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The Interaction of Enteric Bacterial Effectors with Host Engulfment Pathway Regulates Host Immune Response

Abstract

The clearance of enteric bacteria by phagocytes is an essential role of host response against infection. Previously, we have reported that BAI1 (Brain Angiogenesis Inhibitor 1) binds bacterial Lipopolysaccharide (LPS) and facilitates the engulfment of gram-negative bacteria by utilizing ELMO1 (Engulfment and cell motility protein 1). Interestingly, ELMO1 interacts with Salmonella effector SifA that controls bacterial survival. Therefore, we hypothesized that the interaction between ELMO1 and SifA affects the pathogenesis of enteric infection, the bacterial clearance, and provides differential immune responses between pathogens and commensals. In silico analysis of bacterial database reveals that Salmonella effector SifA interacts with ELMO1 in the WxxxE signature motif which is present in several effectors from other enteric pathogens but is absent in commensals. In addition, SifA is involved in bacterial vacuole integrity. With ELMO1, SifA is involved in the endosomal-lysosomal pathway by interacting with the late endosomal protein Rab9. A pulldown of GST-SifA was performed with murine macrophage cell lysate followed by the identification of host proteins via Liquid-Chromatography Mass Spectroscopy. SifA interacts with Ribophorin 1(RPN1), which is involved in the transport of newly synthesized proteins across the membrane of the rough endoplasmic reticulum, and MOGS, a glycoside hydrolase that functions within the N-glycosylation pathway. Our data showed that ELMO1-depleted cells had significantly delayed bacterial clearance, and ELMO1 is a novel cytosolic sensor that determines bacterial pathogenesis and provides new insight to bacterial clearance via mechanisms of the endosomal-lysosomal system.

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