The Norwalk-like Caliciviruses Associated With Epidemic

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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 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. [unreadable] 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 this year focused on the continued development of murine norovirus as a model because it is the only member of the genus Norovirus that grows in cell culture. We reported the first complete genetic map of murine norovirus (strain MNV-1) that defines the borders of the viral proteins, and this knowledge will enable study of individual proteins involved in virus replication. We also discovered a new murine norovirus strain in NIH laboratory mice. This virus may be naturally attenuated because it is not associated with disease in normal mice. Furthermore, it is not lethal when administered to mice with impaired innate immunity (unlike the original strain MNV-1, discovered in Dr. Virgin's laboratory at Washington University). This year, with Dr. Purcell, we reinitiated studies in nonhuman primates to address the mechanisms of human norovirus pathogenesis and immunity. Intestinal biopsies were obtained from a chimpanzee shown to be infected with Norwalk virus. Studies are in progress to localize the site of virus replication and to examine the effect of Norwalk virus infection on host cell gene expression. This animal model offers a promising alternative to human volunteer studies in the initial development and testing of norovirus vaccine candidates.