R01HL165258

Mechanisms of Atherosclerotic Cardiovascular Complications in COVID-19 - Project Summary

The Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), remains a global health concern. Despite the fast-track development of vaccines and the imminent prospect of new antiviral drugs, COVID-19 is expected to become endemic.

COVID-19 is associated with atherosclerotic cardiovascular (CV) complications like Acute Coronary Syndrome (ACS), Myocardial Infarction (MI), and Stroke. This risk remains high for up to one year following recovery, but the underlying mechanisms are poorly understood.

In preliminary work using atherosclerotic tissue from COVID-19 patients at autopsy and subjects who recovered from COVID-19, along with an ex-vivo SARS-CoV-2 model of human vascular explants, we identified SARS-CoV-2 viral material in human plaques that persists in plaques of patients who recovered from COVID-19.

Single cell RNA sequencing (scRNAseq) of human atherosclerotic plaques identified high levels of Neuropilin-1 (NRP1), a receptor for SARS-CoV-2 entry, in plaque macrophages and foam cells. NRP-1 blockade abrogated the accumulation of viral material in SARS-CoV-2 treated human plaques.

These data suggest that SARS-CoV-2 or its viral components can accumulate in human plaques, where they exacerbate inflammation and disease progression by engaging NRP-1.

Using the Syrian Golden Hamster model, which faithfully mimics human SARS-CoV-2 infection, we found that viral replication in the heart, lungs, and olfactory bulb of infected hamsters did not correlate with expression levels of ACE2, supporting a role for alternative mechanisms of viral entry such as NRP-1.

Moreover, this model revealed acute and sustained tissue-specific inflammatory responses (i.e., NFKB1, IL6, IL1B) in several tissues due to the persistence in the circulation of noninfectious viral RNA debris (VRNA) for up to several weeks following viral clearance.

Based on these exciting preliminary data, we propose two independent aims to study how SARS-CoV-2 aggravates plaque inflammation and atherosclerosis and to determine the molecular basis for the increased risk of acute and long-term CV events in COVID-19 patients.

In Aim 1, we will identify the role of NRP-1 in SARS-CoV-2-induced atherosclerotic plaque inflammation and atherosclerosis progression. Aim 2 will identify the contribution of SARS-CoV-2 VRNA debris to inflammation and atherosclerosis. We will also determine the effect of persistent VRNA on inflammation and atherogenesis following viral clearance and recovery from COVID-19.

These studies will address important gaps in knowledge on the effect of SARS-CoV-2 infection on plaque inflammation and atherosclerosis and will tackle the molecular basis for the increased CV risk in patients with COVID-19.

We foresee that this information will help guide the future design of precise therapies to prevent CV outcomes in patients with COVID-19.

New York University

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

New York, New York 10016 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 291% from $803,677 to $3,139,538.