EMMANUEL FRANCK MONGODIN
$633,045
Lianghui Zhang
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Pennsylvania
National Heart Lung and Blood Institute (NHLBI)
Post-acute sequelae of COVID-19 (PASC) is an emerging public health priority with up to 18% prevalence. Noteably, almost 30% patients diagnosed with PASC experence exercise intolerance. This activity limitation continues to negatively impact our workforce, and poses a persistent socialeconimic burden on our society. Our Post-Covid Recovery Clinic, a RECOVERY Vital site, has evaluated exercise intolerant PASC for nearly 4 years. We recently discovered pathophysiologic endotypes that contribute to exercise intolerance in PASC via invasive cardiopulmonary exercise testing (iCPET). Yet, the molecular drivers for this population remain elusive. Four- years after the onset of the pandemic we are left without PASC-defining biomarkers, or targeted therapeutics. Thus, it is crucial to investigate the interconnected molecular and pathophysiologic links in exercise intolerant PASC, a task uniquely within our team’s expertise. Angiotensin-converting enzyme 2 (ACE2) is not just an entry receptor for SARS-CoV-2 but also an enzyme with a protective function through regulation of the renin- angiotensin system. Studies have shown that a high level of plasma ACE2 is associated with an increased risk of SARS-CoV-2-related mortality. Our preliminary data showed that the catalytic activity of increased plasma ACE2 was significantly impaired in the exercise intolerant PASC patients, and closely correlated with reduced exercise capacity as measured by peak oxygen consumption evaluated during iCPET. Furthermore, to study the pathogenic mechanism of exercise intolerance in PASC, we established a novel PASC mouse model. In this model, we observed the persistence of the SARS-CoV-2 RNAs in lung microvascular ECs, impaired ACE2 activity, chronic pulmonary inflammation, along with a significant reduction in exercise capacity. Thus, we hypothesize that dysfunctional ACE2 shed from pulmonary ECs is a major driver for exercise intolerance in PASC and an engineered solube ACE2 with enhanced ACE2 activity will improve exercise capacity of PASC. To test our hypotheses, we will investigate the predictive value of ACE2 activity as a clinical biomarker and assess its association with exercise capacity over 12 months in PASC patients in Aim 1. We will define an engineered soluble ACE2 with enhanced ACE2 activity as an innovative therapeutic intervention to improve exercise capacity and vascular function in the PASC mouse model in Aim 2. Furthermore, we will explore the mechanism of ACE2 dysfunction shed from the pulmonary vasculature in Aim 3. If successful, we will identify a diagnostic and therapeutic paradigm urgently needed for PASC patients experiencing exercise intolerance, and remediate the deficient response to this global public health threat.