CONTRIBUTION OF HIF2Α IN IRON BIOAVAILABILITY AGAINST ADHERENT INVASIVE ESCHERICHIA COLI INFECTION
Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. CD is strongly associated with expansion of the pathobiont adherent-invasive E.coli (AIEC) in the ileum, which plays an important role in CD pathogenesis. Comparative genomics revealed that AIEC genomes are enriched in iron acquisition genes relative to commensals. In line with this observation, iron has been described to be one of the key nutrients to favor AIEC virulence in vitro and our ongoing study demonstrated that AIEC infected-mice (LF82 strain) had a more persistent infection under iron supplementation.
To limit nutrient availability to pathogens, vertebrates have evolved diverse mechanisms, known as “nutritional immunity”. Based on our preliminary results, we hypothesize that the transcriptional factor HIF-2α, known to regulate iron absorption, could be involved in the nutritional immunity against AIEC by restricting iron bioavailability in the gut. We infected mice lacking HIF-2α specifically in the intestinal epithelium (KOHIF2IEC) and WT littermates with LF82 and observed that, 4 days post-infection, KOHIF2IEC failed to restrict LF82 infection compared to WT mice. This persistent infection in KOHIF2IEC was associated with a defect in DMT1 expression (qPCR and WB) and a decrease of FTL expression (WB) in the ileum of infected KOHIF2IEC mice compared to WT. Analyses of a cohort of AIEC-associated CD patients is ongoing to correlate AIEC infection and HIF-2α target gene expression in ileum.
These results, showing that HIF-2α is critical to limit AIEC colonization, suggest that targeting intestinal HIF-2α can serve as a potential therapeutic for AIEC-associated CD.
To limit nutrient availability to pathogens, vertebrates have evolved diverse mechanisms, known as “nutritional immunity”. Based on our preliminary results, we hypothesize that the transcriptional factor HIF-2α, known to regulate iron absorption, could be involved in the nutritional immunity against AIEC by restricting iron bioavailability in the gut. We infected mice lacking HIF-2α specifically in the intestinal epithelium (KOHIF2IEC) and WT littermates with LF82 and observed that, 4 days post-infection, KOHIF2IEC failed to restrict LF82 infection compared to WT mice. This persistent infection in KOHIF2IEC was associated with a defect in DMT1 expression (qPCR and WB) and a decrease of FTL expression (WB) in the ileum of infected KOHIF2IEC mice compared to WT. Analyses of a cohort of AIEC-associated CD patients is ongoing to correlate AIEC infection and HIF-2α target gene expression in ileum.
These results, showing that HIF-2α is critical to limit AIEC colonization, suggest that targeting intestinal HIF-2α can serve as a potential therapeutic for AIEC-associated CD.