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NOD2 promotes coxsackievirus entry and pathogenesis

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Project Summary NOD2 is a cytosolic pattern recognition receptor that senses and responds to bacterial peptidoglycan, activated small Rho GTPases, endoplasmic reticulum stress and viral, fungal and parasitic infections. NOD2 is localized in the cytosol, and upon activation, associates with the plasma membrane and endosomes, which is essential for NOD2 function. Activation of NOD2 results in recruitment of RIPK2 leading to a pro-inflammatory response dependent on NF-?B and MAPK signaling pathways. NOD2 restriction of bacterial invasion at the intestinal epithelial surface has been strongly implicated in inflammatory bowel diseases such as Crohn's disease (CD) as loss-of-function mutations in Nod2 can promote the development and onset of CD. Moreover, NOD2 is broadly antiviral as it restricts cytomegalovirus, respiratory syncytial virus, vesicular stomatitis virus and influenza A virus infections. Paradoxically, NOD2 promoted coxsackievirus B3 (CVB3) infection in mice. We found that NOD2 and RIPK2 enhance CVB3 entry in vitro, and NOD2 increases CVB3 pathogenesis in vivo. The following are unknown regarding the impact of NOD2 on CVB3 infection: (1) the mechanism underlying the requirement of NOD2 for efficient CVB3 replication, (2) the novel function for NOD2 during CVB3 entry and (3) the effect of NOD2 on CVB3 infection in the gastrointestinal tract, the initial and natural site of infection. We hypothesize that CVB3 has evolved to usurp NOD2 for optimal viral replication in the gastrointestinal tract to promote CVB3 dissemination to other organs, which causes increased CVB3- induced pathogenesis. We will test our hypothesis by pursuing two aims. For Aim 1, we will use in vitro cell culture infection models in intestinal epithelial cells (IEC) to determine the mechanism for NOD2 enhancement of CVB3 entry into cells. We will investigate whether NOD2 impacts CVB3 binding to its receptor (CAR), if NOD2 is recruited to sites of CVB3 entry and whether membrane localization is required for CVB3 to enter cells. We will also assess whether NOD2 affects CVB3 uptake by influencing the cell cytoskeleton. Aim 2 will examine the in vivo contribution of NOD2 on CVB3 infection. We will identify what cell lineage is critical for the impact of NOD2 on CVB3 infection and pathogenesis in a mouse model. As CVB3 is a fecal-oral transmitted virus that infects the intestine prior to spreading to other organs, we will use an oral infection model in our Nod2-sufficient and -deficient mice, using an Interferon alpha/beta receptor knock-out (Ifnar1-/-) background to render mice more orally susceptible, to ascertain the importance of NOD2 during intestinal CVB3 infection. Altogether, these studies will define how CVB3 exploits the innate immune receptor NOD2. Information from the proposed research could lead to the development of therapeutics for coxsackievirus infections and possibly other enteroviruses, will help us understand host intestinal influences on CVB3 and will propel future studies focused on other viral infections.
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