title: Host defense peptide resistance contributes to colonization and maximal intestinal pathology by Crohn's disease-associated adherent-invasive Escherichia coli.
abstract: Host defense peptides secreted by colonocytes and Paneth cells play a key role in innate host defenses in the gut. In Crohn's disease, the burden of tissue-associated Escherichia coli commonly increases at epithelial surfaces where host defense peptides concentrate, suggesting that this bacterial population might actively resist this mechanism of bacterial killing. Adherent-invasive E. coli (AIEC) is associated with Crohn's disease; however, the colonization determinants of AIEC in the inflamed gut are undefined. Here, we establish that host defense peptide resistance contributes to host colonization by Crohn's-associated AIEC. We identified a plasmid-encoded genomic island (called PI-6) in AIEC strain NRG857c that confers high-level resistance to α-helical cationic peptides and α- and β-defensins. Deletion of PI-6 sensitized strain NRG857c to these host defense molecules, reduced its competitive fitness in a mouse model of infection, and attenuated its ability to induce cecal pathology. This phenotype is due to two genes in PI-6, arlA, which encodes a Mig-14 family protein implicated in defensin resistance, and arlC, an OmpT family outer membrane protease. Implicit in these findings are new bacterial targets whose inhibition might limit AIEC burden and disease in the gut.
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: McPhee
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Cherrie L
authors.initials: CL
authors.lastname: Small
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Reid-Yu
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Brannon
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Moual
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada coombes@mcmaster.ca.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Coombes
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000276:immunology*; D003424:Crohn Disease / Q000382:microbiology*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D044404:Genomic Islands; D006801:Humans; D051379:Mice; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D029968:Escherichia coli Proteins; D037521:Virulence Factors; C000591390:ArlC protein, E coli; D010447:Peptide Hydrolases