# Elucidating the roles of the beta-2 adrenergic receptor and epidermal growth factor receptor in flavivirus NS1-mediated endothelial dysfunction

> **NIH NIH K22** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $162,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Research Project: Dengue virus (DENV) is a medically important pathogen posing a major public health threat.
DENV infection can result in potentially fatal cases of severe dengue associated with vascular leak as a result
of endothelial dysfunction, but the triggers of these pathologies were unknown. We and others have defined a
direct role for the DENV non-structural protein 1 (NS1) in mediating endothelial dysfunction in vitro and vascular
leak in vivo, independently from viral infection, via direct interactions with endothelial cells. Our preliminary data
indicate that NS1 binding to endothelial cells and uptake via clathrin-mediated endocytosis are distinct steps that
are both critical for NS1-mediated endothelial dysfunction, but the NS1 receptors on endothelial cells that
mediate uptake of NS1 are unknown. My preliminary data identified a role for beta-2 adrenergic receptor (β2AR)
and epidermal growth factor receptor (EGFR) in NS1-mediated endothelial dysfunction. Further, activation of
β2AR has been reported to transactivate EGFR, triggering endocytosis. Thus, I hypothesize that β2AR and
EGFR serve as a NS1 receptor complex where NS1 functions as a β2AR agonist to trigger EGFR-
mediated endocytosis. This proposal will test this hypothesis by investigating the capacity of NS1 to activate
β2AR and EGFR signaling pathways in Aim 1. Aim 2 will investigate the capacity of β2AR and EGFR to serve
as NS1 receptors. The proposal holds the potential to characterize a fundamental and novel step in dengue virus
pathogenesis via identification of NS1 receptors which also serve as therapeutic targets for treatment of dengue.
Candidate and Career Goals: The candidate for this K22 proposal has a strong track record investigating host-
pathogen interactions from his work studying entry mechanisms of Nipah virus as an undergraduate student in
the labs of Dr. Benhur Lee and Dr. Hector Aguilar-Carreno at the University of California, Los Angeles,
investigating innate immune mechanisms by which interferons control viral infection as a graduate student in Dr.
Seungmin Hwang’s lab at the University of Chicago, and investigating flavivirus NS1-mediated pathogenesis as
a postdoctoral scholar in Dr. Eva Harris’s lab at the University of California, Berkeley. In Dr. Harris’s lab, Dr.
Biering recently identified candidate NS1 receptors on endothelial cells and will investigate their role in NS1
pathogenesis in this proposal. Dr. Biering is committed to establishing his own research group at a major
research university where he will investigate mechanisms by which viral pathogens cause disease.
Career Development Plans and Environment: Dr. Biering will work with his mentor (Dr. Eva Harris) and
mentoring committee (Dr. Britt Glaunsinger, Dr. Michael Diamond, Dr. Kamil Godula, Dr. Suzanne Fleiszig, and
Dr. P. Robert Beatty) to acquire additional training in biochemistry, advanced-microcopy, glycobiology, and in
vivo models of virus infection whic...

## Key facts

- **NIH application ID:** 10507221
- **Project number:** 1K22AI170797-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Scott Benjamin Biering
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $162,000
- **Award type:** 1
- **Project period:** 2024-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10507221

## Citation

> US National Institutes of Health, RePORTER application 10507221, Elucidating the roles of the beta-2 adrenergic receptor and epidermal growth factor receptor in flavivirus NS1-mediated endothelial dysfunction (1K22AI170797-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10507221. Licensed CC0.

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