SARS-CoV-2 infection of human iPSC-derived cardiac cells predicts novel cytopathic features in hearts of COVID-19 patients

Pérez-Bermejo, Juan A.; Kang, Serah S; Rockwood, Sarah J.; Simoneau, Camille R.; Joy, David A; Ramadoss, Gokul N.; Silva, Ana C.; Flanigan, Will; Li, Huihui; Nakamura, