Human norovirus infection is the leading cause of severe childhood diarrhea and gastroenteritis worldwide. Studying human noroviruses is complicated by their limited growth in cultured cell lines and lack of a small animal model. Therefore, murine norovirus (MNV) has been utilized as a model to study norovirus biology. The Karst research group has previously demonstrated that interferon-deficient STAT1^-/- adult mice infected with MNV-1 develop gastrointestinal disease; however, these animals also develop severe systemic disease that is ultimately lethal, which is not observed in human norovirus infection. Additionally, adult immunocompetent mice do not develop the characteristic symptom of diarrhea upon MNV infection, which significantly reduces the applicability of this model to human norovirus. The Karst research group has more recently discovered that neonatal BALB/c mice are susceptible to self-resolving gastroenteritis following oral MNV-1 infection which nicely mirrors the disease course seen in humans. Interestingly, virulence significantly differs between highly genetically similar MNV strains as MNV-CR6 is attenuated in this model. These phenotypic differences allow for the use of chimeric viruses to elucidate the mechanism of MNV infection. The Karst research group has designed chimeric viruses that swap the genes encoding the structural capsid proteins for virulent MNV-1 and attenuated MNV-CR6. Using these chimeric viruses, the Karst lab has determined that VP1 is necessary and sufficient for virulence while VP2 is sufficient but not necessary.  

In my previous project for the Emerging Scholars Program, I demonstrated that expression of the proinflammatory cytokine TNF-α is positively correlated with virulence in the colons of infected mice. TNF-α is well-established to disrupt epithelial tight junction barriers following infection. Therefore, I hypothesize that virulent norovirus strains like MNV-1 induce proinflammatory cytokines that disrupt tight junction barriers, increasing intestinal permeability and consequently causing diarrhea. Based on our results with chimeric viruses, I aim to determine whether the MNV-1 VP1 and VP2 proteins lead to increased TNF-α expression. We hypothesize that these structural capsid proteins cause the induction of proinflammatory cytokines in the small and large intestine of infected neonates, ultimately corresponding to the increased diarrhea phenotype seen in MNV-1 infection.