Absence of Platelet Endothelial Cell Adhesion Molecule - 1 ( PECAM - 1 / CD 31 ) in vivo 2 increases resistance to oral Salmonella enterica serovar Typhimurium infection in mice

37 38 PECAM-1/CD31 is known to regulate inflammatory responses and exhibit pro and 39 anti-inflammatory functions. This study was designed to determine the functional role of 40 PECAM-1 in susceptibility to murine primary in vivo infection with Salmonella enterica var 41 Typhimurium (S. Typhimurium) and in in vitro inflammatory responses of peritoneal 42 macrophages. Lectin profiling showed that cellular and recombinant human PECAM-1-Ig 43 contains high levels of mannose sugars and N-acetylglucosamine. Consistent with this 44 carbohydrate pattern, both recombinant human and murine PECAM-1-Ig chimera were 45 shown to bind S. Typhimurium in a dose-dependent manner in vitro. Using oral and faecal46 oral transmission models of S. Typhimurium SL1344 infection, PECAM-1 mice were found 47 to be more resistant to S. Typhimurium infection than wild-type (WT) C57BL/6 mice. While 48 faecal shedding of S. Typhimurium was comparable between wild type and PECAM-1 49 mice, the PECAM-1 deficient mice had lower bacterial loads in systemic organs such as 50 liver, spleen, and mesenteric lymph nodes compared to WT mice, suggesting that 51 extraintestinal dissemination was reduced in the absence of PECAM-1. This reduced 52 bacterial load correlated with reduced TNF, IL-6 and MCP levels in serum of PECAM-1 53 mice. Following in vitro stimulation of macrophages with either whole S. Typhimurium, 54 LPS (TLR4 ligand) or polyI:C (TLR3 ligand), production of TNF and IL-6 was reduced by 55 PECAM-1 macrophages. Together, these results suggest that PECAM-1 may have multiple 56 functions in resistance to infection with S. Typhimurium, including binding to host cells, 57 extraintestinal spread to deeper tissues and regulation of inflammatory cytokine production 58 by infected macrophages. 59