Noroviruses and Epidemic Gastroenteritis

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

The Caliciviridae is a family of nonenveloped, positive-strand RNA viruses and now consists of 11 genera: Norovirus, Sapovirus, Bavovirus, Lagovirus, Minovirus, Nacovirus, Nebovirus Recovirus, Salovirus, Valovirus, and Vesivirus. The diseases caused by caliciviruses vary, according to the virus and its host species. Members of the Caliciviridae causing diarrheal disease in humans belong to the genera Norovirus and Sapovirus. The Caliciviruses Section (CS) in LID conducts research related to caliciviruses, with an emphasis on the noroviruses. Noroviruses are markedly diverse and strains infecting humans belong to either Genogroup I (GI) or Genogroup II (GII), with multiple genotypes within each group. The role of genetic and antigenic diversity in the epidemiology of these viruses has been an ongoing area of active research in our laboratory because this information is essential in the design of vaccines and therapeutics. We have been tracking the molecular epidemiology of noroviruses associated with chronic infection in immunocompromised patients enrolled in protocols at the NIH Clinical Research Center for several years. Taken together, our work indicates that most circulating noroviruses in the community have the capacity to establish a chronic or persistent infection in an individual with a compromised immune system. Clearance of the virus has been observed in our cohort only when a patient has undergone successful gene therapy or stem cell transplantation to restore their immune system. Our lab has developed assays to profile the norovirus genotype specificity of the serum antibodies in patients before and after immune reconstitution. In tandem, our collaborators at CNMC have initiated studies to examine the norovirus specificity of the cellular immune response once such a patient clears norovirus. Identification of the immune mechanisms contributing to this clearance in a restored immune system will be important in the design of immunotherapies and in the interpretation of data from the norovirus T cell therapy trial. Our laboratory has continued to work in the improvement of tools for preclinical studies of vaccines and therapeutics. We are modifying and optimizing cell culture systems, including intestinal enteroids, so that we can increase the replicative capacity of human noroviruses in vitro. Current efforts are underway to immortalize intestinal cells so that we can maintain cell cultures that are more efficient to manage than intestinal enteroids. This year, we have successfully developed a new cell-based replication system in which the murine norovirus receptor was engineered into a stable human intestinal cell line. This system allows infection of the human cells with an efficiently replicating murine norovirus in lieu of a human norovirus that does not replicate. In addition, we are using technologies such as single cell RNAseq to define specific host factors in cells (in both cell culture and biopsied tissue) that are essential for norovirus replication. Until we have achieved efficient, lytic replication of the human noroviruses in continuous cell lines, our tools should enhance replication studies of the noroviruses.