Bacterial pathogenesis review by sammyc2007

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									• The plague doctor in clothing worn to protect from contagion, circa 1656. We are haunted by images of the horrors of disease and death, but with the current influx of data from microbial genomes, we can expect some answers to questions about how microorganisms have evolved, causing much fear. Apart from using these data to design new drugs and vaccines, we can also explore what the molecular signature of a microorganism may mean to a host population and predict more precisely the effects of intervention.

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A fact

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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

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Human and microbes
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Normal flora (beneficial or ignored):
GI track, skin, upper respiratory track

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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

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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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Big person in microbiology
Robert Koch,1843-1910, 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

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

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Infection/entry
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Ingestion (fecal-oral) Inhalation (respiratory) Trauma (burn) Arthropod bite (zoonoses: mosquito, flea, tick, Tsetse fly) Sexual transmission Needle stick (blood transfusion) Maternal-neonatal

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Bacteria, virus, fungi
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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

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Maternal-neonatal: HIV, HBV, Neisseria, etc.

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BC Yang

另外一種分類法

Modes of infectious disease transmission
• Contact transmission
– Direct contact (person-to-person): syphilis, gonorrhear, herpes – Indirect contact (fomites): 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

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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.

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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  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

Sammonella Mycobacteria
lysosomes

Legionella Chlamydia
Phagosomes

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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) For lecture only BC Yang

Barrier systems
Host cell membrane Production Of antibody Antimicrobia cell-mediated response Taken up by phagocyte and resist killing Degrade antibody Activate T cells non-specifically and Productively Inhibitory molecule IgA protease Mycobacterium

Streptococcus

Superantigen

Staphylococcus

Antimicrobial immune response

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

Borrelia

Streptococcus

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Virulence factors
• Factors enhance the ability of bacteria to cause disease An example of Pseudomonas aeruginosa
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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
BC Yang

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Pathogenic action of bacteria
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Tissue destruction: flesh-eating
bacteria: Necrotizing fasciitis

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Obstruction: Cytic fibrosis Toxins: bacterial components that directly
harm tissue or trigger disease symptoms

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Endotoxin: lipopolysaccharides Exotoxin: A-B toxins

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Immunopathogenesis
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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
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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

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Botulinum neutotoxin type B 肉毒素
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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.
BC Yang

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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

Tetanus toxin:

Patient number in Canada After antitoxin vaccine 1941-1995

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Toxins: affect on nerve-muscle transmission

The x-ray crystal structure for the tetanus toxin showing how the amino acid chain is folded.

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Superantigens

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

Known and suspected association of superantigens with human disease (1)
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Acute diseases
 Food poisoning:  Staph

SEs

TSS
TSST-1

Menstrual: TSST-1 Nonmenstrual: SEB, SEC,

 StrepTSS:SPe’s  Sudden

infant death syndrome: SEs?, SPe,s

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BC Yang

Known and suspected association of superantigens with human disease (2)
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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:
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EVASION STRATEGIES (1)
Defence Wash-out Microbial strategy Bind to cell Inhibit ciliary activity Mechanism Adhesins Ciliotoxic/ Ciliostatic molecule Example Neisseria Bordetella Streptococcus

Ingestion and killing by phagocyte

Disrupt Chemotaxis cytotoxic

Leucocidins

Staphylococcus

Inhibit phagocytosis Inhibit lysosomal fusion
Multiply
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Capsule Inhibitory molecule
Unknown

Streptococcus Mycobacterium
Listeria
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EVASION STRATEGIES (2)
Defence Restrict FeLactoferrin Transferrin Activate complement

Microbial strategy
Compete

Mechanism
Siderophore

Example
Mycobacterium Escherichia

Interfere with alternative pathway
Inactivate Antigen projects beyond surface

Fully sialylated surface
Elastase Activation occurs at the wrong site

Neisseria

Pseudomonas Gram-negatives

Interfere with complementmediated phagocytosis
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C3b receptor competition, microbe and phagocyte

Streptococcus

BC Yang


								
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