# Targeting abnormal alveolar immune activation and failed epithelial repair in COVID-19

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $742,194

## Abstract

PROJECT SUMMARY
This application directly stems from our recent publication in Nature in which we analyzed bronchoalveolar
lavage (BAL) fluid from 88 patients with critical SARS-CoV-2 pneumonia using a combination of flow cytometry,
bulk transcriptomic profiling of flow sorted alveolar macrophages and, in some patients, single cell RNA-
sequencing. We compared these data with analogous samples collected from 211 patients with pneumonia
secondary to other pathogens before and during the pandemic with a goal of identifying unique pathobiologic
features of SARS-CoV-2 pneumonia. Using these data, we generated the hypothesis that SARS-CoV-2 causes
a slowly unfolding, spatially limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 and
cross-reactive T cells form a positive feedback loop that drives progressive alveolar inflammation. We
address key questions from this hypothesis in three interrelated Specific Aims.
Aim 1. To determine whether alveolar macrophage infection and activation of cross-reactive memory T
cells drive alveolar macrophage/T cells circuits in patients with SARS-CoV-2 pneumonia. We will examine
the role of cross-reactive antibodies in mediating alveolar macrophage infection with SARS-CoV-2. We will also
examine the role of cross-reactive memory T cells recognizing SARS-CoV-2 and other coronaviruses in
establishing and maintaining positive feedback loops between T cells and infected alveolar macrophages and
the role of these signaling loops in initiating persistent lung and systemic inflammation.
Aim 2. To determine whether calcium channel activation by the envelope protein of SARS-CoV-2 is
necessary for activation of IL-1β in human alveolar macrophages. We will infect human alveolar
macrophages with mutant SARS-CoV-2 viruses lacking calcium channel activity in the envelope protein and
measure their generation of IL-1β in human alveolar macrophage in vitro.
Aim 3. To determine whether a pharmacologic inhibitor of CRAC channel activation can attenuate
alveolitis in patients with severe SARS-CoV-2 pneumonia by disrupting circuits between infected
alveolar macrophages and cross-reactive T cells. We are actively enrolling in a clinical trial to determine the
biologic effects of a small molecule inhibitor of CRAC channel activation using sequential analysis of BAL fluid
collected from patients with SARS-CoV-2 pneumonia requiring mechanical ventilation. We will use novel data
science approaches to integrate the clinical and genomic data generated from this study.
We have assembled a unique group of investigators with expertise in lung immunology, clinical trials, calcium
channels and virology. Our studies will explore possible reasons for the observed variability in disease severity
after SARS-CoV-2 infection, offer mechanisms to credential CRAC channel inhibitors as both anti-inflammatory
and possible antiviral therapeutics in patients with severe SARS-CoV-2 pneumonia, and provide a framework
for future clinical trials des...

## Key facts

- **NIH application ID:** 10596990
- **Project number:** 5R01HL158139-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** GR Scott Budinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $742,194
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596990

## Citation

> US National Institutes of Health, RePORTER application 10596990, Targeting abnormal alveolar immune activation and failed epithelial repair in COVID-19 (5R01HL158139-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10596990. Licensed CC0.

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