# Mechanisms of childhood obesity underlying the susceptibility to multisystem inflammatory syndrome in children (MIS-C)

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $442,500

## Abstract

PROJECT SUMMARY/ABSTRACT
 Unpredictability is the hallmark of Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a
severe pediatric complication of SARS-CoV-2 infection. MIS-C is distinct from COVID-19. It is not associated
with pre-existing cardiopulmonary, autoimmune, or hematologic disorders. It can occur either during acute phase
with detectable SARS-CoV-2 virus, or in the post-infectious period of several weeks after acute infection. Milder
symptoms of MIS-C include fevers, rashes, and gastrointestinal symptoms, but can progress to cytopenias,
coagulopathy, myocardial dysfunction, coronary aneurysms, and/or shock. We and others have found that MIS-
C is associated with pediatric overweight and obesity, thereby identifying over 380 million children at risk for this
disease. The mechanisms by which overweight and obesity influence the development of MIS-C are unknown.
Until a vaccine against SARS-CoV-2 is globally available to all children, they will remain vulnerable to MIS-C.
 Our preliminary studies indicate that MIS-C is a highly inflammatory disease that incites more severe
immune cell activation than COVID-19, particularly in overweight and obese children. Overweight and obese
children with MIS-C had more T cell lymphopenia and T cell activation than their normal weight counterparts,
suggesting an increased risk for more severe disease. Deleterious genetic variants increasing IFN and
inflammatory signaling were exclusively found in patients with MIS-C, rather than severe COVID-19. This is a
mechanistic counterpoint to defective IFN signaling associated with severe COVID-19 in adults. Our central
hypothesis is that pediatric overweight and obesity prime interferon signaling, thereby increasing T cell
activation and ultimately, the risk of MIS-C
Aim 1 will elucidate how pediatric overweight and obesity drive immune cell dysfunction during MIS-C.
The proposed studies will test the hypotheses that pediatric overweight and obesity are associated with more
severe MIS-C, characterized by excessive interferon signaling and T cell activation.
Aim 2 will identify mechanistic risk factors for MIS-C. The proposed studies will test the hypothesis that,
even in the absence of infection, circulating immune cells from overweight and obese children exhibit an
increased interferon signature that promotes T cell activation. We will develop a strategy for stratifying MIS-C by
integrating genetic screening with measures of body mass index.
Building on collaborations spanning over a decade and unique cohorts of children with MIS-C and/or obesity,
our investigator team brings expertise in MIS-C, host immunity, pediatric obesity and endocrinology, and
multiomics. This project will generate causal insights of how overweight and obesity influence the development
and severity of MIS-C, with the goal of developing strategies for a population that remains at risk for this disease.

## Key facts

- **NIH application ID:** 10450145
- **Project number:** 5R01DK130465-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Janet Chou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,500
- **Award type:** 5
- **Project period:** 2021-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450145

## Citation

> US National Institutes of Health, RePORTER application 10450145, Mechanisms of childhood obesity underlying the susceptibility to multisystem inflammatory syndrome in children (MIS-C) (5R01DK130465-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10450145. Licensed CC0.

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