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Helicobacter pylori is a gram-negative, microaerophilic bacterium that infects the stomach and can lead to, among other disorders, the development of gastric cancer. The inability of the host to clear the infection results in a chronic inflammatory state with continued oxidative stress within the tissue. Reactive oxygen species and reactive nitrogen species produced by the immune and epithelial cells damage the host cells and can result in DNA damage. H pylori has evolved to evoke this damaging response while blunting the hostâs efforts to kill the bacteria. This long-lasting state with inflammation and oxidative stress can result in gastric carcinogenesis. Continued efforts to better understand the bacterium and the host response will serve to prevent or provide improved early diagnosis and treatment of gastric cancer. Keywords: AP Endonuclease, DNA Damage, H pylori, Gastric Cancer, Oxidative Stress

Background & Aims: After invading intestinal epithelial cells, enteric bacteria encounter phagocytes, but little is known about how phagocytes internalize the bacteria to generate host responses. BAI1 (brain angiogenesis inhibitor 1) binds and internalizes Gram-negative bacteria through an engulfment and cell motility protein 1 (ELMO1)/Ras-related C3 botulinum toxin substrate 1 (Rac1)-dependent mechanism. We delineate the role of ELMO1 in host inflammatory responses after enteric infection. Methods: ELMO1-depleted murine macrophage cell lines, intestinal macrophages, and ELMO1-deficient mice (total or myeloid-cell specific) were infected with Salmonella enterica serovar Typhimurium. The bacterial load, inflammatory cytokines, and histopathology were evaluated in the ileum, cecum, and spleen. The ELMO1-dependent host cytokines were detected by a cytokine array. ELMO1-mediated Rac1 activity was measured by pull-down assay. Results: The cytokine array showed a reduced release of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1), by ELMO1-depleted macrophages. Inhibition of ELMO1 expression in macrophages decreased Rac1 activation (â¼6-fold) and reduced internalization of Salmonella. ELMO1-dependent internalization was indispensable for TNF-α and MCP-1. Simultaneous inhibition of ELMO1 and Rac function virtually abrogated TNF-α responses to infection. Activation of nuclear factor κB, extracellular signal-regulated kinases 1/2, and p38 mitogen-activated protein kinases were impaired in ELMO1-depleted cells. Bacterial internalization by intestinal macrophages completely depended on ELMO1. Salmonella infection of ELMO1-deficient mice resulted in a 90% reduction in bacterial burden and attenuated inflammatory responses in the ileum, spleen, and cecum. Conclusions: These findings suggest a novel role for ELMO1 in facilitating intracellular bacterial sensing and the induction of inflammatory responses after infection with Salmonella. Keywords: Engulfment Pathway, Enteric Infection, Host Cellular Responses, Intestinal Inflammation, Salmonella