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Bacterial Pathogenesis 楊倍昌 1 The plague doctor in clothing worn to protect from contagion, circa 1656. We are haunted by images of the horrors of disease.

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Presentation on theme: "Bacterial Pathogenesis 楊倍昌 1 The plague doctor in clothing worn to protect from contagion, circa 1656. We are haunted by images of the horrors of disease."— Presentation transcript:

1 Bacterial Pathogenesis 楊倍昌 1 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

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. 2

3 3 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. 共存 共生 + Trichonympha (protozoan)

4 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 Malignant neoplasms: 56.7 Heart diseases 56.2 Cerebrovascular diseases 44.6 Diabetes mellitus 31.1 Accidents 25.7 Pneumonia 22.5 Chronic liver disease and cirrhosis 22.2 Nephritis, nephrotic syndrome, and nephrosis 17.2 Suicide 8.6 Hypertensive disease Gastritis, enteritis, and colitis 135 Pneumonia 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 Death per 100,000, 1952 versus 2007 (WHO 2008) Some facts

6 6 low- and middle-income countries: 1.Heart disease 2.Stroke 3.Lower respiratory infections 4.HIV/AIDS 5.Fetus/newborn (perinatal) conditions 6.Chronic obstructive pulmonary disease (COPD) 7.Diarrhea 8.Tuberculosis 9.Malaria 10.Road traffic accidents high-income countries: 1.Heart disease 2.Stroke 3.Lung cancer 4.Lower respiratory infections 5.Chronic obstructive pulmonary disease (COPD) 6.Colon and rectum cancers 7.Alzheimer's disease 8.Type 2 diabetes 9.Breast cancer 10.Stomach cancer 2001 Some facts

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

8 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 9 (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 Why we do not get ill? How Microbs Cause Disease: It takes about 1 hr 30 min.

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

11 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 12 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. Modes of infectious disease transmission

13 13 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 另外一種分類法

14 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 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 16 The environment in a cell Cytosol: pH=7 Phagosome: pH=6 Phagolysosome: pH=5

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

18 18 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) Infection cycle of Listeria monocytogenes.

19 19 Barrier systems Host cell membrane Taken up by phagocyte and resist killing Inhibitory molecule Mycobacterium Production Of antibody Degrade antibody IgA proteaseStreptococcus Antimicrobia cell-mediated response Activate T cells non-specifically and Productively SuperantigenStaphylococcus Antimicrobial immune response Vary presenting microbial antigen Switch on production of different antigens Borrelia Genetic recombination Streptococcus

20 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 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 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 23 Endotoxin: lipopolysaccharide Pseudomonas aeruginosa Fever Disseminated intravascular coagulation Septic shock death IL-1 TNF

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

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

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

27 27 Toxins: cause hyperactivation Vibrio cholerae

28 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 29 Toxins: affect on nerve-muscle transmission Ästhetik-Forum Berlin Block the release of ACH

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

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

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

33 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 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 35 Defence Microbial strategyMechanismExample Wash-outBind to cellAdhesinsNeisseria Inhibit ciliary activity Ciliotoxic/ Ciliostatic molecule Bordetella Streptococcus Ingestion and killing by phagocyte Disrupt Chemotaxis cytotoxic LeucocidinsStaphylococcus Inhibit phagocytosis CapsuleStreptococcus Inhibit lysosomal fusion Inhibitory molecule Mycobacterium MultiplyUnknownListeria EVASION STRATEGIES (1)

36 36 Defence Microbial strategy MechanismExample Restrict Fe- Lactoferrin Transferrin CompeteSiderophoreMycobacterium Escherichia Activate complement Interfere with alternative pathway Fully sialylated surface Neisseria InactivateElastasePseudomonas Antigen projects beyond surface Activation occurs at the wrong site Gram-negatives Interfere with complement- mediated phagocytosis C3b receptor competition, microbe and phagocyte Streptococcus EVASION STRATEGIES (2)

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. 37

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