# Genetic and Epigenetic Programming of Allergic Airway Inflammation

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $127,625

## Abstract

ABSTRACT
This supplement was written in response to the original NOT-AI-20-031: Notice of Special Interest (NOSI):
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19),
and submitted under PA-18-591]. COVID19, caused by the betacoronavirus clade SARS-CoV-2, ranges
from asymptomatic disease to fatal multi-organ failure. Both innate and T cell-mediated adaptive immunity are
important for limiting viral replication. Nevertheless, hyperactivation of the immune response in patients with
more severe disease may precipitate a “cytokine storm” that results in aggravated morbidity and high mortality.
Relevant to the role of immune hyperactivation in COVID disease pathogenesis are our recent studies on
asthmatic inflammation showing how allergens and air pollution particulate matter (PM) overcome immune
tolerance mechanisms operating in the airway to license tissue inflammation. We identified the JAG1-NOTCH4
axis as a key pathogenic mechanism activated by the allergens and PM that acts as a molecular switch to break
down immune tolerance in the lung and consequently promote inflammation. Along this mechanism we identified
that NOTCH4 was selectively induced on lung Treg cells in an allergen and interleukin-6 (IL-6)-dependent
manner, and it directed their subversion into Th2/Th17 effector-like T cells. Importantly, our preliminary results
reveal that NOTCH4 expression is upregulated on circulating Treg cells of COVID19 subjects as a function of
disease severity, thus implicating this mechanism in disease pathogenesis in COVID19 subjects. Our central
hypothesis is that dysregulation of innate and adaptive immunity in COVID19 involves the subversion of
Treg cells in an IL-6 and NOTCH4-dependent manner. Our study team is composed of a multidisciplinary
group of R01-funded investigators with prior collaborative work, clinical expertise in the care of critically ill
COVID19 patients, and research expertise in the role of Treg cells in immunological tolerance. We propose to
profile the innate and adaptive immune responses in subjects with mild-moderate and severe COVID19 disease
as compared to convalescent and healthy control subjects. We will correlate these changes with NOTCH4
expression on circulating Treg cells and the latter’s immune regulatory functions. We will also examine the impact
of Notch4 expression on transcriptional alterations in Treg and T effector cells in patients with COVID-19. Our
studies offer a mechanistic approach to the elucidation of the enigma of immune hyperactivation in COVID19
and the promise to identify targets for precision therapy in this disease.

## Key facts

- **NIH application ID:** 10169796
- **Project number:** 3R01AI065617-19S1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Talal Amine Chatila
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $127,625
- **Award type:** 3
- **Project period:** 2020-06-12 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169796

## Citation

> US National Institutes of Health, RePORTER application 10169796, Genetic and Epigenetic Programming of Allergic Airway Inflammation (3R01AI065617-19S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10169796. Licensed CC0.

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