Human noroviruses are a leading cause of gastrointestinal disease worldwide. This genetically diverse NIAID Category B pathogen has a complex epidemiology, with new clinically important strains emerging every 2-3 years through antigenic drift and recombination. The frequency and mechanisms of recombination and why certain recombinants lead to pandemics is not understood.
In the norovirus component of the GCID U19 project, we will use high throughput genomic analysis of clinical samples, together with functional studies in novel physiologically active intestinal cultures to address key questions on genomic diversity and virulence of human noroviruses. Our panel of clinical specimens covers the spectrum of norovirus illness including: (i) acute gastroenteritis in immunocompetent children from two geographically distinct populations, (ii) well-controlled human volunteer challenge studies, (iii) transplant and immunocompromised patients with chronic norovirus infection, and (iv) the first randomized double-blind clinical trial of nitazoxanide for treatment of chronic norovirus infections in transplant recipients. Full-length genomic analyses of noroviruses in these clinical samples will provide critical information on virus diversity in different populations, over time and in diverse hosts. We also will evaluate microbiome signatures associated with different virus genotypes and patient groups. Our successful development of an intestinal cultivation system for noroviruses using stem cell-derived human intestinal organoids (HIOs) will facilitate the development of novel in vitro platforms for understanding viral recombination and emergence of treatment resistance.
This project will generate a large database of full-length genomes for human noroviruses and a combination of analytical genomics and functional studies that address key questions on norovirus diversity, evolution and virulence. Identifying biomarkers of norovirus infection, and viral and host targets of pathogenesis will guide future vaccine design and development of therapeutics.