title: Mapping of genetic loci that modulate differential colonization by Escherichia coli O157:H7 TUV86-2 in advanced recombinant inbred BXD mice.
abstract: BACKGROUND
  Shiga toxin (Stx)-producing E. coli (STEC) are responsible for foodborne outbreaks that can result in severe human disease. During an outbreak, differential disease outcomes are observed after infection with the same STEC strain. One question of particular interest is why some infected people resolve infection after hemorrhagic colitis whereas others progress to the hemolytic uremic syndrome (HUS). Host age and infection dose have been implicated; however, these parameters do not appear to fully account for all of the observed variation in disease severity. Therefore, we hypothesized that additional host genetic factors may play a role in progression to HUS.
  
  
  RESULTS
  To mimic the genetic diversity in the human response to infection by STEC, we measured the capacity of an O157:H7 outbreak isolate to colonize mouse strains from the advanced recombinant inbred (ARI) BXD panel. We first infected the BXD parental strains C57BL/6 J (B6) and DBA/2 J (D2) with either 86-24 (Stx2a+) or TUV86-2, an Stx2a-negative isogenic mutant. Colonization levels were determined in an intact commensal flora (ICF) infection model. We found a significant difference in colonization levels between the parental B6 and D2 strains after infection with TUV86-2 but not with 86-24. This observation suggested that a host factor that may be masked by Stx2a affects O157:H7 colonization in some genetic backgrounds. We then determined the TUV86-2 colonization levels of 24 BXD strains in the ICF model. We identified several quantitative trait loci (QTL) associated with variation in colonization by correlation analyses. We found a highly significant QTL on proximal chromosome 9 (12.5-26.7 Mb) that strongly predicts variation in colonization levels and accounts for 15-20 % of variance. Linkage, polymorphism and co-citation analyses of the mapped region revealed 36 candidate genes within the QTL, and we identified five genes that are most likely responsible for the differential colonization.
  
  
  CONCLUSIONS
  The identification of the QTL on chromosome 9 supports our hypothesis that individual genetic makeup affects the level of colonization after infection with STEC O157:H7.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Russo
authors.affiliation: University of Cincinnati College of Medicine & Cincinnati VA Medical Center, Cincinnati, OH, USA.|Department Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Nourtan F
authors.initials: NF
authors.lastname: Abdeltawab
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Alison D
authors.initials: AD
authors.lastname: O'Brien
authors.affiliation: University of Cincinnati College of Medicine & Cincinnati VA Medical Center, Cincinnati, OH, USA.|Department of Basic Biomedical Sciences, University of North Dakota, Grand Forks, ND, USA.
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. angela.melton-celsa.ctr@usuhs.edu.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Melton-Celsa
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D004274:DNA, Recombinant / Q000235:genetics*; D019453:Escherichia coli O157 / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D008040:Genetic Linkage; D014644:Genetic Variation; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D040641:Quantitative Trait Loci / Q000235:genetics*; D022621:Shiga Toxin / Q000378:metabolism; D013045:Species Specificity; D013997:Time Factors
chemical_list: D004274:DNA, Recombinant; D022621:Shiga Toxin