Factors That Influence Murine Norovirus Stability and Tropism




Budicini, Melissa Renee

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In this work I investigated factors that influence murine norovirus stability and tropism through two independent projects. Murine norovirus (MNV) is a model system used to study human noroviruses due to its robust replication in cell culture and mouse model. I first investigated the interactions between MNV and bacteria in vitro by determining what bacteria and bacterial components could impact viral thermostability. I found that that specific Gram-positive bacteria and conditioned medium from Gram-positive bacteria could stabilize MNV against heat inactivation. However, I found that Gram-negative bacteria and conditioned medium had no impact on viral stability. These stabilizing effects of bacteria may play a role in viral transmission due to the fact that the virus must remain stable in the environment to transmit to a new host. In my second project I used a forward genetic approach to select for MNV variants with increased host cell range. I found that by serially passaging murine norovirus in human HeLa cells I could select for mutant viruses that increased replication as compared with the parental strain in a non-natural host. The passaged viruses had many mutations spanning the viral genome, however I determined three specific mutations in the NS1/2 protein that allowed for the virus to grow better in human cells. I determined that the adapted viruses have increased replication because they overcame a post-entry replication block in HeLa cells, not because they have increased attachment. This was surprising given that HeLa cells do not have the MNV receptor. These studies show that MNV tropism is not only determined by receptor availability. Overall, these studies illuminate unique aspects of MNV biology that may be applicable to other viruses.

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