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SBM 2044: Lecture 10 AIMS: To provide
Brief introduction to E. coli: a versatile pathogen Overview of Enterotoxigenic E. coli (ETEC)
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Types of pathogenic E. coli
Intestinal Disease Enterotoxigenic E. coli (ETEC) Enteroaggregative E. coli (EAEC) Diffusely adhering E. coli (DAEC) Cholera-like watery diarrhoea Enteropathogenic E. coli (EPEC) Enterohaemorrhagic E. coli (EHEC) Colitis or haemorrhagic colitis Enteroinvasive E. coli (EIEC) Dysentery Extraintestinal Urinary tract/ pyelonephritis Uropathogenic E. coli (UPEC) Septicemia/ meningitis Septic E. coli strains
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EAEC First recognised in 1987 as distinct from other ETEC
Characteristic adhesion pattern in vitro reflects bacteria- bacteria (in addition to bacteria-host) adhesion Known virulence factors: AAF - Aggregative adherence fimbriae EAST-1 – EAEC heat stable toxin (similar to ETEC Sta) Pet – Plasmid-encoded enterotoxin mucus release Pic – role in intestinal colonisation? - various activities (mucinase, serum resistance, haemagglutinin)
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EAEC
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Strains displaying a distinct adhesion pattern
Enteroaggregrative E. coli (EAEC)
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Diffusely adhering E. coli (DAEC)
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DAEC Doubts about their importance as pathogens
Like EAEC and ETEC, appear to be heterogeneous group of strains, sharing certain common factors Four different adhesins identified – F1845 fimbriae & 3 non-fimbrial adhesins No significant information on potential toxins
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Enteropathogenic E. coli (EPEC)
First associated with diarrhoea in 1940s Major cause of watery diarrhoea in infants (< 6 months) Developing countries - endemic Developed countries – sporadic outbreaks in nurseries, paediatric wards, day centres, etc No detectable enterotoxin 1970s – first seen by EM to produce unique ‘attaching & effacing’ effects on enterocytes - producing unique lesions, now called A/E lesions
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EPEC interactions with epithelial cells
1. Initial (non-intimate) attachment 2. Intimate adhesion + effacement 3. Formation of pedestals Studies on mechanisms very limited until late 1980s
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EPEC interactions with epithelial cells
1. Initial (non-intimate) attachment 2. Intimate adhesion + effacement 3. Formation of pedestals NDP-phalloidin Intimin (EaeA) [OM protein] Actin rearrangements Involved: BFP
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Filaments ‘connecting’
Knutton et al (1998) EMBO Journal 17: Anti-EspA Activation of EPEC Type III secretion EM Filaments ‘connecting’ EPEC & host cells Immuno-gold antibodies Filaments composed of EspA
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EPEC Type III secretion filament EspB/D pore
Host cell membrane Deduced from studies combining: Mutants protein-protein binding Labelling with specific Ab Electron microscope EPEC OM EscC EPEC IM EscJ IM-associated ‘machinery’ Esc R,S,T,U,V,N,D
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Salmonella Type III ‘needles’
Kubori et al (1998) Science 280: Salmonella Type III ‘needles’ Similar ‘needles’ in EPEC, but Salmonella lack ‘filament’
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Tir: Translocated intimin receptor
EPEC: Kenny et al (1997) Cell 91: Remarkable discovery: Receptor for intimin (adhesin) is NOT a host cell protein It is an EPEC protein Translocated into host cell, phosphorylated, & inserted into the host cell membrane Tir: Translocated intimin receptor
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EPEC: Model of A/E Lesion Formation
Initial adhesion (via Bfp ) Quorum sensing ? Activation of Type III secretion filaments EspB/D pore Tir + ? signals translocated into host cell Tir- P Ca++ Intimate adhesion by EaeA to Tir- P Details of signalling still unclear Actin polymerization pedestal formation
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Enterohaemorrhagic E. coli (EHEC)
