Host and pathogen determinants of verocytotoxin-producing Escherichia coli -associated hemolytic uremic syndrome
2009; Elsevier BV; Volume: 75; Linguagem: Inglês
10.1038/ki.2008.608
ISSN1523-1755
Autores Tópico(s)Viral gastroenteritis research and epidemiology
ResumoVerocytotoxin (VT)-producing Escherichia coli (VTEC) infection is associated with a spectrum of clinical manifestations that includes diarrhea, hemorrhagic colitis, and the hemolytic uremic syndrome (HUS). The occurrence of HUS in a minority of individuals in outbreaks of VTEC infection is a function of several pathogen and host factors. Pathogen factors include the inoculum size and serotype of the infecting strain, horizontally acquired genetic elements known as pathogenicity islands, and probably the VT type. Host factors that increase the risk of developing HUS include age, pre-existing immunity, gastric acidity, the use of antibiotics and anti-motility agents, and, probably, stress and genetic factors that modulate host response to infection, such as innate immunity and toxin receptor type, expression, and distribution. A better understanding of the pathogen and host determinants of HUS can aid in the development of more effective public health strategies to reduce the risk of developing HUS. Verocytotoxin (VT)-producing Escherichia coli (VTEC) infection is associated with a spectrum of clinical manifestations that includes diarrhea, hemorrhagic colitis, and the hemolytic uremic syndrome (HUS). The occurrence of HUS in a minority of individuals in outbreaks of VTEC infection is a function of several pathogen and host factors. Pathogen factors include the inoculum size and serotype of the infecting strain, horizontally acquired genetic elements known as pathogenicity islands, and probably the VT type. Host factors that increase the risk of developing HUS include age, pre-existing immunity, gastric acidity, the use of antibiotics and anti-motility agents, and, probably, stress and genetic factors that modulate host response to infection, such as innate immunity and toxin receptor type, expression, and distribution. A better understanding of the pathogen and host determinants of HUS can aid in the development of more effective public health strategies to reduce the risk of developing HUS. Verocytotoxin (VT)-producing Escherichia coli (VTEC) infection is associated with a spectrum of clinical manifestations that includes diarrhea, hemorrhagic colitis, and the hemolytic uremic syndrome (HUS).1Karmali M.A. Petric M. Steele B.T. et al.Sporadic cases of hemolytic-uremic syndrome associated with fecal cytotoxin and cytotoxin-producing Escherichia coli.Lancet. 1983; 1: 619-620Abstract PubMed Scopus (814) Google Scholar, 2Karmali M.A. Petric M. 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Shen S. et al.Association of genomic O island 122 of Escherichia coli EDL 933 with verocytotoxin-producing Escherichia coli seropathotypes that are linked to epidemic and/or serious disease.J Clin Microbiol. 2003; 41: 4930-4940Crossref PubMed Scopus (388) Google Scholar suggesting that bacterial factors other than VTs also contribute to the development of HUS. The whole genome sequences of two E. coli O157:H7 outbreak strains6Hayashi T. Makino K. Ohnishi M. et al.Complete genome sequence of enterohemorrhagic Escherichia coli O157:H7 and genomic comparison with a laboratory strain K-12.DNA Res. 2001; 8: 11-22Crossref PubMed Scopus (1047) Google Scholar, 7Perna N.T. Plunkett III, G. 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Lacher D.W. et al.Evolution of genomic content in the stepwise emergence of Escherichia coli O157:H7.J Bacteriol. 2005; 187: 1783-1791Crossref PubMed Scopus (169) Google Scholar Some O157:H7 strains appear to be non-pathogenic for humans,10Kim J. Nietfeldt J. Benson A.K. Octamer-based genome scanning distinguishes a unique subpopulation of Escherichia coli O157:H7 strains in cattle.Proc Natl Acad Sci USA. 1999; 96: 13288-13293Crossref PubMed Scopus (148) Google Scholar whereas others may have developed an enhanced propensity to cause HUS.11Manning S.D. Motiwala A.S. Springman A.C. et al.Variation in virulence among clades of Escherichia coli O157:H7 associated with disease outbreaks.Proc Natl Acad Sci USA. 2008; 105: 4868-4873Crossref PubMed Scopus (349) Google Scholar The purpose of this paper is to review the disease mechanisms of VTEC with special reference to the pathogen and host determinants of HUS. The low infectious dose of E. coli O157:H7 (∼100–500 organisms)12Griffin P.M. Epidemiology of shiga toxin-producing Escherichia coli infections in humans in the United States.in: Kaper J.B. O'Brien A.D. Escherichia coli O157:H7 and Other Shiga Toxin-Producing E. coli Strains. ASM Press, Washington, DC1998: 15-22Google Scholar is a major determinant of its ability to cause severe and epidemic disease, although the underlying mechanisms for this are not fully understood. Gastric acid is an important first barrier to ingested pathogens, and thus the reported resistance of the organism to gastric acid13Lin J. Smith M.P. Chapin K.C. et al.Mechanisms of acid resistance in enterohemorrhagic Escherichia coli.Appl Environ Microbiol. 