# A Secreted Viral Protein Determines Norovirus Persistence By Immune Evasion

> **NIH NIH R00** · BROWN UNIVERSITY · 2021 · $244,979

## Abstract

Project Summary/Abstract
 This proposal describes a four year career development plan and a research strategy for Dr. Sanghyun
Lee to transition from a postdoctoral fellow to an independent academic faculty position investigating virus-host
interactions. The overall research goal of the proposal is to elucidate the mechanism by which a secreted viral
non-structural protein antagonizes host immunity, and to evaluate this viral factor as a novel vaccine target.
Candidate: I have focused my science career on understanding virus and host interactions at both molecular
and physiological levels. In my Ph.D. work with Dr. Kwangseog Ahn at Seoul National University in Korea, I
worked on understanding the virulence of human cytomegalovirus (HCMV), and specifically focused on the
factors contributing to HCMV virulence in human patients. As a postdoc in Dr. Skip Virgin's lab at Washington
University School of Medicine, I studied the cellular tropism of norovirus and the key host immune system
determinants controlling norovirus infection in the gut.
Career Development Plan: In addition to the research proposal outlined here, I will devote approximately 15%
of my time to training activities. I will continue my professional development under the guidance of my mentor
Dr. Virgin's and my co-mentor Dr. Gaya Amarasinghe. I have assembled a career advisory committee
composed of Dr. Michael Diamond, Dr. Megan Baldridge, and Dr. Haina Shin that will evaluate and facilitate
my research progress and transition to independence. Beyond these training activities, I will prepare to
transition to an independent faculty position by improving grant-writing and interviewing skills through
workshops at WUSM, and begin planning for the new financial, management, and mentorship responsibilities
of an independent investigator.
Research Project: Human noroviruses (HNoVs) are the leading global cause of gastroenteritis. However,
there are no approved vaccines or therapeutics. With Murine norovirus (MNoV) model, we identified Tuft cells,
a rare type of intestinal epithelial cell (IEC), as the reservoir for MNoV fecal shedding and persistence. Genetic
studies revealed that viral non-structural protein NS1, rather than a viral surface protein, is the determinant of
Tuft cell tropism, and interferon-lambda (IFN-λ) to be a key host determinant. Our preliminary data suggests
that the NS1 protein is cleaved by host caspase(s) and secreted into the extracellular space, and NS1 blocks
IFN-λ production. Therefore, we hypothesize that secreted NS1 protein antagonizes IFN-λ production, and that
this antagonism is the key determinant of in vivo Tuft cell tropism. The long-term goal of this study is to
understand the molecular mechanism of NS1 secretion and IFN-λ immune evasion by MNoV, and to apply our
findings to evaluate secreted NS1 as a candidate for vaccine and therapeutic development in humans.

## Key facts

- **NIH application ID:** 10219936
- **Project number:** 5R00AI141683-03
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Sanghyun Lee
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $244,979
- **Award type:** 5
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219936

## Citation

> US National Institutes of Health, RePORTER application 10219936, A Secreted Viral Protein Determines Norovirus Persistence By Immune Evasion (5R00AI141683-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10219936. Licensed CC0.

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