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Bacterial Pathogenesis

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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:
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.

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