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 infecting humans belong to either Genogroup I (GI) or Genogroup II (GII), with multiple genotypes within each genogroup. The genetic diversity of the human noroviruses presents a major challenge in the development of vaccines and therapeutic drugs that are needed to reduce the disease burden. To address the urgent need for antiviral therapy in immunocompromised individuals with chronic norovirus disease, we have continued to provide laboratory expertise for research protocols led by our clinical collaborators. One of these is a clinical trial conducted as a collaborative effort between NIAID and Children’s National Medical Center (CNMC) to investigate the efficacy of norovirus-specific T cells as therapy (ATLANTIC). This collaboration is important also in our ongoing basic research studies to understand the key components of an effective immune response to norovirus and the mechanisms of viral pathogenesis. We have provided data to advance natural history studies of norovirus led by Dr. Jessica Durkee-Shock in LID, who specializes in the treatment of immune deficiencies associated with inborn errors of immunity. We analyzed clinical samples from a number of her patients to explore immune mechanisms contributing to viral clearance in patients receiving therapy for immune reconstitution (such as HSCT) or immune modulation. Such studies will continue to be important in the design of immunotherapies and in the interpretation of data from the ongoing norovirus T cell therapy trial. A noteworthy advance this year was the successful performance of single cell RNA sequencing (scRNA- seq) analyses of intestinal biopsies obtained by endoscopy from three NIH patients with chronic norovirus infection. These large datasets are currently undergoing bioinformatics analyses in comparison with those from healthy individuals or patients with underlying digestive tract diseases such as irritable bowel syndrome. We have performed the first direct scRNA-seq comparison of the cell populations in fresh tissue compared to that from tissue-derived enteroids (organoids) cultured in vitro. Our work in progress seeks to discover virus-infected target cells in human gut tissue and enteroids using this unbiased single cell RNA sequencing analysis, characterize these cells, and apply this knowledge to the development of improved in vitro replication systems for the noroviruses. Knowledge of the cellular and tissue tropisms of noroviruses in the human host as well as improved in vitro cell culture systems can then be directly applied to the evaluation of therapeutic interventions.