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- Title
Bacterial Factors Associated with Lethal Outcome of Enteropathogenic Escherichia coli Infection: Genomic Case-Control Studies.
- Authors
Donnenberg, Michael S.; Hazen, Tracy H.; Farag, Tamer H.; Panchalingam, Sandra; Antonio, Martin; Hossain, Anowar; Mandomando, Inacio; Ochieng, John Benjamin; Ramamurthy, Thandavarayan; Tamboura, Boubou; Zaidi, Anita; Levine, Myron M.; Kotloff, Karen; Rasko, David A.; Nataro, James P.
- Abstract
Background: Typical enteropathogenic Escherichia coli (tEPEC) strains were associated with mortality in the Global Enteric Multicenter Study (GEMS). Genetic differences in tEPEC strains could underlie some of the variability in clinical outcome. Methods: We produced draft genome sequences of all available tEPEC strains from GEMS lethal infections (LIs) and of closely matched EPEC strains from GEMS subjects with non-lethal symptomatic infections (NSIs) and asymptomatic infections (AIs) to identify gene clusters (potential protein encoding sequences sharing ≥90% nucleotide sequence identity) associated with lethality. Results: Among 14,412 gene clusters identified, the presence or absence of 392 was associated with clinical outcome. As expected, more gene clusters were associated with LI versus AI than LI versus NSI. The gene clusters more prevalent in strains from LI than those from NSI and AI included those encoding proteins involved in O-antigen biogenesis, while clusters encoding type 3 secretion effectors EspJ and OspB were among those more prevalent in strains from non-lethal infections. One gene cluster encoding a variant of an NleG ubiquitin ligase was associated with LI versus AI, while two other nleG clusters had the opposite association. Similar associations were found for two nleG gene clusters in an additional, larger sample of NSI and AI GEMS strains. Conclusions: Particular genes are associated with lethal tEPEC infections. Further study of these factors holds potential to unravel the mechanisms underlying severe disease and to prevent adverse outcomes. Author Summary: Typical enteropathogenic E. coli (tEPEC) strains are associated with high mortality among infants with moderate-to-severe diarrhea, but most infants infected with tEPEC strains survive, and some have no symptoms. To investigate the bacterial factors associated with severe outcome, we determined the genomic sequences of 70 EPEC strains. Twenty four tEPEC strains came from children with lethal infections. The prevalence of each gene was compared to that in strains from 23 matched infants who had non-lethal symptomatic infection and to that in 23 matched infants who had asymptomatic infection. We identified 392 genes associated with outcome, some of which were more prevalent in strains from lethal infections, while others were less prevalent. The genes included several encoding potential virulence factors such as type 3 secreted effectors and enzymes involved in O-antigen synthesis. A PCR assay validated the association of groups of alleles encoding variants of the NleG ubiquitin ligase with clinical outcome. Further study of the factors associated with severe outcome could lead to novel diagnostic, therapeutic and prevention strategies.
- Subjects
ESCHERICHIA coli diseases; BEGOMOVIRUSES; ESCHERICHIA coli; CASE-control method; GENE clusters; NUCLEOTIDE sequence
- Publication
PLoS Neglected Tropical Diseases, 2015, Vol 9, Issue 5, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0003791