# COVID-19 imprints airway basal cells to impair epithelium regeneration

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $208,750

## Abstract

PROJECT SUMMARY
COVID-19 (CoV19) is caused by SARS-CoV-2 infection of the airway epithelium resulting in extensive
damage in the lower respiratory tract. Since 2020, CoV19 has claimed over 1 million lives in the United
States surpassing the death toll of the 1918 H1N1 influenza pandemic. Clinical studies show that the
mortality and morbidity of CoV19 is associated with secondary infection. Given a central role of the airway
epithelium as a barrier against pathogens, preliminary studies tested whether airway basal stem cells
(BSCs) are impaired in their regenerative function in CoV19 patients. Of note, BSCs are a major type of
stem cells responsible for epithelium regeneration following respiratory viral infection in humans. In
preliminary studies, we derived 6 lines of BSCs from severe cases of CoV19 using tracheal aspirate (TA)
as a source of bronchial BSCs. These CoV19-exposed BSCs were tested free of virus; however, they
show early cell cycle arrest, sustained STAT3 hyperactivity, and defective differentiation in air-liquid
interface. In contract, BSCs derived from TA of control patients with neurogenic and cardiogenic
respiratory failure have no such defects. Similar to our findings in vitro, antibody staining of fatal CoV19
lung sections revealed increased senescence and defective differentiation of BSCs. In addition, CoV19-
exposed BSCs in vitro maintained, at least partially, an inflammatory gene signature that was found in
BSCs in vivo by single cell-seq of lung samples from CoV19 patients. As such, BSCs derived from TA of
CoV19 patients provide a viable cell model to investigate how CoV19 impairs epithelial regeneration by
inducing an inflammatory memory in BSCs. Mechanistically, CoV19-exposed BSCs exhibit unique
chromatin opening at sites enriched for transcriptional factors mediating the inflammatory pathways, such
as STAT3. Based on these preliminary findings, we hypothesize that inflammation in CoV19 causes
an epigenetic memory in BSCs to impair epithelium regeneration. Leveraging our ability to derive
TA BSCs, Aim1 will test whether CoV19 uniquely reprograms BSCs compared to other acute respiratory
infections. Aim 2 will identify the molecular mediators of the inflammatory memory in CoV19-exposed
BSCs using complementary assays. The rescue assay will test whether blocking STAT3 hyperactivity
and reversing epigenetic modification in CoV19-exposed BSCs will normalize their role in epithelial
regeneration. The disease-mimicking assay will assess the activity of inflammatory signals in memory
induction in healthy control BSCs. The proposed exploratory studies will lay the foundation for future
delineation of inflammatory signals and intracellular mediators in the disease memory of BSCs using
genetic approaches and animal models of SARS-CoV-2 infection. Our findings will inform therapeutics to
facilitate epithelial regeneration in severe cases of CoV19.

## Key facts

- **NIH application ID:** 10914242
- **Project number:** 5R21AI173494-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Xingbin Ai
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $208,750
- **Award type:** 5
- **Project period:** 2023-08-25 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914242

## Citation

> US National Institutes of Health, RePORTER application 10914242, COVID-19 imprints airway basal cells to impair epithelium regeneration (5R21AI173494-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10914242. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*