AIEC-dependent pathogenic Th17 cell transdifferentiation in Crohn’s disease is suppressed by rfaP and ybaT deletion - Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte
Article Dans Une Revue Gut microbes Année : 2024

AIEC-dependent pathogenic Th17 cell transdifferentiation in Crohn’s disease is suppressed by rfaP and ybaT deletion

Résumé

Mucosal enrichment of the Adherent-Invasive E. coli (AIEC) pathotype and the expansion of pathogenic IFN gamma-producing Th17 (pTh17) cells have been linked to Crohn's Disease (CD) pathogenesis. However, the molecular pathways underlying the AIEC-dependent pTh17 cell transdifferentiation in CD patients remain elusive. To this aim, we created and functionally screened a transposon AIEC mutant library of 10.058 mutants to identify the virulence determinants directly implicated in triggering IL-23 production and pTh17 cell generation. pTh17 cell transdifferentiation was assessed in functional assays by co-culturing AIEC-infected human dendritic cells (DCs) with autologous conventional Th17 (cTh17) cells isolated from blood of Healthy Donors (HD) or CD patients. AIEC triggered IL-23 hypersecretion and transdifferentiation of cTh17 into pTh17 cells selectively through the interaction with CD-derived DCs. Moreover, the chronic release of IL-23 by AIEC-colonized DCs required a continuous IL-23 neutralization to significantly reduce the AIEC-dependent pTh17 cell differentiation. The multi-step screenings of the AIEC mutant's library revealed that deletion of ybaT or rfaP efficiently hinder the IL-23 hypersecretion and hampered the AIEC-dependent skewing of protective cTh17 into pathogenic IFN gamma-producing pTh17 cells. Overall, our findings indicate that ybaT (inner membrane transport protein) and rfaP (LPS-core heptose kinase) represent novel and attractive candidate targets to prevent chronic intestinal inflammation in CD.
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hal-04868800 , version 1 (08-01-2025)

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G. Leccese, M. Chiara, I. Dusetti, D. Noviello, Elisabeth Billard, et al.. AIEC-dependent pathogenic Th17 cell transdifferentiation in Crohn’s disease is suppressed by rfaP and ybaT deletion. Gut microbes, 2024, 16 (1), pp.2380064. ⟨10.1080/19490976.2024.2380064⟩. ⟨hal-04868800⟩
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