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PECAM-1/CD31 is known to regulate inflammatory responses and exhibit pro and anti-inflammatory functions. This study was designed to determine the functional role of PECAM-1 in susceptibility to murine primary in vivo infection with Salmonella enterica var Typhimurium (S. Typhimurium) and in in vitro inflammatory responses of peritoneal macrophages. Lectin profiling showed that cellular and recombinant human PECAM-1-Ig contains high levels of mannose sugars and N-acetylglucosamine. Consistent with this carbohydrate pattern, both recombinant human and murine PECAM-1-Ig chimera were shown to bind S. Typhimurium in a dose-dependent manner in vitro. Using oral and faecal-oral transmission models of S. Typhimurium SL1344 infection, PECAM-1-/- mice were found to be more resistant to S. Typhimurium infection than wild-type (WT) C57BL/6 mice. While faecal shedding of S. Typhimurium was comparable between wild type and PECAM-1-/- mice, the PECAM-1 deficient mice had lower bacterial loads in systemic organs such as liver, spleen, and mesenteric lymph nodes compared to WT mice, suggesting that extraintestinal dissemination was reduced in the absence of PECAM-1. This reduced bacterial load correlated with reduced TNF, IL-6 and MCP levels in serum of PECAM-1-/- mice. Following in vitro stimulation of macrophages with either whole S. Typhimurium, LPS (TLR4 ligand) or polyI:C (TLR3 ligand), production of TNF and IL-6 was reduced by PECAM-1-/- macrophages. Together, these results suggest that PECAM-1 may have multiple functions in resistance to infection with S. Typhimurium, including binding to host cells, extraintestinal spread to deeper tissues and regulation of inflammatory cytokine production by infected macrophages.