Norwalk-like Caliciviruses &Epidemic Gastroenteritis

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Abstract

The Caliciviridae are a family of positive-strand RNA viruses and consist of four genera designated: (1) Norovirus (with species Norwalk virus) (2) Sapovirus (with species Sapporo virus); (3) Vesivirus (with species, feline calicivirus and vesicular exanthema of swine virus); and (4) Lagovirus (with species rabbit hemorrhagic disease virus and European brown hare syndrome virus). Norwalk virus (NV) is the prototype strain for the genus Norovirus and was discovered by LID researchers in 1972. The Noroviruses are the major cause of nonbacterial epidemic gastroenteritis that occurs in family, school, institutional, or community-wide outbreaks, affecting all age groups. The human noroviruses are genetically diverse and cannot be grown in cell culture, which has been a continuing research obstacle. A major goal of this laboratory is the development of control strategies for the caliciviruses (predominantly the noroviruses) associated with gastroenteritis. In order to accomplish this goal, basic knowledge of the epidemiology, immunology, and replication strategies of these viruses is needed. Our work with our model, feline calicivirus (FCV), showed that VP2 may play an important role in the maturation of virus particles, and that the 3'-end of the calicivirus genome contains an essential replication signal. We also demonstrated that the ProPol of the human noroviruses is a bifunctional enzyme, with both proteinase and RNA-dependent RNA polymerase activity. A major breakthrough in our laboratory this year was the development of a cell-based replicon system for NV. Cells (BHK21) containing self-replicating NV RNA (norovirus replicons) were selected in the presence of neomycin following transfection of RNA transcripts derived from a cDNA clone of the NV genome bearing a neomycin resistance gene. For the first time, the effect of various compounds on NV protein and genome expression could be examined. Our collaboration with Dr. Herbert (Skip) Virgin at Washington University in the study of murine norovirus continued this year, and we were involved in the characterization of the first cell culture system for a norovirus (murine norovirus) developed in his laboratory. This cell culture system is yielding important new insight into norovirus growth and replication.