# Sex-Dependent Regulation of Host Factors Influencing SARS-CoV-2 Infection and COVID-19 Disease

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $241,688

## Abstract

Project Summary
COVID-19, the disease caused by the SARS-CoV-2 virus, commonly presents as pneumonia, with those most
severely affected progressing to Acute Respiratory Distress Syndrome (ARDS). Notably, males seem to be at
significantly higher risk for severe or fatal outcomes from COVID-19, and male-specific skewing was also
observed with related coronaviruses SARS-CoV and MERS. The X chromosome is enriched for immunity-related
genes, and females (XX) mount stronger immune responses than do males (XY). X-chromosome Inactivation
(XCI) normalizes the gene dosage effect between the sexes and we have previously found that immune cells
have novel and dynamic XCI mechanisms that allow for gene-specific transcriptional activation from the inactive
X (Xi) in a cell-type specific manner. Notably, our preliminary data suggest the regulation of XCI in lung alveolar
type 2 (AT2) cells, the predominant target of SARS-CoV-2 in the lung and a cell type critically involved in lung
repair following viral injury, phenocopies that seen in immune cells. As such, we will test the novel hypothesis
that X-linked genes, including immune genes and ACE2, escape XCI in a lineage-specific fashion and contribute
to the relative resistance of females to COVID-19 (Aim 1). We will test the hypothesis that our novel humanized
ACE2 mice, which are susceptible to SARS-CoV-2 infection, will exhibit sex differences with resulting lung
pathologies in aged mice (Aim 2). Together, these studies will further our understanding of the mechanisms that
predispose males to COVID-19 disease and will reveal novel strategies to reduce disease severity.

## Key facts

- **NIH application ID:** 10451255
- **Project number:** 1R21AI164006-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Montserrat C Anguera
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $241,688
- **Award type:** 1
- **Project period:** 2022-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451255

## Citation

> US National Institutes of Health, RePORTER application 10451255, Sex-Dependent Regulation of Host Factors Influencing SARS-CoV-2 Infection and COVID-19 Disease (1R21AI164006-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10451255. Licensed CC0.

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