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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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
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 (WHO 2008)
Death per 100,000,
1952 versus 2007
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.
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
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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Facts:
1.疾病的種類會隨著生活形態、
社會結構而變。
2.人與微生物的演變沒那麼快。
受影響的是:
1. 與人與微生物接觸的機會。
2. 治療的技術。
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Innocent or Murder?
Who is to be blamed?
Not decided. Until…
Robert Koch,1843-1910,
Koch’s postulates:
Germany
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
楊倍昌 (2012) 病原的推論邏輯： 科霍法則是不是實驗科學的終極證明？In: 科學之美：生物科
學史閱讀手記，頁93-130，巨流圖書出版。
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Why we do not get ill?
1. the entire invading population is killed by
phagocytic cells, such as neutrophils, or circulating
bacteriocidal compounds, such as complement.
2. the density of bacteria traversing the integument
is collectively too low to condition the tissue to allow
their population to grow.
3. the mutations or phase shifts required to get
across the mucosa or survive in the blood do not
occur.
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
七種途徑 (人體結構)
1.
2.
3.
4.
5.
6.
7.
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
1.
Ingestion: Salmonella, Shigella, Vibrio,
Clostridium etc..
2.
Inhalation: Mycobacterium, Mycoplasma,
Chlamydia etc..
3.
4.
Trauma: Clostridium tetani
Arthropod bite: Rickettsia, Yersinia pestis,
Dengue virus.
5.
Sexual transmission: Neisseria gonorrhoeae,
HIV, Chlamydia, etc
6.
7.
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 (自然環境)
1. Contact transmission
1.
Direct contact (person-to-person): syphilis, gonorrhea, herpes
2.
Indirect contact: enterovirus infection, measles
3.
Droplet (less than 1 meter): whooping cough, strep throat
2. Vehicle transmission
1.
Airborne: influenza, tuberculosis, chickenpox
2.
Water-borne (fecal-oral infection): cholera, diarrhea
3.
Food-borne: hepatitis, food poisoning, typhoid fever
3. Vector transmission
1.
Biological vectors: malaria, plaque, yellow fever
2.
Mechanical vectors: E. coli diarrhea, salmonellosis
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較快速的反應
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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較快速的反應
EVASION STRATEGIES (2)
Defence
Microbial strategy
Mechanism
Example
Restrict FeLactoferrin
Transferrin
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
Activate
complement
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較慢的反應
Adaptive immune systems-related
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
microbial antigen
1. Switch on
production of
different antigens
2. Genetic
recombination
Borrelia
Streptococcus
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Where to find the pathogen in host (生存的環境)?
 Extracellular parasites (生長快速)
 being destroyed when phagocytosed.
 damaging tissues as they remain outside cells.
 inducing the production of opsonizing antibodies
(expose to immune system).
 usually producing acute diseases of relatively short
duration.
 Intracellular parasites (生長緩慢)
 multiply within phagocytes.
 low immunogenicity
 frequently causing 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,
Treponema pallidum, Neisseria gonorrhoeae,
 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 internalization 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 polymerization 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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Factors enhance the ability of bacteria to cause disease
(virulence factors: example of Pseudomonas aeruginosa)
1.
Adhesins: attachment
2.
Alginate production: mucoid layer
3.
Exoenzyme S: interferes with phagocytic killing
4.
Exotoxin A: inhibits host protein synthesis
5.
Elastolytic activity: degrades elastin
6.
Phospholipase C: damages tissue
7.
Pyocyanin: damages tissue by ROS
8.
Antibiotic resistance: complicates therapy
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Pathogenic actions of bacteria to host
Tissue destruction: flesh-eating bacteria:
1.
Necrotizing fasciitis
Obstruction: Cytic fibrosis
Toxins: bacterial components that directly
2.
3.
harm tissue or trigger disease symptoms


Endotoxin: lipopolysaccharides
Exotoxin: A-B toxins
Immunopathogenesis
4.


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
•
“Stop Diarrhoea” program run by the non-profit Save the Children
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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
• In the most common type the
spasms begin in the jaw and then
progress to the rest of the body,
may be so severe that bone
fractures may occur.
• Spasms usually last a few minutes
each time and occur frequently for
3-4 weeks.
• 10% death rate.
Tetanus toxin:
Patient number in Canada
After antitoxin vaccine
1941-1995
Incomplete vaccine deployment among the population at risk is the major factor.
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Toxins: affect on nerve-muscle transmission
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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
Sudden infant death syndrome: SEs?, SPe,s
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Known and suspected association of
superantigens with human disease (2)

Autoimmune diseases

Lyme disease
 Rheumatic fever, rheumatic hart disease: M
proteins, SPe’s?
 Kawasaki disease: TSST-1?, SPe’s?
 Reumatoid arthritis
 Multiple sclerosis
 Sjögren’s syndrome:
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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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