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.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-8 (01))
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Louisiana State University Hsc Shreveport
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Kim, Jung Heon; Collins-McMillen, Donna; Buehler, Jason C et al. (2017) Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34+ Human Progenitor Cells. J Virol 91:
Martinez, Nicholas E; Sato, Fumitaka; Kawai, Eiichiro et al. (2015) Th17-biased ROR?t transgenic mice become susceptible to a viral model for multiple sclerosis. Brain Behav Immun 43:86-97
Kawai, Eiichiro; Sato, Fumitaka; Omura, Seiichi et al. (2015) Organ-specific protective role of NKT cells in virus-induced inflammatory demyelination and myocarditis depends on mouse strain. J Neuroimmunol 278:174-84
DiGiuseppe, Stephen; Bienkowska-Haba, Malgorzata; Hilbig, Lydia et al. (2014) The nuclear retention signal of HPV16 L2 protein is essential for incoming viral genome to transverse the trans-Golgi network. Virology 458-459:93-105
Stevenson, Emily V; Collins-McMillen, Donna; Kim, Jung Heon et al. (2014) HCMV reprogramming of infected monocyte survival and differentiation: a Goldilocks phenomenon. Viruses 6:782-807
Coleman, Carrie B; McGraw, Jennifer E; Feldman, Emily R et al. (2014) A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo. PLoS Pathog 10:e1003916
Fernando, Viromi; Omura, Seiichi; Sato, Fumitaka et al. (2014) Regulation of an autoimmune model for multiple sclerosis in Th2-biased GATA3 transgenic mice. Int J Mol Sci 15:1700-18
Martinez, Nicholas E; Karlsson, Fridrik; Sato, Fumitaka et al. (2014) Protective and detrimental roles for regulatory T cells in a viral model for multiple sclerosis. Brain Pathol 24:436-51
Sato, Fumitaka; Omura, Seiichi; Kawai, Eiichiro et al. (2014) Distinct kinetics of viral replication, T cell infiltration, and fibrosis in three phases of myocarditis following Theiler's virus infection. Cell Immunol 292:85-93
Sato, Fumitaka; Martinez, Nicholas E; Shahid, Maira et al. (2013) Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis. Am J Pathol 183:1390-1396

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