Exacerbation of Coxsackievirus B3-Induced Pancreatitis by NOD2 Autoregulation Across the Gut-Pancreas Axis

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Coxsackieviruses are single stranded RNA viruses in the enterovirus genus that cause a wide variety of disease symptoms in humans, especially in young children. The CDC reports that in the United States, there are approximately 10-15 million non-polio enterovirus infections each year, most of which are caused by coxsackieviruses. Despite this high case number, there are currently no specific treatments available for coxsackievirus infections. Coxsackievirus B3 (CVB3) is a common serovar that colonizes humans via the fecal- oral route and disseminates to other tissues such as the heart, pancreas, and central nervous system. In the pancreas, CVB3 infection can cause viral pancreatitis, a life-threatening inflammatory disease that often leads to complications like pancreatic cancer, organ failure, and type 1 diabetes. Furthermore, CVB3-induced pancreatitis is thought to precede CVB3-induced myocarditis, another lethal inflammatory disease caused by viral colonization of heart muscle tissue. While Coxsackievirus-induced myocarditis has received significant research attention, very little is still known about Coxsackievirus-induced pancreatitis. Recently, it was demonstrated that the cytoplasmic pattern recognition receptor NOD2, which induces innate immune signaling in response to infection and damage patterns in the cell, exacerbates pathogenesis and disease in CVB3 infected mice. This is surprising since NOD2 is host-protective during many viral and bacterial infections. Using a similar mouse model of CVB3 infection, we observed that inflammatory cytokine expression in the pancreas was significantly lower when NOD2 is not expressed in the intestinal epithelium, suggesting that intestinal NOD2 promotes inflammation in the pancreas during CVB3 infection. NOD2 is known to upregulate intestinal barrier function and upregulate mitophagy in response to the bacterial peptidoglycan fragment muramyl dipeptide (MDP). Additionally, mitophagy can downregulate inflammation due to a reduction in mitochondrial reactive oxygen species (ROS) production, which in turn downregulates NLRP3 inflammasome activation. If intestinal NOD2-mediated barrier function sufficiently inhibits translocation of bacteria to the pancreas during CVB3 infection, it may promote pancreatic NLRP3 inflammasome activation by limiting MDP/NOD2-mediated mitophagy. Since excessive host inflammatory response contributes significantly to disease severity during viral pancreatitis, the relationship between inflammasome activation and NOD2 autoregulation across the gut- pancreas axis may play an important role in disease outcome during CVB3 infection. These questions will be investigated with the following aims: Aim 1: Determine whether intestinal NOD2 barrier function inhibits host-protective activation of pancreatic NOD2 during CVB3-induced pancreatitis; and Aim 2: Determine if MDP-dependent activation of NOD2 in pancreas cells inhibits ROS-dependent inflammasome activation by upregulating mitophagy. These studies will elucidate the mechanisms of NOD2 signaling in both the intestinal epithelium and pancreas that promote inflammatory disease during viral pancreatitis.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Coxsackievirus infections are common among young children, cause life-threatening inflammatory diseases including viral pancreatitis, and do not have any antiviral treatments. The role of innate immunity during coxsackievirus-induced pancreatitis remains largely understudied, but recent evidence suggests functional immune signaling in the intestine promotes harmful inflammation in the pancreas during infection. This proposal aims to characterize the mechanisms of innate immunity in the gut that aggravate viral pancreatitis during coxsackievirus infection.