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

Abstract

Heart injury has been reported in up to 20% of COVID-19 patients, yet the cause of myocardial histopathology remains unknown. Here, using an established in vivo hamster model, we demonstrate that SARS-CoV-2 can be detected in cardiomyocytes of infected animals. Furthermore, we found damaged cardiomyocytes in hamsters and COVID-19 autopsy samples. To explore the mechanism, we show that both human pluripotent stem cell-derived cardiomyocytes (hPSC-derived CMs) and adult cardiomyocytes (CMs) can be productively infected by SARS-CoV-2, leading to secretion of the monocyte chemoattractant cytokine CCL2 and subsequent monocyte recruitment. Increased CCL2 expression and monocyte infiltration was also observed in the hearts of infected hamsters. Although infected CMs suffer damage, we find that the presence of macrophages significantly reduces SARS-CoV-2 infected CMs. Overall, our study provides direct evidence that SARS-CoV-2 infects CMs in vivo and suggests a mechanism of immune-cell infiltration and histopathology in heart tissues of COVID-19 patients.

Interaction of SARS-CoV-2 with cardiomyocytes: Insight into the underlying molecular mechanisms of cardiac injury and pharmacotherapy

“…PKC also phosphorylates the sodium-calcium exchanger (NCX), which interferes with the cardiac electrical activity and calcium homeostasis in cardiomyocytes [66] . These changes in calcium homeostasis combined along with reduced contractility (down to complete cessation in beating) were recently documented in SARS-CoV-2 infected cardiomyocytes [40] , [67] . Furthermore, many of these above-mentioned pathways signal through the mammalian target of rapamycin (mTOR) that could initiate autophagy in cardiomyocytes [68] .…”

“…Interestingly, the presence of SARS-CoV-2 particles in autopsies of infected hamsters and humans was confirmed, along with the ability of the virus to infect cardiomyocytes and to reduce their contractility by altering the gene expression of contractile proteins and calcium homeostasis. Not only are cardiomyocytes struck by the SARS-CoV-2, but also, they were able to amplify and to release the virus in the extracellular space [40] , [41] . These studies show a permissivity of cardiomyocytes to the virus along with an alarming risk of re-infection once these particles are released in the myocardial interstitial milieu ( Fig.…”

“…Nonetheless, some of the cardiac injuries stated in this section may not occur during infection but later after clearance from SARS-CoV-2 which falls within the category of the virus long-term sequelae including myocarditis, fibrosis, myocardial infarction, and sustained hypertension. In fact, the ability of the SARS-CoV-2 to increase the production of reactive oxygen species in several cells (lung and blood) including cardiomyocytes puts the heart at high risk of pathological remodelling [40] , [56] .…”

Viral Myocarditis—From Pathophysiology to Treatment

“…In agreement, a further case report of a patient with fulminant myocarditis revealed positive myocardial detection of SARS-CoV-2 RNA accompanied by massive macrophages and CD8 + cytotoxic t lymphocytes infiltration. Furthermore, in vitro data show an increased secretion of CCL2 cytokine from SARS-CoV-2-infected cardiomyocytes, resulting in an enhanced recruitment of monocytes [154]. Importantly, SARS-CoV-2 might also play a role in the pathogenesis of autoimmune myocarditis.…”

Myeloid dysregulation and therapeutic intervention in COVID-19

“…Elevation of GM-CSF is unique to fatal COVID-19 but not influenza, suggesting GM-CSF as a disease-specific mechanism [ 44 ]. The chemoattractant cytokine CCL2 has been shown to be secreted by SARS-CoV-2 infected cardiomyocytes, promoting monocyte recruitment to the heart [ 79 ]. Although myeloid cells can limit viral replication through engulfment of infected cells upon arrival at the site of infection, an excessive production of proinflammatory cytokines, such as IL-6, TNF-α, IL-8, IL-1β, GM-CSF, IL-18, S100A8/9, etc., were observed during COVID-19.…”