Cardiomyocytes recruit monocytes upon SARS-CoV-2 infection by secreting CCL2

Yang, Liuliu; Nilsson-Payant, Benjamin E.; Han, Yuling; Zhu, Jiajun; Wang, Pengfei; Zhang, Tuo; Redmond, David; Houghton, Sean; Möller, R.; Hoagland, Daisy A.; Carrau, Lucía; Horiuchi, Shu; Goff, Marisa; Lim, Jean K.; Bram, Yaron; Richardson, Chanel; Chandar, Vasuretha; Huang, Yaoxing; Xiang, Jenny; Ho, David D.; Schwartz, Robert E.; tenOever, Benjamin R.; Evans, T.E.; Chen, Shuibing

doi:10.1016/j.stemcr.2021.09.008

Cited by 13 publications

(21 citation statements)

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“…Besides, mild ischemia (early stages) is characterized by increased glycolytic flux with concomitant increased glucose uptake 48 . Furthermore, an in vivo study in hamsters infected with SARS-CoV-2 found increased expression of ROS-related genes in heart tissue 60 . Of note, viral transcripts were detected in the left ventricle and atrium, and the right atrium, but not the right ventricle; this suggests that the sampling site might matter.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis

et al. 2022

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SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. Here, by expressing individual SARS-CoV-2 proteins in the Drosophila heart, we demonstrate interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1). Complementing transcriptomic data from the fly heart reveal that this interaction blocks the antagonistic MGA/MAX complex, which shifts the balance towards MYC/MAX and activates glycolysis—with similar findings in mouse cardiomyocytes. Further, the Nsp6-induced glycolysis disrupts cardiac mitochondrial function, known to increase reactive oxygen species (ROS) in heart failure; this could explain COVID-19-associated cardiac pathology. Inhibiting the glycolysis pathway by 2-deoxy-D-glucose (2DG) treatment attenuates the Nsp6-induced cardiac phenotype in flies and mice. These findings point to glycolysis as a potential pharmacological target for treating COVID-19-associated heart failure.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis

et al. 2022

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“…In addition to using samples from COVID-19 patients for research, developing animal models for COVID-19 and subjecting them to scRNA-seq could facilitate preclinical analysis of vaccines and therapeutic agents. Although there are many studies using infected animals for COVID-19 research, 87,88 only a few studies performed scRNA-seq on COVID-19-infected animals like monkeys, 89 hamsters, 90 macaques, 91 ferrets, 92 and K18-hACE2 transgenic mice. 93 Several studies demonstrated the antiviral immune responses of animal models after receiving newly developed vaccines with scRNA-seq, [94][95][96][97] revealing induced gene modules of different immune cell populations.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

Delineating COVID-19 immunological features using single-cell RNA sequencing

et al. 2022

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“…44 Ferroptosis of SAN-like pacemaker cells induced by SARS-CoV-2 infection might contribute to the pathogenesis of patients with COVID-19 and explain some of the cardiac arrhythmias observed in patients. Interestingly, although many types of cells/organoids, including hESC-SAN–like pacemaker cells, cardiomyocytes, 45 hPSC-derived lung alveolar organoids, 46 hPSC-derived pancreatic endocrine cells, 47 hPSC-derived liver organoids, 47 can be infected by SARS-CoV-2, ferroptosis is only detected in SARS-CoV-2–infected hESC-SAN–like pacemaker cells, indicating a cell type–specific response to SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells

Han

Zhu

Yang

et al. 2022

Circulation Research

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Background: Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling. Methods: We used both a hamster model and human ESC (hESC)–derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2:GFP;MYH6:mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN–like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2–induced ferroptosis. Results: Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis. Conclusions: Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.

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Cardiomyocytes recruit monocytes upon SARS-CoV-2 infection by secreting CCL2

Cited by 13 publications

References 0 publications

SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis

SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis

Delineating COVID-19 immunological features using single-cell RNA sequencing

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells

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