Abstract
The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients.
Highlights
The coronavirus disease 2019 (COVID-19) caused a global pandemic that has progressed rapidly and continues to date, manifesting severe effects through contributing additive factors in specific individuals
To examine whether the increase of angiotensinconverting enzyme 2 (ACE2) and TMPRSS2 protein contribute to the exacerbation of inflammatory response, we investigated the viral entry of SARS-CoV2 pseudovirus in iCMs
As demonstrated by the incorporation of the fluorescent signal, tumor necrosis factor-α (TNF-α) treatment significantly increased the entry of SARS-CoV-2 pseudovirus into the host cells, as compared with iCMs treated with vehicle alone (Figure 5E,F)
Summary
The coronavirus disease 2019 (COVID-19) caused a global pandemic that has progressed rapidly and continues to date, manifesting severe effects through contributing additive factors in specific individuals. We have used iPSC-derived retinal organoids that express ACE2 and TMPRSS2 as the platform for investigating the pathogenesis of SARS-CoV2 infection in the retina [16]. Recent reports have shown that human iPSC-derived cardiomyocytes are susceptible to SARS-CoV-2 [17,18,19], and the viral infection can impair the electrical and mechanical functions [18]. The immune cells release various cytokines to respond to the SARS-CoV-2 virus infection, including TNF-α and the members of the interleukin family [22,23]. To examine whether the upregulation of TNF-α plays a role in viral infection, we assessed the expression of ACE2 and the TMPRSS2, the viral entry receptor proteins involved in the spike protein (S-protein) priming. Our data indicated that TNF-α increases the susceptibility of iCMs to SARS-CoV2
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