Gastrointestinal Infections

E. coli
1. EHEC
  1. 0157:H7, Gram -ve rod, facultative anaerobe
  2. Bacteriophage-derived Shiga toxins (Stx1/Stx2)
    1. AB5
    2. Bind to glycolipid Gb3 (globotriacylceramide), many in renal epithelium
    3. RNA N-glycosidase, ie cleaves nucleobases from ribosomal RNA & inhibits protein synthesis
    4. Haemolysin causes Haemolytic Uraemic Syndrome (HUS), Renal failure
  3. Incubation: 2-6 days, Infection: 1 week
  4. Identification: MALDITOF, serology, selective culture medium, Lactose/Sorbitol fermentor
  5. Burgers!!
  6. Type III secretion system- see EPEC
2. ETEC
  1. Heat-labile or Stable Toxin
    1. AB5, acitvates adenyl cyclase, cAMP, activates CFTR, K+/Na+/Cl- ions enter cell, water flows out, diarrhoea!
  2. CFA1 fimbriae
3. Type I pilus
  1. Regulated expression, ie Phase Variation
    1. Environmental signal, fimS (invertible, cis, promoter), fimB (off switch), fimE (on switch), express fimA (pilus rod)/fimC (chaperone)/fimD (OM usher)
      1. New findings: HibF another fimS inverter, on switch
      2. Signals: pH, temp, osmolarity, nutrient availability
  2. Highly immunogenic
  3. Motility
4. (a)EPEC
  1. "Attaching & Effacing", localised (EPEC) vs diffuse (aEPEC)
  2. Pedestal Formation
    1. Encoded on LEE (Locus of Enterocyte Effacement)
      1. Pathogenicity Island
      2. EHEC, EPEC, aEPEC
      3. Type III Secretion System injects effector proteins
        E.g. Injects Tir into membrane, Centre binds intimin, N+C cytoplasmic, phosphorylated by kinases, WASP cascade, actin polymerisation
        E.g. EspB (homologous to YopD), binds alpha1 antitrypsin, alpha catenin (disrupting adherence junctions), myosin-1c (inhibiting phagocytosis)
        Functional redundancy, e.g. EspH+EspJ antagonise (opsono-) phagocytosis
        E.g. NleH, anti-apoptotic factor
      4. Acquired via HGT, located on tRNA
      5. Subverts cell processes to colonise/multiply
  3. EAF plasmid (EPEC Adherence Factor), encodes bundle-forming pilus (not in aEPEC)
5. Case Study: Germany Outbreak 2011
  1. E.coli 0104:H4
  2. EHEC with virulence genes from EAEC
  3. Diagnostics unsuitable, bias for 0157 (no 0157 agglutination, ferments sorbital)
  4. Suggested diagnostics: Selective agar (Cefuxime tellurite sorbitol MacConkey agar) --> pink colonies, PCR (intimin target)
  5. Future diagnostics: multiplex PCR, microarray
Campylobacter
1. C. jejuni
  1. Gram -ve, curved/spiral/s-shaped
  2. Motile (1-2 flagella)
  3. Oxidase +ve
  4. Non-fermentor
  5. Incubation: 2-10 days, infection: 1 week
  6. Autoimmune response possible- similar motif to host proteins--> reactive arthritis or Guillan-Barre Syndrome (myelin, demyelination, paralysis, 019)
  7. Zipper vs Trigger model of cell entry. CapF, CiaB, Type III secretion system?
2. C. upsaliensis
3. C. coli
4. C. lari
5. C. fetus
6. C. rectus
7. Mostly poultry
8. Pathogenesis
  1. No suitable non-primate models
  2. Capsular Polysaccharide: GI/Cell Invasion
  3. LOS: adhesion, protection from complement
  4. Potential Vaccine
    1. Against Serotype HS15
    2. Multivalent, CPS
    3. CPS-CRM conjugate
    4. Ab response in mice but no challenge experiments
  5. LuxS Operon
  6. Newly Found Virulence Factors
Salmonella
1. Enteritis
  1. S. enterica serovar typhimurium
  2. S. enterica serovar enteritidis
  3. G-ve, bacillus, facultative anaerobe
  4. Non-fermentor, oxidase -ve
2. Pathogenicity
  1. Pathogenicity Islands
    1. spv locus, pSLT plasmid
    2. SPI1, inv genes
      1. Type III Secretion System
        Injects Effector Proteins for Membrane Ruffling
        SptP (tyrosine phosphatase, mimics signal transduction)
        SipA (binds actin, prevents depolymerisation)
        SopE (activates Rac/Cdc42 for actin polymerisation)
  2. 103-106 infectious dose (high)
  3. M cells in lamia propia engulfs bacterium, to present to B+T cells BUT survives/multiplies & stimulates inflammatory response (incl. cAMP)
  4. Fimbriae
    1. Type 1 and/or 3 (fim genes)
    2. Plasmid encoded (pef genes)
    3. Long polar (lpf genes)
    4. Thin aggregative (agf genes)
  5. OMP Porins
  6. Complement evasion
    1. Rck, adhesion factor, inhibits MAC
    2. Pgte, protease, cleaves C3, C4 & C5
Shigella
1. S. flexneri
2. S. sonnei
3. S. dysenteriae
4. S. boydii
5. Usually water contamination
6. Pathogenesis
  1. OspF (MAPK phosphothreonine lyase), inactivates MAPK--> dampens inflammatory response
  2. Targets Ubiquitin
    1. OspI, deaminates Ubc13 (ubiquitin conjugating enzyme 13)--> dampens NF-KB response
    2. IpaH (ubiquitin ligase)
    3. Ubiquitin Function: label proteins for destruction or other cell functions, e.g INFLAMMATORY RESPONSE
7. Peak (outbreak?) in 1992
8. Low infectious dose, only 10 bacteria can cause infection!
9. Incubation: 16-72hrs, infection: 2 weeks
10. Haemolysin
Rotavirus
1. dsRNA virus
2. 7 serotypes: A-G, A most common
3. No effective antiviral therapy, new targets researched
  1. Lipogenesis inhibitors reduce viral replication, e.g. triacsin C (fungi) analogues inhibit ACSL, analogue E=amino-benzinoic acid ED50=0.1um
    1. IN VITRO!!
4. Damages vili
5. Malabsorption of fluid
6. Infection 6hrs-3days
7. NSP4, enterotoxic effects
8. New vaccine introduced in UK: Rotarix (GSK), attenuated live oral vaccine, for 6+wks then 4wks later, since v common in <5yr olds
9. Vomiting & diarrhoea
Norovirus
1. RNA virus
2. Infection: 24-48hrs
3. Vomiting & diarrhoea
4. No animal model & difficult to culture
5. Five genogroups: GI-GV, GI &GII most common
6. Highly contagious

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