RESUMO
[This corrects the article DOI: 10.1371/journal.ppat.1005907.].
RESUMO
Crohn's disease (CD) is a chronic inflammatory condition of diverse etiology. Exposure to foodborne pathogens causing acute gastroenteritis produces a long-term risk of CD well into the post-infectious period but the mechanistic basis for this ongoing relationship to disease onset is unknown. We developed two novel models to study the comorbidity of acute gastroenteritis caused by Salmonella Typhimurium or Citrobacter rodentium in mice colonized with adherent-invasive Escherichia coli (AIEC), a bacterial pathobiont linked to CD. Here, we show that disease activity in the post-infectious period after gastroenteritis is driven by the tissue-associated expansion of the resident AIEC pathobiont, with an attendant increase in immunopathology, barrier defects, and delays in mucosal restitution following pathogen clearance. These features required AIEC resistance to host defense peptides and a fulminant inflammatory response to the enteric pathogen. Our results suggest that individuals colonized by AIEC at the time of acute infectious gastroenteritis may be at greater risk for CD onset. Importantly, our data identify AIEC as a tractable disease modifier, a finding that could be exploited in the development of therapeutic interventions following infectious gastroenteritis in at-risk individuals.
Assuntos
Coinfecção/complicações , Doença de Crohn/microbiologia , Gastroenterite/complicações , Animais , Citrobacter rodentium , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/complicações , Escherichia coli , Infecções por Escherichia coli/complicações , Feminino , Imuno-Histoquímica , Inflamação/complicações , Inflamação/microbiologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Salmonelose Animal/complicações , Salmonella typhimuriumRESUMO
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 ß-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.