1. Interaction of bacteria with human being
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 Essential roles of bacteria in health maintenance.
How bacteria become aliens.
How to identify a disease pathogen.
The modes of infectious disease transmission.
How bacteria damage host cells.
The mechanisms used by bacteria to evade host defense system.

4. 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

5. Patho-genesis Vs Health-genesis
Hygiene theory for asthma
Microbiome of inflammatory bowel disease
The Role of the Microbiota in Gastrointestinal Health and Disease
Physical and morphological changes associated with microbial colonization. Shown here are ceca from a germfree mouse (left), monoassociated mouse (center), and conventional microbiota mouse (right). Note the increased size of the cecum from the GF mouse. 
In:  "Inflammatory Bowel Disease" book edited by Imre Szabo, ISBN , (2012 )

6. 中醫方劑《肘後備急方》東晉葛洪編著，共八卷70篇。治傷寒時氣溫病方第十三：又方，大蚓一升破去，以人溺煮，令熟，去滓服之。直生絞汁及水煎之。並善，又絞糞汁，飲數合至一二升，謂之黃龍湯，陳久者佳。
《本草綱目》認為，人中黃可以「清熱涼血，瀉火解毒」。
Els van Nood et al. (2013) Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med 368:
The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin.
The study was stopped after an interim analysis. Of 16 patients in the infusion group, 13 (81%) had resolution of C. difficile–associated diarrhea after the first infusion. T

7. 吃甚麼，變甚麼！
David LA et al Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:

8. 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

9. Facts:
疾病的種類會隨著生活形態、社會結構而變。
人與微生物的演變沒那麼快。
受影響的是:
與人與微生物接觸的機會(衛生)。
治療的技術。
營養。

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

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

12. Infection/entry Ingestion (fecal-oral) Inhalation (respiratory)
七種途徑 (人體結構)
Ingestion (fecal-oral)
Inhalation (respiratory)
Trauma (burn)
Arthropod bite (zoonoses: mosquito, flea, tick, Tsetse fly)
Sexual transmission
Needle stick (blood transfusion)
Maternal-neonatal

13. Modes of infectious disease transmission
Ingestion: Salmonella, Shigella, Vibrio, Clostridium etc..
Inhalation: Mycobacterium, Mycoplasma, Chlamydia etc..
Trauma: Clostridium tetani
Arthropod bite: Rickettsia, Yersinia pestis, Dengue virus.
Sexual transmission: Neisseria gonorrhoeae, HIV, Chlamydia, etc
Needle stick: Staphylococcus, HIV, HBV
Maternal-neonatal: HIV, HBV, Neisseria, etc.

14. 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

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

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

17. Defense versus Evasion
Wash-out
 Ingestion and killing by phagocyte
Restrict Fe-Lactoferrin Transferrin
Activate complement
Production of antibody
Antimicrobial cell-mediated response
Antimicrobial immune response

18. EVASION STRATEGIES (1) 較快速的反應 Defense 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

19. EVASION STRATEGIES (2) 較快速的反應 Defense 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

20. Adaptive immune systems-related
較慢的反應
Adaptive immune systems-related
Defense
Microbial strategy
Mechanism
Example
Production
of antibody
Degrade
antibody
IgA protease
Streptococcus
Antimicrobial
cell-mediated
response
Activate T cells
non-specifically
and
Productively
Superantigen
Staphylococcus
immune
Vary presenting
microbial antigen
1. Switch on
production of
different antigens
2. Genetic recombination
Borrelia

21. 4 major pathogenic actions of bacteria to host
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
Inhibiting protein synthesis (cell death): Diphtheria
Hyperactivation: Cholera toxin
Interfering neuro- transmission:
Tetanus
Botulinum
Immune overactivation: 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
“Stop Diarrhoea” program run by the non-profit Save the Children

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
Block the release of ACH
Ästhetik-Forum Berlin

30. Tetanus 破傷風
Tetanus toxin:
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.
Patient number in Canada
After antitoxin vaccine
Incomplete vaccine deployment among the population at risk is the major factor.

31. Toxins: affect on nerve-muscle transmission

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. Key Takeaways
Microbes are essential to keep health. 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.