Date of Award

7-12-2023

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Coronavirus Disease 2019 (COVID-19) is caused by SARS-CoV-2, a member of beta-coronaviridae family. This single-stranded RNA virus is transmitted through a respiratory route, binds to a host receptor ACE2 and enters lung pneumocytes, causing fulminant pulmonary disease in a subset of patients. In addition to pulmonary disease, SARS-CoV-2 can also lead to extrapulmonary manifestations, affecting brain, kidneys, blood vessels and heart. Cardiac complications are common in COVID-19 patients with both mild and severe clinical courses. However, it remains unclear which cardiac cell types are susceptible to SARS-CoV-2 and what the consequences of their infection are. In this work, I identified human cardiomyocytes and cardiac pericytes as cells that can be targeted by SARS-CoV-2 in the heart, established models of cell type-specific viral infection in vitro and developed a novel animal model of cardiac disease caused by this virus. Cardiomyocytes are specialized muscle cells that perform primary contractile function in the heart. Pericytes are one of the cellular components of the blood vessel wall and are important for endothelial cell homeostasis, blood vessel permeability, angiogenesis and direct modulation of blood flow. Infected human stem-cell derived cardiomyocytes produce infectious virions, release inflammatory cytokines, lose sarcomeres and contractile function and die. Human primary cardiac pericytes support productive viral replication, produce abundant inflammatory and vasoactive mediators, activate endothelial cells, and undergo cell death after being infected with SARS-CoV-2. Finally, I developed a mouse model to study SARS-CoV-2 associated cardiac disease using transgenic mice with cardiomyocyte-restricted expression of human ACE2. This model allowed me to study cardiac dysfunction as a result of cardiac infection with SARS-COV-2 isolated from the effects of pulmonary disease and associated systemic inflammation. These human ACE2-expressing mice support cardiac infection and show cardiac dysfunction, injury, and immunopathology that resembles cardiac manifestations of COVID-19. Cardiac injury observed in these animals is dependent on recruitment of CCR2+ cells, which maintain viral burden by impeding viral clearance. Taken together, this thesis defines cardiovascular cell types that are susceptible to SARS-CoV-2 infection, identifies molecular consequences of such infection in vitro and in vivo and offers new insights into the mechanistic basis of cardiovascular complications seen in patients with COVID-19.

Language

English (en)

Chair and Committee

Kory Lavine

Committee Members

Michael Diamond

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