The enteric pathogen Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) is an important causal agent of enterocolitis in humans but can also cause systemic disease in newborns. It thereby contributes significantly to childhood mortality particularly in developing countries. S. Typhimurium translocates effector molecules via its Salmonella pathogenicity island- 1 encoded type 3 secretion system (T3SS) into intestinal epithelial cells to induce its uptake but also to manipulate other cellular functions. The SPI-1 T3SS effector protein Salmonella outer protein B (SopB) has been shown to induce bacterial internalization by intestinal epithelial cells, manipulate cell survival, cell trafficking and host cell signaling. Using a recently established murine neonatal infection model, we analyzed the function of SopB by comparing SopB-deficient (ΔsopB) with SopB proficient S. Typhimurium infected animals. Unexpectedly, ΔsopB S. Typhimurium infected animals showed an accelerated disease course with premature mortality. Although the intraepithelial bacterial burden and systemic spread were unaltered, a significantly increased early proinflammatory cytokine response with increased expression levels of Cxcl1, Cxcl2, Mcp1 and Tnfα were noted in the absence of SopB. Neutrophils and monocytes were recruited to the lamina propria of ΔsopB S. Typhimurium infected mice in much higher numbers leading to a more pronounced inflammatory response and necroptosis-dependent epithelial cell death. This effect in vivo was independent of the phosphatidylinositol phosphatase activity of SopB but required an intact N-terminal domain. A phosphoproteome analysis revealed activation of ERK/MAPK signaling in the absence of SopB in vitro. Taken together, my results suggest that SopB suppresses early ERK/MAPK signaling in a phosphatidylinositol phosphatase-independent manner to reduce mucosal inflammation and prevent early mortality likely leading to enhanced host transmission.
Nour Diab (Wed,) studied this question.