This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Project 4: Replication of murine norovirus 1, MNV-1Project PI: Stephanie M. Karst, Ph.D.Introduction: Human noroviruses are important pathogens responsible for 95% of non-bacterial epidemic gastroenteritis worldwide. However, they have been very difficult to study due to a lack of tissue culture and small animal model systems. We discovered murine norovirus, MNV-1, in immunodeficient mouse colonies and have shown that it productively infects both macrophages and dendritic cells in tissue culture. We are investigating the mechanism(s) by which interferon (IFN) signaling protects from MNV-1 induced disease. Methods: Infection of normal mice is compared to infection of mice deficient in specific components of IFN signaling to determine the role that IFN plays in MNV-1 protection in vivo. Comparing infection of permissive cells in the presence or absence of IFN treatment allows us to investigate the molecular mechanism(s) by which IFN signaling inhibits MNV-1 replication. Results: We have determined that IFN signaling prevents replication of MNV-1 in the intestine, controls virus spread to peripheral tissues, and protects cells from apoptosis in vivo. We have also determined that IFN blocks MNV-1 replication at a very early step in the replication cycle preceding viral translation. Discussion: Human norovirus infection causes debilitating disease but is resolved rapidly, suggesting that components of the innate immune response are critical in norovirus protection. Because long-term immunity is not thought to develop upon norovirus infection, understanding the innate immune responses to infection is critical for developing rational treatment regimes. Thus, mechanistic studies of the role(s) played by IFN signaling in protection from norovirus infection will lay the foundation for future translational designs.
Showing the most recent 10 out of 92 publications