1982: two cases of severe food-poisoning (hamburgers) in USA associated with rare serotype of E. coli - O157:H7 1983: E. coli O157:H7 produces a Shiga-like toxin 1986: Like EPEC, O157:H7 produce A/E lesions ‘Enterohaemorrhagic E. coli’ (EHEC) first used in 1987 to describe what seemed to be a new type of pathogenic E. coli Main difference with EPEC is production of Shiga-toxin
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Origin of E. coli O157:H7 ? First isolated in US in now worldwide Quantitative population genetic studies (MLEE) O157:H7 isolates throughout world are single clone that emerged relatively recently - closely related to a much less virulent EPEC clone Both SLT-I & SLT-II genes encoded by bacteriophages, - could facilitate their transmission into new strains O157:H7 probably emerged when an EPEC strain (already capable of producing A/E lesions & diarrhoea) acquired slt phages, resulting in a dramatic increase in virulence
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A1 Shiga-toxins Typical A-B subunit toxins A1 subunit - N-glycosidase
27kDa Hydrolyses eucaryotic cell 28S rRNA S 4kDa A2 Pentameric B subunit (5 x 7kDa) B Receptor: glycolipid called Gb-3 Gb3-rich cells (particularly sensitive to STx) include vascular endothelial cells haemorrhage absorptive enterocytes diarrhoea kidney endothelial cells renal failure
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STx: Entry via RME retrograde transport via Golgi & ER
From: Groisman
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E. coli Shiga-toxins (STx)
Role in disease haemorrhage diarrhoea Local effects of toxin in colon Absorption – systemic effects Renal failure (10% - 20% cases) Haemolytic uraemic syndrome (HUS) Very serious – often fatal. S. dysenteriae E. coli producing high levels of STx Strongly associated:
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E. coli O157:H7 Clinical reports that therapy with certain antibiotics
increased severity of O157 infections WHY ? Some antibiotics (e.g. quinolones) inhibit DNA replication. DNA damage SOS response Induces lysogenic phage higher levels of STx in gut
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Urinary tract infections
(community acquired)
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source: UPEC in colon - harmless commensals
Uropathogenic E. coli (UPEC) Bloodstream septicemia Kidneys pyelonephritis Urine Flushing Ureter ureteritis Bladder cystitis Removes non-adherent bacteria Urethra urethritis Ascending infection source: UPEC in colon - harmless commensals
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Uropathogenic E. coli - virulence mechanisms
Adhesion - essential to avoid removal by urine Survival - studies limited to some aspects only iron-acquisition (siderophores) capsules (evasion of host defences) - more important in kidney than lower UT - critical if organism enters bloodstream Toxicity inflammation LPS (endotoxin) a-haemolysin (membrane damaging toxin) cytotoxic necrotizing factor 1(CNF-1)
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E. coli a-haemolysin (HlyA)
Membrane-damaging toxin: Produces small hydrophilic pores in mammalian cells high concentrations ion leakage osmotic lysis lower concentrations more subtle cytotoxic effects Produced by about: 50% strains from upper UTI – most tissue damage Note: Do not confuse with “a-haemolysins” produced by other species 30% strains from lower UTI 10% GI strains Suggests strong association with UTI
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E. coli a-haemolysin (HlyA)
Role in kidney damage supported by studies in mouse models: Parent strain expressing P fimbriae + HlyA colonized bladder + kidneys 66% mice died Isogenic mutant expressing P fimbriae, but not HlyA colonized as above, but no apparent damage or deaths Note: Do not confuse with “a-haemolysins” produced by other species
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Cytotoxic necrotizing factor 1 (CNF-1)
Large (110,000Da) protein, produced by ca 30% UPEC Studies in vitro: epithelial cells: rearrangements of actin filaments & membrane ruffling bladder cells: reduced migration & proliferation – - impede repair of damage bladder ?? No direct evidence for role in UTI
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