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Abstract

Glycans play important roles in host-microbe interactions. Tissue-specific expression patterns of the blood group glycosyltransferase β-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2) are variable in wild mouse populations, and loss of B4galnt2 expression is associated with altered intestinal microbiota. We hypothesized that variation in B4galnt2 expression alters susceptibility to intestinal pathogens. To test this, we challenged mice genetically engineered to express different B4galnt2 tissue-specific patterns with a Salmonella Typhimurium infection model. We found B4galnt2 intestinal expression was strongly associated with bacterial community composition and increased Salmonella susceptibility as evidenced by increased intestinal inflammatory cytokines and infiltrating immune cells. Fecal transfer experiments demonstrated a crucial role of the B4galnt2-dependent microbiota in conferring susceptibility to intestinal inflammation, while epithelial B4galnt2 expression facilitated epithelial invasion of S. Typhimurium. These data support a critical role for B4galnt2 in gastrointestinal infections. We speculate that B4galnt2-specific differences in host susceptibility to intestinal pathogens underlie the strong signatures of balancing selection observed at the B4galnt2 locus in wild mouse populations.

Author Summary: Human blood groups are among the oldest known genetic polymorphisms. It has been proposed that blood group variation is a byproduct of pathogen-driven selection, including in the gastrointestinal tract where blood-group-related genes are often variably expressed. The B4galnt2 gene is responsible for the synthesis of the Sd(a)/Cad carbohydrate blood group antigen and displays variable tissue-specific expression patterns in wild mouse populations. Using an established model for Salmonella Typhimurium induced colitis, we found that loss of B4galnt2 expression in the intestinal epithelium decreases susceptibility to infection. These effects were strongly associated with the influence of B4galnt2 expression on the intestinal microbiota, whereby microbial diversity prior to infection was highly predictive of reduced inflammation and resistance to Salmonella Typhimurium infection. Additionally, B4galnt2 expression in blood vessels also distinctly influenced intestinal phenotypes and Salmonella susceptibility. These data lend new insights into bacterial community diversity as an “extended phenotype” that can be mediated by host genetic variation at blood-group-related genes. This work further provides strong experimental evidence in support of a scenario of complex selection on the B4galnt2 tissue-specific expression variants via host-microbe relationships and susceptibility to infectious disease.