# Molecular mechanisms of sex difference in COVID-19 enabling novel therapeutics

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $155,866

## Abstract

ABSTRACT
The central focus of this Administrative Supplement application to is to identify detailed molecular mechanisms of
estrogen-dependent sex difference in COVID-19 to enable development of novel therapeutics that are in urgent need
to control the pandemic. The outbreak of coronavirus disease 2019 (COVID-19) has become a worldwide pandemic
that has remained uncontained. We have previously published a classical article to recognize sex difference of
COVID-19 for the first time, documenting that males are more susceptible to COVID-19 than females, and more often
to develop more severe disease with higher mortality (Cai H, Lancet Respiratory Medicine, April 2020, Citation: 549
by 01/22/22). This important observation has been further confirmed by additional literatures. The gender difference
observed in COVID-19 patients is potentially linked to higher prevalence of cigarette smoking in men that was shown
to be associated with higher viral receptor ACE2 levels. However, we found that protein levels of ACE2 and TMPRSS2
were not changed in endothelial cells exposed to cigarette smoking extract (CSE). The otherwise observed worse
outcomes in COVID-19 patients who are smokers, is likely linked to baseline respiratory diseases associated with
chronic smoking. Instead, we hypothesize that estrogen mediated protection might however underlie less severe
disease in females, and that short term estrogen administration might be used as a robust therapeutic option for the
treatment of COVID-19, especially in men and postmenopausal women. This is supported by strong preliminary data
and our latest publication indicating that SARS-CoV-2 spike protein (S protein) and interleukin-6 (IL-6) stimulated
endothelial cell NADPH oxidase isoform 2 (NOX2) activation and oxidative stress, as well as upregulation of viral
receptor ACE2 and inflammatory protein MCP-1, were all substantially attenuated by estrogen treatment (Redox
Biology, Aug 2021). The upregulation in NOX2 and MCP-1 by S protein is mediated by activation of ACE2 since
blockage of ACE2 with neutralizing antibody was able to abrogate the responses. These data indicate that oxidative
stress and endothelial dysfunction triggered by initial viral infection (S protein), and by cytokine storm (IL-6) at later
stage, which represent major pathological features of acute lung injury (ALI)/acute respiratory distress syndrome
(ARDS)/multi-organ failure, can all be remarkably alleviated by estrogen to effectively reduce disease severity and
mortality. The current project aims to address two specific aims: 1) To examine whether estrogen treatment alleviates
SARS-CoV-2 S protein induced ALI/ARDS and multi-organ injuries in vivo via abrogation of p22phox and p47phox-
dependent activation of NOX2 and activation of netrin-1 signaling. 2) To identify and validate novel genes and gene
pathways/networks regulated by S protein and estrogen with a special focus on netrin-1 signaling, enabling
discoveries of novel therapeutic ta...

## Key facts

- **NIH application ID:** 10555078
- **Project number:** 3R01HL142951-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Hua Linda Cai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $155,866
- **Award type:** 3
- **Project period:** 2020-04-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10555078

## Citation

> US National Institutes of Health, RePORTER application 10555078, Molecular mechanisms of sex difference in COVID-19 enabling novel therapeutics (3R01HL142951-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10555078. Licensed CC0.

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