# Impact of Heterogeneous Airway Epithelial ACE2 Expression and Interferon Responses on SARS-CoV2 Infectivity and Replication

> **NIH NIH K24** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $193,352

## Abstract

Project Summary
This application is an Emergency Competitive Revision (PA-20-135) to existing NIH award K24AI150991
proposing immediate work to help address the urgent need for research on Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19). While the majority of
cases of COVID19 result in mild symptoms, some progress to respiratory and multi-organ failure. The case
fatality rate for COVID19 varies widely according to age group and underlying medical comorbidities. There an
urgent need to improve our understanding of mechanisms that underlie the heterogeneity of disease severity
with SARS-CoV2 infection between individuals and explain why children are more resistant to developing
severe COVID-19 than adults. Such knowledge will be critical in developing novel therapeutic interventions to
treat and prevent SARS-CoV2 infection and COVID19 disease. One theory for the widely varying COVID-19
disease severity between children and adults, and even between older adults, is heterogeneity between
individuals in how the virus gains entry to airway epithelial cells (AECs). The spike protein of SARS CoV2 uses
angiotensin converting enzyme 2 (ACE-2) as its cell binding site and the membrane serine protease TMPRSS2
primes the spike protein. In humans it is unknown if epithelial expression of ACE-2 or TMPRSS2 are lower
among children as compared to adults. In animals two common antihypertension medications (angiotensin II
receptor blockers, ARBs; and angiotensin-converting-enzyme inhibitors, AECi) increase ACE-2 expression,
fueling debate about the effect of these drugs on the infectivity of SARS-CoV2 and risk of COVID-19. We
recently observed that ACE-2 expression by bronchial AECs from children increases following infection with
human rhinovirus, prompting us to question whether a recent rhinovirus infection modulates SARS-CoV2
infection and the risk of COVID-19. The first aim of this Competitive Revision is to determine whether bronchial
AEC expression of ACE-2 varies with age or pre-infection with human rhinovirus, and whether treatment of
AECs with ARBs, ACEi or exogenous ACE-2, modulate SARS CoV2 infectivity and replication. A second
potential explanation for varying COVID-19 disease severity is heterogeneity in type I and III interferon (IFN
I/III) responses between individuals to SARS-CoV2. The second aim of this Competitive Revision, which
logically extends from the goals of the applicant’s parent award (K24AI150991), is to determine if heterogeneity
of AEC IFN I/III responses following SARS-CoV2 infection of primary AECs from children and adults is
associated with viral replication, and whether the drug azithromycin increases AEC IFN I/III responses to
SARS-CoV2 and reduces viral replication. Finally, this supplement to K24AI150991 will also support the direct
mentorship of 3 junior faculty physician-scientists and a PhD candidate who are all engaged in mechanistic
COVID-19 patient-oriented research und...

## Key facts

- **NIH application ID:** 10154401
- **Project number:** 3K24AI150991-01S1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** JASON S DEBLEY
- **Activity code:** K24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,352
- **Award type:** 3
- **Project period:** 2020-07-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10154401

## Citation

> US National Institutes of Health, RePORTER application 10154401, Impact of Heterogeneous Airway Epithelial ACE2 Expression and Interferon Responses on SARS-CoV2 Infectivity and Replication (3K24AI150991-01S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10154401. Licensed CC0.

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