# Mechanisms of Cardioprotection by the Innate Immune System During Influenza Virus Infections

> **NIH NIH R21** · OHIO STATE UNIVERSITY · 2020 · $187,776

## Abstract

SUMMARY
Although influenza virus has been known for more than a century to be a cause of infectious myocarditis, the
underlying mechanisms and susceptibility factors for these cardiac complications are not well understood.
Cardiac dysfunction is primarily seen in severe infections, and severe influenza in humans has been
reproducibly linked to deleterious polymorphisms in the Interferon-Induced Transmembrane Protein 3 (IFITM3)
gene. IFITM3 is an innate immune protein that blocks virus entry into cells and regulates inflammatory immune
pathways. Despite the knowledge that IFITM3 influences the outcome of human infections, its role in cardiac
complications of influenza has not been previously investigated. Our experiments using a newly developed
IFITM3 knockout mouse model indicate that IFITM3 is essential for limiting influenza virus spread to the heart
and for preventing cardiac fibrosis and electrical dysfunction caused by the virus. We have also observed that
immune cells are depleted from hearts of IFITM3 knockout mice during infection, thus preventing cardiac
clearance of virus. In Aim 1, we will investigate the cause of this immune cell depletion by testing the
hypothesis that IFITM3-deficient immune cells residing in, or recruited to, the heart are directly infected by virus
and undergo apoptosis. In Aim 2, we will identify the mechanism by which fibrosis and cardiac dysfunction
occur during infection by testing the hypothesis that virus infection activates specific inflammatory and fibrotic
gene profiles in cardiomyocytes and cardiac fibroblasts in the absence of IFITM3. Overall, our research will
reveal mechanisms underlying cardiac fibrosis and dysfunction in severe influenza virus infections and will thus
identify new strategies for combatting this infection-induced pathology.

## Key facts

- **NIH application ID:** 9929529
- **Project number:** 5R21AI146690-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Murugesan Rajaram
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $187,776
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929529

## Citation

> US National Institutes of Health, RePORTER application 9929529, Mechanisms of Cardioprotection by the Innate Immune System During Influenza Virus Infections (5R21AI146690-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9929529. Licensed CC0.

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