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Cardiovascular SARS-CoV-2 Tropism and Immunopathology- [electronic resource]

자료유형: 학위논문파일 국외

최종처리일시: 20240214101238

ISBN: 9798379893361

DDC: 616.079

저자명: Dmytrenko, Oleksandr.

서명/저자: Cardiovascular SARS-CoV-2 Tropism and Immunopathology - [electronic resource]

발행사항: [S.l.]: : Washington University in St. Louis., 2023

발행사항: Ann Arbor : : ProQuest Dissertations & Theses,, 2023

형태사항: 1 online resource(190 p.)

주기사항: Source: Dissertations Abstracts International, Volume: 85-01, Section: B.

주기사항: Advisor: Lavine, Kory J.;Diamond, Michael S.

학위논문주기: Thesis (Ph.D.)--Washington University in St. Louis, 2023.

사용제한주기: This item must not be sold to any third party vendors.

초록/해제: 요약Coronavirus Disease 2019 (COVID-19) is caused by SARS-CoV-2, a member of 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-CoV2. 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 SARSCoV-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.