# Mechanisms of innate resistance to virus infections

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $471,166

## Abstract

SUMMARY
Cardiac dysfunction is among the most common extrapulmonary complications of severe influenza virus
infections. Although the heart complications of influenza virus infection are a clearly recognized clinical
problem, they are poorly studied in terms of pathogenic mechanisms. We lack basic scientific understanding of
1) whether influenza virus directly or indirectly causes heart damage, 2) what viral features facilitate cardiac
tropism of certain strains, 3) how virus disseminates from the lung specifically to the heart in the absence of
viremia, and 4) how the immune system influences heart pathogenesis. The major barrier to mechanistic
research in this area has been the lack of tractable animal models that recapitulate significant cardiac
dysfunction in severe influenza. We have overcome this obstacle by developing interferon-induced
transmembrane protein 3 (IFITM3) KO mice as a model of severe influenza virus infection that includes viral
replication in the heart and significant cardiac electrical dysfunction, inflammation, and fibrosis. Importantly,
IFITM3 is an antiviral protein of the innate immune system in which common deficiencies in the human
population render individuals more susceptible to severe infections, making IFITM3 KO mice a relevant and
informative model. We will make use of this groundbreaking model in the following three Aims. In Aim 1, we
will determine whether virus dissemination and replication directly in heart tissue is required for this pathology
or whether influenza virus indirectly induces heart dysfunction through systemic inflammation from the severely
infected lung. To address this fundamental controversy in the field, we have developed a novel and innovative
recombinant influenza virus strain with specific inability to replicate in heart cells while being fully replicative in
the lung. In Aim 2, we will identify viral features that endow specific virus strains with cardiac tropism by using
a candidate viral gene approach with reassortant viruses, as well as an adaptive passaging approach. In Aim
3, we will solve the mystery of how influenza virus moves specifically from the lung to the heart in the absence
of viremia and other organ infections. For this, we will test whether infection of migratory immune cells
facilitates virus trafficking to the heart. We will further investigate how IFITM3 expression in hematopoietic
immune cells influences cardiac dissemination of virus and cardiac dysfunction during infection. Overall, our
research will answer fundamental questions in the influenza field, and will reveal new strategies for combatting
influenza-associated cardiac dysfunction.

## Key facts

- **NIH application ID:** 10367235
- **Project number:** 2R01AI130110-06
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jacob Yount
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $471,166
- **Award type:** 2
- **Project period:** 2017-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367235

## Citation

> US National Institutes of Health, RePORTER application 10367235, Mechanisms of innate resistance to virus infections (2R01AI130110-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10367235. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*