# Viral Diversity and Pathogenicity in Mucosal Respiratory and Gastrointestinal Disease

> **NIH NIH U19** · BAYLOR COLLEGE OF MEDICINE · 2021 · $499,999

## Abstract

PROJECT SUMMARY
Human norovirus (HuNoV), a NIAID Category B pathogen, is the leading cause of acute gastroenteritis globally,
and respiratory syncytial virus (RSV), a Category C pathogen, is the major global respiratory pathogen of
children. HuNoV infections result in significant acute morbidity in all age groups, chronic disease in
immunocompromised cancer and transplant patients, and death in young children and older adults. RSV is the
leading cause of lower respiratory tract morbidity and mortality among children, and contributes significantly to
illness and death in the immunocompromised, those with co-morbidities and older adults. The burden of disease
and economic impact of these mucosal pathogens have stimulated extensive efforts for vaccine development.
With vaccines anticipated in the next 5 years for both pathogens, this pre-licensure window, together with our
recent development of a successful cultivation system for HuNoVs using stem cell-derived human intestinal
organoids (HIOs) and the recent description of RSV infections in human lung organoids (HLOs) provide an ideal
window to apply analytical genomics and functional studies in relevant human culture systems to address key
questions about HuNoV and RSV diversity, evolution and virulence. Our proposed studies utilize carefully
selected clinical specimens covering the spectrum of HuNoV and RSV illness, including: (i) acute gastroenteritis
in immunocompetent children from two populations (USA and Hong Kong), (ii) acute respiratory infections in
children in the CDC sponsored New Vaccine Surveillance Network, (iii) well-controlled volunteer HuNoV
challenge studies, (iv) transplant and immunocompromised patients with chronic HuNoV infection or acute RSV
infection, (v) the first randomized double-blind clinical trial of nitazoxanide (NTZ) for treatment of chronic HuNoV
in transplant recipients, and (vi) women and infants in the first phase III trial of an RSV-F vaccine (Novavax) in
healthy pregnant women for preventing disease in their infants. In addition to pathogen-targeted sequencing, we
will evaluate the role of the ecological niche in viral pathogenesis using high throughput, integrated sequencing
approaches to profile the bacteriome and virome of clinical samples. Full-length (FL) genomic analyses of
HuNoV and functional studies in HIEs will provide critical information on virus diversity in different populations
and over time in diverse hosts, the presence of intragenotypic and intergenotypic recombinants, and the
appearance of mutants with treatment resistance to NTZ. FL genomic analyses of RSV and functional studies in
HLOs and other cell lines will establish specific viral signatures of RSV disease severity, enable understanding
the effects of immune pressure and immunotherapeutics on the viral genome including antigenic site specific
motifs, and changes in B and T cell epitopes. The scientific community will benefit immensely from large
databases of FL genomes for HuNoV and RS...

## Key facts

- **NIH application ID:** 10446474
- **Project number:** 3U19AI144297-03S1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Mary Kolb Estes
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $499,999
- **Award type:** 3
- **Project period:** 2021-08-17 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446474

## Citation

> US National Institutes of Health, RePORTER application 10446474, Viral Diversity and Pathogenicity in Mucosal Respiratory and Gastrointestinal Disease (3U19AI144297-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10446474. Licensed CC0.

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