1. Bacterial Pathogenesis
The plague doctor in clothing worn to protect from contagion, circa We are haunted by images of the horrors of disease and death.
Very short introduction to Bacteria: worth to see
楊倍昌

2. 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.

3. 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.

4. Most human infections are caused by opportunistic pathogen.
The function of commensal microbe.
Probiotics are defined as live cultures of micro-organisms 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.

5. Death per 100,000, 1952 versus 2007 Some facts (WHO 2008)
Gastritis, enteritis, and colitis
Pneumonia 134.5
Tuberculosis, all forms
Heart disease
Vascular lesions affecting central nervous system
Cause of perinatal mortality
Nephritis and nephrosis
Malignant neoplams
Bronchitis
Malaria
Malignant neoplasms:
Heart diseases
Cerebrovascular diseases
Diabetes mellitus
Accidents
Pneumonia
Chronic liver disease and cirrhosis
Nephritis, nephrotic syndrome, and nephrosis
Suicide
Hypertensive disease

6. 2001 Some facts low- and middle-income countries: Heart disease Stroke
Lower respiratory infections
HIV/AIDS
Fetus/newborn (perinatal) conditions
Chronic obstructive pulmonary disease (COPD)
Diarrhea
Tuberculosis
Malaria
Road traffic accidents
high-income countries:
Heart disease
Stroke
Lung cancer
Lower respiratory infections
Chronic obstructive pulmonary disease (COPD)
Colon and rectum cancers
Alzheimer's disease
Type 2 diabetes
Breast cancer
Stomach cancer

7. Innocent or Murder? Who is to be blamed? Not decided. Until…
Robert Koch, ,
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

8. 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

9. How Microbs Cause Disease: http://www.youtube.com/watch?v=fNaAisFiPdU
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:
It takes about 1 hr 30 min.

10. Bacterial pathogenesis
Infection/entry
Virulence factors
Pathogenesis
Escape of immune surveillance

11. 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

12. 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.

13. Modes of infectious disease transmission
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

14. 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.

15. 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

16. The environment in a cell
Cytosol: pH=7
Phagosome: pH=6
Phagolysosome: pH=5

17. Intracellular bacteria
Listeria
Shigella
Endosomes
Phagolysosomes
Legionella
Chlamydia
Sammonella
Mycobacteria
lysosomes
Phagosomes

18. 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)

19. 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
Vary presenting
microbial antigen
Switch on
production of
different
antigens
Borrelia
Genetic
recombination

20. 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

21. 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

22. Endotoxins: heat stable
IL-6 induced in monocytes exposed to LPS and PM extracts from indoor and outdoor air. Cytokines were measured after exposure of monocytes to particle extracts for six hours.

23. Endotoxin: lipopolysaccharide
Pseudomonas aeruginosa
IL-1
TNF
Fever
Disseminated intravascular coagulation
Septic shock
death

24. Some exotoxins: heat labile
Diphtheria
Cholera toxin
Tetanus
Botulinum
Superantigens

25. Toxins: Inhibition of protein synthesis
Subunit A
Corynebacterium diphtheriae
Beta-phage: lysogenic

26. Development of vaccine for toxins
Diphtheria antitoxin
1901 Nobel prize

27. Toxins: cause hyperactivation
Vibrio cholerae

28. 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.

29. Toxins: affect on nerve-muscle transmission
Ästhetik-Forum Berlin
Block the release of ACH

30. Tetanus 破傷風 Tetanus toxin: Patient number in Canada
After antitoxin vaccine

31. Toxins: affect on nerve-muscle transmission
The x-ray crystal structure for the tetanus toxin showing how the amino acid chain is folded.

32. Aberrant cytokines, cell death
Superantigens
Polyclonal T cell activation
Antigen/MHC-1
Aberrant cytokines, cell death
Specific T cell activation
Anti-microbes immunity

33. 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

34. 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:

35. EVASION STRATEGIES (1) Defence Microbial strategy Mechanism Example
Wash-out
Bind to cell
Adhesins
Neisseria
Inhibit ciliary
activity
Ciliotoxic/
Ciliostatic
molecule
Bordetella
Streptococcus
Ingestion
and
killing by
phagocyte
Disrupt
Chemotaxis
cytotoxic
Leucocidins
Staphylococcus
Inhibit
phagocytosis
Capsule
Inhibit lysosomal
fusion           
Inhibitory
Mycobacterium
Multiply
Unknown
Listeria

36. EVASION STRATEGIES (2) Defence Microbial strategy Mechanism Example
Restrict Fe- Lactoferrin Transferrin
Compete
Siderophore
Mycobacterium Escherichia
Activate complement
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 complement- mediated phagocytosis     
C3b receptor competition, microbe and phagocyte
Streptococcus

37. 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.