Human noroviruses are a leading cause of gastroenteritis worldwide. This genetically diverse NIAID Category B pathogen has a complex epidemiology, with new clinically important strains emerging every few years through antigenic drift and recombination and replacing the previous circulating variant. The source of introduction of new variants, the frequency and mechanisms of recombination and why certain recombinants spread globally is not understood.
During the last five years, the norovirus project of BCM GCID U19 focused on unraveling the genetic diversity and virulence mechanisms of this complex pathogen using high-throughput genomic analyses in parallel with functional studies in human intestinal organoids. Our studies utilized a broad panel of clinical specimens, ranging from acute infections in children and adults, controlled human infection models, and chronic infections in immunocompromised patients, including a randomized controlled trial of nitazoxanide for the treatment of norovirus in transplant patients. We collaborated with the ST core to establish new capture-based sequencing methods to obtain full-length norovirus sequences with high sensitivity and performed WGS analysis to obtain metagenomic biomarkers of norovirus disease. We performed transcriptomic studies in organoids and discovered strain specific differences in human norovirus epithelial response leading to new discoveries on norovirus pathogenesis. We performed complementary studies to the clinical trial with nitazoxanide and established pipelines for antiviral testing. We also collaborated with the OMAC core to characterize infant human intestinal organoids to develop age-appropriate models of gastrointestinal diseases.
These past accomplishments position us to address key questions on viral and host factors that affect the virulence, pathogenesis, and evolution of noroviruses. Children are often considered the major source of new variant introduction into the community. In the next phase, we propose to perform innovative and extensive sequencing of pediatric stool samples from racially and ethnically diverse population, together with functional validation in physiologically relevant pediatric ex vivo organoid cultures, to identify viral and host factors affecting strain emergence and disease presentation. Our studies will be focused on pediatric samples and organoids as children have long been considered a key population for emergence of new HuNoV variants. Our analyses will span four distinct periods: pre-pandemic, pandemic, post-pandemic, and future introduction of HuNoV-specific interventions. To perform these studies, we will leverage our collaborations with the CDC’s New Vaccine Surveillance Network (NVSN), which monitors pediatric gastrointestinal illnesses across seven U.S. sites through collection of clinical samples and comprehensive metadata. Our research will include full-length HuNoV genomic, microbiome, and virome analyses, alongside functional studies using established pediatric intestinal organoid models. Through these studies, we will (i) track strain emergence and diversity, (ii) identify biomarkers for gastrointestinal disease, (iii) uncover viral signatures linked to pathogenesis, and (iv) elucidate virus–host–microbiome interactions. Overall, our studies will address key questions on HuNoV diversity, evolution and replication needed to enable successful implementation of interventions.
