Dynamics and immune control of norovirus infection in neonatal mice

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Project Summary/Abstract Norovirus (NoV) is the leading global cause of acute gastroenteritis, associated with an estimated 685 million cases annually. NoV infects individuals of all ages but infection is most severe in children under the age of 5, causing approximately 50,000 deaths in this population each year. Young children also experience prolonged fecal shedding with high viral loads, playing a key role in transmission throughout the entire population. However, the host factors which contribute to variability in NoV severity and shedding by age are not well-defined. Murine NoV (MNoV) is used as a model to study viral pathogenesis in vivo, but almost all studies have been conducted in adult mice. The overarching objective of this work is to use neonatal mice as a model to understand the dynamics and immune control of NoV in young animals. Preliminary studies suggest that the cellular and tissue tropism of persistent MNoV infection is altered in neonatal mice compared to adult mice. Further, innate immune responses are central to controlling viral infection in neonates. Neonatal Stat1-/- mice, which lack a transcription factor necessary for interferon signaling, shed higher levels of MNoV and succumb to infection. This lethality is unique to young animals, as adult Stat-/- mice typically survive infection with persistent strains of MNoV. The overall hypothesis of this proposal is that IFN responses limit MNoV replication and tropism in neonates, thereby controlling fecal shedding and lethality. We will test this hypothesis using our neonatal model of MNoV infection. In Aim 1, we will define the kinetics of viral replication and shedding of infectious virions and define the cellular tropism of MNoV in wild-type and Stat1-/- neonates. In Aim 2, we will characterize the timing, localization, and function of individual IFN responses and whether IFN responses control viral mutation and/or extraintestinal dissemination. These studies will help explain host factors which contribute to variation in viral pathogenesis and persistent shedding by age and will represent a significant advancement into understanding the differences in enteric virus dynamics between adults and children. This work will take place at Washington University in St. Louis, which provides exceptional access to the resources and training necessary to complete these studies. Access to cutting-edge facilities such as the Center for Cellular Imaging and DNA Sequencing Innovation lab, as well as ample training opportunities available from on-campus core facilities, make these experiments technically possible. Support from the Molecular Microbiology and Microbial Pathogenesis program and mentorship from sponsors and other faculty on campus will ensure the successful completion of the proposed research.