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B4galnt2-mediated host glycosylation influences the susceptibility to Citrobacter rodentium infection.

ABSTRACT: Histo-blood group antigens in the intestinal mucosa play important roles in host-microbe interactions and modulate the susceptibility to enteric pathogens. The B4galnt2 gene, expressed in the GI tract of most mammals, including humans, encodes a beta-1,4-N-acetylgalactosaminyltransferase enzyme which catalyzes the last step in the biosynthesis of the Sd(a) and Cad blood group antigens by adding an N-acetylgalactosamine (GalNAc) residue to the precursor molecules. In our study, we found that loss of B4galnt2 expression is associated with increased susceptibility to Citrobacter rodentium infection, a murine model pathogen for human enteropathogenic Escherichia coli. We observed increased histopathological changes upon C. rodentium infection in mice lacking B4galnt2 compared to B4galnt2-expressing wild-type mice. In addition, wild-type mice cleared the C. rodentium infection faster than B4galnt2^-/- knockout mice. It is known that C. rodentium uses its type 1 fimbriae adhesive subunit to bind specifically to D-mannose residues on mucosal cells. Flow cytometry analysis of intestinal epithelial cells showed the absence of GalNAc-modified glycans but an increase in mannosylated glycans in B4galnt2-deficient mice compared to B4galnt2-sufficient mice. Adhesion assays using intestinal epithelial organoid-derived monolayers revealed higher C. rodentium adherence to cells lacking B4galnt2 expression compared to wild-type cells which in turn was reduced in the absence of type I fimbriae. In summary, we show that B4galnt2 expression modulates the susceptibility to C. rodentium infection, which is partly mediated by fimbriae-mannose interaction.

SUBMITTER: Suwandi A

PROVIDER: S-EPMC9403859 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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B4galnt2-mediated host glycosylation influences the susceptibility to <i>Citrobacter rodentium</i> infection.

Suwandi Abdulhadi A Alvarez Kris Gerard KG Galeev Alibek A Steck Natalie N Riedel Christian U CU Puente José Luis JL Baines John F JF Grassl Guntram A GA

Frontiers in microbiology 20220811

Histo-blood group antigens in the intestinal mucosa play important roles in host-microbe interactions and modulate the susceptibility to enteric pathogens. The <i>B4galnt2</i> gene, expressed in the GI tract of most mammals, including humans, encodes a beta-1,4-N-acetylgalactosaminyltransferase enzyme which catalyzes the last step in the biosynthesis of the Sd(a) and Cad blood group antigens by adding an N-acetylgalactosamine (GalNAc) residue to the precursor molecules. In our study, we found th ...[more]

PMID: 36033875

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Project description:Microbial sensing plays essential roles in the innate immune response to pathogens. In particular, NLRP3 forms a multiprotein inflammasome complex responsible for the maturation of interleukin (IL)-1?. Our aim was to delineate the role of the NLRP3 inflammasome in macrophages, and the contribution of IL-1? to the host defense against Citrobacter rodentium acute infection in mice. Nlrp3(-/-) and background C57BL/6 (WT) mice were infected by orogastric gavage, received IL-1? (0.5 µg/mouse; ip) on 0, 2, and 4 days post-infection (DPI), and assessed on 6 and 10 DPI. Infected Nlrp3(-/-) mice developed severe colitis; IL-1? treatments reduced colonization, abrogated dissemination of bacteria to mesenteric lymph nodes, and protected epithelial integrity of infected Nlrp3(-/-) mice. In contrast, IL-1? treatments of WT mice had an opposite effect with increased penetration of bacteria and barrier disruption. Microscopy showed reduced damage in Nlrp3(-/-) mice, and increased severity of disease in WT mice with IL-1? treatments, in particular on 10 DPI. Secretion of some pro-inflammatory plasma cytokines was dissipated in Nlrp3(-/-) compared to WT mice. IL-1? treatments elevated macrophage infiltration into infected crypts in Nlrp3(-/-) mice, suggesting that IL-1? may improve macrophage function, as exogenous administration of IL-1? increased phagocytosis of C. rodentium by peritoneal Nlrp3(-/-) macrophages in vitro. As well, the exogenous administration of IL-1? to WT peritoneal macrophages damaged the epithelial barrier of C. rodentium-infected polarized CMT-93 cells. Treatment of Nlrp3(-/-) mice with IL-1? seems to confer protection against C. rodentium infection by reducing colonization, protecting epithelial integrity, and improving macrophage activity, while extraneous IL-1? appeared to be detrimental to WT mice. Together, these findings highlight the importance of balanced cytokine responses as IL-1? improved bacterial clearance in Nlrp3(-/-) mice but increased tissue damage when given to WT mice.

Dataset Information

B4galnt2-mediated host glycosylation influences the susceptibility to Citrobacter rodentium infection.

Publications

B4galnt2-mediated host glycosylation influences the susceptibility to <i>Citrobacter rodentium</i> infection.

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