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. We have characterized noroviruses associated with sporadic cases in the community or with gastroenteritis outbreaks in various settings. In addition, we have analyzed noroviruses associated with chronic infection in immunocompromised patients enrolled in research protocols at the NIH Clinical Research Center in order to understand how they adapt to become chronic. We made progress in tracking the evolution of the norovirus genome over time during chronic infections, and found that such infections were likely established from a single founder virus infection that could form discrete subpopulations of viruses that co-evolved over time. We aim to establish how these subpopulations originate and whether they play a role in viral pathogenesis. We made progress in the development of a clinical protocol to treat chronic norovirus infection with norovirus-specific T cells in collaboration with Dr. Mike Keller and his team at Children's National Medical Center (CNMC). A pipeline has been developed to stimulate T cells present in donor PBMCs with norovirus-specific peptides and to create norovirus-specific T cells (NSTs). In tandem, we have been profiling B cells from these same donors to identify memory B cells that produce functional cross-reactive norovirus-specific antibodies with therapeutic potential. Several promising human antibodies have been identified in these screens. This antibody work, coupled with that of our llama nanobodies isolation, offers a second powerful approach to immune therapy for chronic norovirus infection. 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. We use a variety of techniques to accomplish this work, including the construction of new reverse genetics systems and the modification of cellular genes that improve the replication efficiency of human noroviruses.