The Impact of Bacterial Effector Interactions with ELMO1 on Host Mucosal Immune Responses

The intestinal mucosa maintains immune homeostasis amongst common flora and enteric pathogens. Phagocytes utilize an endocytic process to engulf microbes and generate inflammation but nothing is known in the context of differential immune responses from pathogenic vs non-pathogenic microbes. We found ELMO1 (Engulfment and cell motility protein-1) engulfs enteric bacteria and produces pro-inflammatory responses only following pathogenic bacterial infection. We hypothesize that the interaction of ELMO1 with microbe regulates the innate responses. Myeloid cell specific ELMO1 KO mice produced less pro-inflammatory cytokines (TNF-a, MCP-1) in ileum and spleen after Salmonella infection. Interestingly following infection with commensal flora, the inflammation is significantly reduced and is ELMO1 independent. To understand the mechanism of differential responses, we detected the ELMO1 interacting bacterial effectors as well as host proteins in Salmonella infected murine macrophages. Our in silico analysis, followed by pull down experiment and MALDI-TOF showed that Salmonella effectors SifA and SifB interact with ELMO1. ELMO1 is associated with other host proteins involved in phagocytosis and endocytic pathway during infection. The ELMO1-SifA effector interaction regulates inflammatory responses and bacterial survival inside phagocytes. Our result indicates that the presence of ELMO1 in phagocyte is crucial to maintain the host-microbiota interface and mucosal immune responses.