The human intestinal microbiome includes viruses that replicate in eukaryotic cells, plants, fungi or bacteria. However, very little is known on how viral recognition shapes mucosal immune responses. Furthermore, a detailed understanding of the signaling intermediates that confer the sensing of viruses for induction of type I interferons s critical for strategies to curtail viral mechanisms that impede innate immune defenses. Our work identified the guanine nucleotide exchange factor H1 (GEF-H1), encoded by the arhgef2 gene, as a central component of host defense activation during viral infections. We hypothesize that GEF-H1 serves as a gatekeeper for innate host defenses by controlling interferon response factor activation, which is part of signaling pathways induced by recognition of bacteria and viruses. Defining the functional role of this newly discovered central component of microbial pattern recognition should provide pivotal insights into the integration of antiviral host defenses into immune activation pathways that control the microbiota in the intestine.
A detailed understanding of sensing of microbial components for the induction of host defenses is critical for strategies to curtail microbial mechanisms that disable immune responses or induce chronic inflammation. We aim to unravel the mechanisms that make GEF-H1 a central signaling component that controls the expression of type I interferons and proinflammatory mediators for the defense against viral and bacterial infections.
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|O'Keeffe, Michael S; Song, Joo-Hye; Liao, Gongxian et al. (2015) SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine. Gastroenterology 148:991-1001.e4|