Identifying virulence factors in norovirus infection
Dhairya Shah, Emily S. Winesett, Stephanie M. Karst
Dr. Stephanie M. Karst
College of Medicine
Norovirus is the leading cause of global severe childhood diarrhea and a leading cause of acute gastroenteritis for all ages worldwide. Murine norovirus (MNV-1) was first discovered in 2003, and since then, many other MNV strains have been reported. MNV has been used as a model system for many years to investigate norovirus biology, although a limitation of the model is that immunocompetent adult mice do not develop overt symptoms. Our lab has recently developed a novel model where genetically wild-type neonatal mice develop acute, self-resolving diarrhea following MNV-1 infection, a disease course that mirrors human norovirus pathogenesis. Furthermore, genetically similar strains of MNV show differences in virulence as MNV-CR6 is attenuated compared to MNV-1. This difference in virulence allows us to determine which viral proteins (VP) are important in conferring virulence in vivo by producing chimeric viruses where individual viral proteins are swapped between the MNV-1 and MNV-CR6 strains. Preliminary mouse data have shown that VP1 from MNV-CR6 attenuates MNV-1, but NS1/NS2 and NS7 from MNV-CR6 has no effect. Wild-type MNV-CR6 shows attenuated disease, but by providing it the MNV-1 VP2, it results in increased diarrhea incidence. However, providing MNV-1 the MNV-CR6 VP2, it results in no significant change in diarrhea incidence, showing that VP2 is sufficient but not necessary for virulence. Data show that VP1 partially accounts for virulence in MNV-1 and CR6, which may be attributed to reduced titers in MNV1VP1.CR6 leading to attenuation of disease. However, viral titers are not always correlated with disease as MNV-CR6VP2.MNV1 shows reduced viral titers compared to MNV-CR6 despite increased virulence. This suggests that norovirus disease symptoms are uncoupled from viral titers. In this work, we will determine the mechanism by which the viral capsid proteins VP1 and VP2 contributes to virulence in this model system.
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