1996; 62: 3094-3100Crossref PubMed Google Scholar helps to explain the low infectious dose. Over 200 different serotypes of VTEC have been associated with human disease, but outbreaks of disease and HUS have been associated only with serotype O157:H7 and occasionally with a handful of non-O157 serotypes, such as O26:H11, O103:H2, O111:NM, O121:H19, and O145:NM. The explanation for why only a restricted number of serotypes are associated with HUS has been unclear. However, growing evidence suggests that a major pathogen determinant of serotypes that are associated with outbreaks and HUS is the presence of specific horizontally acquired gene cassettes known as PAIs. The best known PAI is the locus of enterocyte effacement (LEE),14Jerse A.E. Yu J. Tall B.D. et al.A genetic locus of enteropathogenic Escherichia coli necessary for the production of attaching and effacing lesions on tissue culture cells.Proc Natl Acad Sci USA. 1990; 87: 7839-7843Crossref PubMed Scopus (930) Google Scholar, 15McDaniel T.K. Jarvis K.G. 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Arzenio R.A. et al.Attaching and effacing activities of rabbit and human enteropathogenic Escherichia coli in pig and rabbit intestines.Infect Immun. 1983; 41: 1340-1351Crossref PubMed Google Scholar LEE encodes the structural, accessory, and effector molecules of a type III secretion system (TTSS),19Foubister V. Rosenshine I. Donnenberg M.S. et al.The eaeB gene of enteropathogenic Escherichia coli is necessary for signal transduction in epithelial cells.Infect Immun. 1994; 62: 3038-3040PubMed Google Scholar which is a macromolecular complex spanning both bacterial membranes that is used by many Gram-negative bacterial pathogens to inject virulence factors directly into host cells to subvert host cellular function for the benefit of the pathogen.20Hueck C.J. Type III protein secretion systems in bacterial pathogens of animals and plants.Microbiol Mol Biol Rev. 1998; 62: 379-433Crossref PubMed Google Scholar However, LEE cannot alone be the determinant of outbreaks and HUS because several VTEC serotypes that are not associated with HUS and outbreaks are also LEE-positive. On the other hand, the type III secretion system also secretes many other effector molecules, encoded outside the LEE on other PAIs, that are referred to as non-LEE-encoded effectors (Nle's).21Deng W. Puente J.L. Gruenheid S. et al.Dissecting virulence: systematic and functional analyses of a pathogenicity island.Proc Natl Acad Sci USA. 2004; 101: 3597-3602Crossref PubMed Scopus (500) Google Scholar, 22Garmendia J. Frankel G. Crepin V.F. 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Mascarenhas M. et al.Bacterial genetic determinants of non-O157 STEC outbreaks and hemolytic-uremic syndrome after infection.J Infect Dis. 2006; 194: 819-827Crossref PubMed Scopus (96) Google Scholar It is thus becoming clear that a number of PAIs, including LEE, play a major role in enhancing the ability of various serotypes to cause HUS. It should be noted that some O157:H7 strains appear to be non-pathogenic for humans,10Kim J. Nietfeldt J. Benson A.K. Octamer-based genome scanning distinguishes a unique subpopulation of Escherichia coli O157:H7 strains in cattle.Proc Natl Acad Sci USA. 1999; 96: 13288-13293Crossref PubMed Scopus (148) Google Scholar whereas others may have developed an enhanced propensity to cause HUS.11Manning S.D. Motiwala A.S. Springman A.C. et al.Variation in virulence among clades of Escherichia coli O157:H7 associated with disease outbreaks.Proc Natl Acad Sci USA. 2008; 105: 4868-4873Crossref PubMed Scopus (349) Google Scholar However, the genetic basis for these observations has not been fully elucidated. Human VTEC strains elaborate at least four potent bacteriophage-mediated VTs: VT1, VT2, VT2c, and VT2d.16Nataro J.P. Kaper J.B. Diarrheagenic Escherichia coli.Clin Microbiol Rev. 1998; 11: 142-201Crossref PubMed Google Scholar, 25Melton-Celsa A.R. O'Brien A.D. Structure, biology, and relative toxicity of Shiga toxin family members for cells and animals.in: Kaper J.B. O'Brien A.D. Escherichia coli O157:H7 and Other Shiga Toxin-Producing E. coli Strains. ASM Press, Washington, DC1998: 121-128Google Scholar Each may be present alone, or in a combination of two or three different VTs. 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Endocytosis, intracellular transport, and cytotoxic action of Shiga toxin and ricin.Physiol Rev. 1996; 76: 949-966PubMed Google Scholar They then target the endoplasmic reticulum through the Golgi by a process termed 'retrograde transport.'31Sandvig K. van Deurs B. Endocytosis, intracellular transport, and cytotoxic action of Shiga toxin and ricin.Physiol Rev. 1996; 76: 949-966PubMed Google Scholar Inside the host cell, the A subunit is proteolytically nicked to give an enzymatically active A1 fragment,26O'Brien A.D. Tesh V.L. Donohue-Rolfe A. et al.Shiga toxin: biochemistry, genetics, mode of action and role in pathogenesis.Curr Top Microbiol Immunol. 