# Immune mechanisms of influenza-induced exacerbation of atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $389,555

## Abstract

Immune mechanisms of Influenza-induced exacerbation of atherosclerosis
Influenza A infection is a significant cause of mortality and morbidity worldwide. It is estimated that 3-4 million
cases of severe illness and 300,000 deaths due to influenza infection occur annually. During influenza
pandemics, the focus is on lung disease, which is the most common cause of death. However, recent
epidemiological studies reported significant mortality associated with cardiovascular diseases (CVD) during
influenza infection. Atherosclerosis is a common cause of coronary artery disease (CAD), including MI, stroke,
and heart failure. The innate and adaptive immune response to modified lipids and vascular endothelial cells
causes a series of events that result in plaque formation in medium to large-sized arteries. If inflammatory stimuli
continue, plaques become vulnerable to rupture and can cause MI. However, the mechanism involved in the
influenza-induced increase in MI incidence is not clear.
Our long-term research goal is to understand the impact of lung-vascular interactions in atherosclerosis. The
objective of this application is to determine how influenza infection directly or indirectly impacts the outcome of
atherosclerosis. In Aim 1, we will characterize myeloid and lymphoid cellular subsets from lung, aorta, and spleen
at various time points (early, peak, recovery phase) after fluorescent-labeled (Color-flu) influenza infection to
track influenza virus along with the cellular recruitment to the vessel. We will then examine whether antigen
presentation is impacted by oxidized LDL (oxLDL) using bone marrow dendritic cells (BMDCs) and T cell re-
stimulation in vitro. In Aim 2, we will determine the role of type III IFNs (IFNλ) systemically (intraperitoneal) or
locally in the lung (oropharyngeal) in influenza-induced exacerbation of atherosclerosis. Further, we will
determine the effect of IFNλ on foam cell formation in macrophages. Finally, we will determine the effect of
conditioned media from influenza or type I (IFNβ), type II (IFNγ), and type III (IFNλ)-treated human bronchial
epithelial cells (HBE) on human primary aortic endothelial cells (HAEC) to identify the mechanism involved in
the lung-vascular interactions in atherosclerosis. In Aim 3, we will determine the effect of IL-17 neutralization
systemically (intraperitoneal) or locally in the lung (oropharyngeal) in influenza induced-exacerbation of
atherosclerosis. Further, we will determine the effect of lung epithelial IL-17RC signaling during influenza
infection in atherosclerotic Apoe-/- mice. Finally, we will determine the effect of conditioned media from influenza-
infected or IL-17-treated human bronchial epithelial cells (HBE) on vascular endothelial cells (HAEC) to identify
the mechanism involved in the lung-vascular interactions in atherosclerosis. At the completion of these studies,
we expect to have made mechanistic insights into the cellular trafficking, viral trafficking, systemic and...

## Key facts

- **NIH application ID:** 10050331
- **Project number:** 1R01HL146479-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Radha Gopal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,555
- **Award type:** 1
- **Project period:** 2020-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050331

## Citation

> US National Institutes of Health, RePORTER application 10050331, Immune mechanisms of influenza-induced exacerbation of atherosclerosis (1R01HL146479-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10050331. Licensed CC0.

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