndrome:
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EVASION STRATEGIES (1)
Defence
Microbial strategy
Mechanism
Example
Wash-out
Bind to cell
Adhesins
Neisseria
Inhibit ciliary
activity
Ciliotoxic/
Ciliostatic
molecule
Bordetella
Streptococcus
Disrupt
Chemotaxis
cytotoxic
Leucocidins
Staphylococcus
Inhibit
phagocytosis
Capsule
Streptococcus
Inhibit lysosomal
fusion
Inhibitory
molecule
Mycobacterium
Multiply
Unknown
Listeria
Ingestion
and
killing by
phagocyte
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EVASION STRATEGIES (2)
Defence
Restrict FeLactoferrin
Transferrin
Activate
complement
Microbial
strategy
Mechanism
Example
Compete
Siderophore
Mycobacterium
Escherichia
Interfere with
alternative
pathway
Fully sialylated
surface
Neisseria
Inactivate
Elastase
Pseudomonas
Antigen projects
beyond surface
Activation
occurs at the
wrong site
Gram-negatives
Interfere with
complementmediated
phagocytosis
C3b receptor
competition,
microbe and
phagocyte
Streptococcus
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Key Takeaways
• Most human infections are caused by opportunistic pathogen.
• Koch’s postulate is the key in pathogen identification that include:
1. Suspected pathogen must be present, 2. Pathogen must be
isolated and grown in pure culture, 3. Cultured pathogen must
cause the disease, 4. Same pathogen must be re-isolated from
the subject.
• Three modes of disease transmission: Contact, Vehicle, Vector
• Virulence factors: factors enhance the ability of bacteria to cause
disease.
•
Pathogenic actions: Tissue destruction, Obstruction, Toxins,
Immunopathogenesis.
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