| Autor: |
Leccese, G., Chiara, M., Dusetti, I., Noviello, D., Billard, E., Bibi, A., Conte, G., Consolandi, C., Vecchi, M., Conte, MP, Barnich, N., Caprioli, F., Facciotti, F., Paroni, M. |
| Zdroj: |
Gut Microbes; December 2024, Vol. 16 Issue: 1 |
| Abstrakt: |
ABSTRACTMucosal enrichment of the Adherent-Invasive E. coli(AIEC) pathotype and the expansion of pathogenic IFNγ-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 ybaTor rfaPefficiently hinder the IL-23 hypersecretion and hampered the AIEC-dependent skewing of protective cTh17 into pathogenic IFNγ-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. |
| Databáze: |
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