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Published on: July 26, 2018
Infiltrating monocytes drive cardiac dysfunction in a cardiomyocyte-restricted mouse model of SARS-CoV-2 infection
Oleksandr Dmytrenko1, Shibali Das1, Attila Kovacs1
1Department of Medicine, Cardiovascular Division, Washington University in St. Louis, St. Louis, Missouri, USA.
Insights
This study developed a mouse model to investigate how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects heart cells. The findings show that cardiomyocyte infection and immune responses contribute to COVID-19 related heart dysfunction.
Area of Science:
- Cardiology
- Virology
- Immunology
Background:
- Cardiovascular complications of COVID-19, including myocardial injury and heart failure, are linked to increased mortality and long-term disability.
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antigens have been detected in the heart muscle of COVID-19 patients, suggesting direct cardiac involvement.
- While SARS-CoV-2 can infect cardiomyocytes in vitro, a direct causal link between cardiomyocyte infection and cardiac pathology in vivo remains unestablished.
Purpose of the Study:
- To establish a mouse model for studying cardiomyocyte-restricted SARS-CoV-2 infection.
- To investigate the direct impact of SARS-CoV-2 infection on cardiac function and pathology.
- To elucidate the roles of viral replication and innate immune responses in COVID-19-associated cardiac dysfunction.
Main Methods:
- Generation of a transgenic mouse model (Myh6-Cre Rosa26loxP-STOP-loxP-hACE2) expressing the human angiotensin-converting enzyme 2 (hACE2) receptor specifically in cardiomyocytes.
- Inoculation of these mice with an ancestral SARS-CoV-2 strain.
- Assessment of viral replication, cardiac pathology, left ventricular (LV) systolic function, and immune cell infiltration (macrophages).
- Intervention by blocking monocyte trafficking to evaluate its impact on cardiac dysfunction and viral clearance.
Main Results:
- SARS-CoV-2 replicated within the heart in the engineered mouse model.
- Cardiomyocyte infection led to macrophage accumulation and moderate left ventricular systolic dysfunction.
- Cardiac pathology was transient, resolving with viral clearance.
- Blocking monocyte trafficking reduced macrophage infiltration, improved LV systolic function, and enhanced viral clearance.
Conclusions:
- The developed mouse model successfully recapitulates key features of SARS-CoV-2-induced cardiac dysfunction.
- Both direct viral replication in cardiomyocytes and the subsequent innate immune response contribute to cardiac pathology in COVID-19.
- This model provides a valuable tool for further research into the mechanisms of COVID-19 cardiac sequelae and for testing therapeutic strategies.
Abstract:
Cardiovascular manifestations of coronavirus disease 2019 (COVID-19) include myocardial injury, heart failure, and myocarditis and are associated with long-term disability and mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antigens are found in the myocardium of COVID-19 patients, and human cardiomyocytes are susceptible to infection in cell or organoid cultures. While these observations raise the possibility that cardiomyocyte infection may contribute to the cardiac sequelae of COVID-19, a causal relationship between cardiomyocyte infection and myocardial dysfunction and pathology has not been established. Here, we generated a mouse model of cardiomyocyte-restricted infection by selectively expressing human angiotensin-converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, in cardiomyocytes. Inoculation of Myh6-Cre Rosa26loxP-STOP-loxP-hACE2 mice with an ancestral, non-mouse-adapted strain of SARS-CoV-2 resulted in viral replication within the heart, accumulation of macrophages, and moderate left ventricular (LV) systolic dysfunction. Cardiac pathology in this model was transient and resolved with viral clearance. Blockade of monocyte trafficking reduced macrophage accumulation, suppressed the development of LV systolic dysfunction, and promoted viral clearance in the heart. These findings establish a mouse model of SARS-CoV-2 cardiomyocyte infection that recapitulates features of cardiac dysfunctions of COVID-19 and suggests that both viral replication and resultant innate immune responses contribute to cardiac pathology.IMPORTANCEHeart involvement after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurs in multiple ways and is associated with worse outcomes in coronavirus disease 2019 (COVID-19) patients. It remains unclear if cardiac disease is driven by primary infection of the heart or immune response to the virus. SARS-CoV-2 is capable of entering contractile cells of the heart in a culture dish. However, it remains unclear how such infection affects the function of the heart in the body. Here, we designed a mouse in which only heart muscle cells can be infected with a SARS-CoV-2 strain to study cardiac infection in isolation from other organ systems. In our model, infected mice show viral infection, worse function, and accumulation of immune cells in the heart. A subset of immune cells facilitates such worsening heart function. As this model shows features similar to those observed in patients, it may be useful for understanding the heart disease that occurs as a part of COVID-19.