1992; 180: 65-94Crossref PubMed Scopus (327) Google Scholar which cleaves the N-glycosidic bond at position A4324 of the 28S rRNA of the 60S ribosomal subunit.32Endo Y. Tsurugi K. 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ASM Press, Washington, DC1998: 287-292Google Scholar Cytokines, especially TNF (tumor necrosis factor)-α and IL1 (interleukin 1)-β, potentiate toxin action through upregulation of the cellular receptor, Gb3. It is thought that increased cytokine production might be the result of VT action on monocytes.33Monnens L. Savage C.O. Taylor C.M. Pathophysiology of hemolytic-uremic syndrome.in: Kaper J.B. O'Brien A.D. Escherichia coli O157:H7 and Other Shiga Toxin-Producing E. coli Strains. ASM Press, Washington, DC1998: 287-292Google Scholar The different VTs show differences in specific binding affinities and cytotoxic activities in cell culture,26O'Brien A.D. Tesh V.L. Donohue-Rolfe A. et al.Shiga toxin: biochemistry, genetics, mode of action and role in pathogenesis.Curr Top Microbiol Immunol. 1992; 180: 65-94Crossref PubMed Scopus (327) Google Scholar, 34Head S.C. Karmali M.A. Lingwood C.A. 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The highest age-specific frequency of VTEC-associated HUS is in infants and young children.43Rowe P.C. Orrbine E. Wells G.A. et al.Epidemiology of hemolytic-uremic syndrome in Canadian children from 1986 to 1988. The Canadian Pediatric Kidney Disease Reference Centre.J Pediatr. 1991; 119: 218-224Abstract Full Text PDF PubMed Scopus (159) Google Scholar The age-specific frequency declines with increasing age and increases again in the elderly. This age distribution of HUS correlates inversely with the age-specific frequency of antibodies to VT1 and VT2,44Karmali M.A. Mascarenhas M. Petric M. et al.Age-specific frequencies of antibodies to Escherichia coli Verocytotoxins (Shiga Toxins) 1 and 2 among urban and rural populations in Southern Ontario.J Infect Dis. 2003; 188: 1724-1729Crossref PubMed Scopus (33) Google Scholar suggesting that pre-existing immunity plays a significant role in host resistance to HUS. Gastric acidity is an important initial host barrier to ingested pathogens. Evidence for its protective role against E. coli O157:H7 infection is that individuals with low gastric acidity (for example, owing to gastrectomy or pernicious anemia) are at a significantly higher risk of developing HUS than those with normal physiological gastric function.45Carter A.O. Borczyk A.A. Carlson J.A.K. et al.A severe outbreak of Escherichia coli O157:H7-associated hemorrhagic colitis in a nursing home.N Engl J Med. 1987; 317: 1496-1500Crossref PubMed Scopus (426) Google Scholar The genes that regulate colonization of the bowel by E. coli O157:H7 may be modulated by hormone-like soluble factors produced by other bacterial cells in a density-dependent manner in a process referred to as 'quorum sensing.'47Clarke M.B. Hughes D.T. Zhu C. et al.The QseC sensor kinase: a bacterial adrenergic receptor.Proc Natl Acad Sci USA. 2006; 103: 10420-10425Crossref PubMed Scopus (445) Google Scholar Interestingly, the quorum sensing pathway can also be activated by host stress hormones such as epinephrine and norepinephrine.48Hughes D.T. Sperandio V. Inter-kingdom signalling: communication between bacteria and their hosts.Nat Rev Microbiol. 2008; 6: 111-120Crossref PubMed Scopus (539) Google Scholar, 49Sperandio V. Torres A.G. Jarvis B. et al.Bacteria–host communication: the language of hormones.Proc Natl Acad Sci USA. 2003; 100: 8951-8956Crossref PubMed Scopus (678) Google Scholar The pathophysiological implications of this, as well as the possible role of stress as a risk factor for severe disease, are under study. Host genetic factors may influence host–pathogen interactions, including the innate immune response to infection and the nature of the toxin–cell interaction. However, knowledge of this is in its infancy. A better understanding of the pathogen and host determinants of HUS can aid in the development of more effective public health strategies to reduce the risk of developing HUS. For example, knowledge of specific pathogen risk factors for HUS can contribute to the identification of potential vaccine candidates as well as to the improvement of diagnosis and surveillance of high-risk VTEC to allow for more rapid recognition and containment of outbreaks, thus reducing morbidity and mortality. Similarly, knowledge of host risk factors, such as the use of antibiotics and anti-motility agents, can help to modify behaviors that can mitigate the risk of HUS. The author has declared no financial interests.
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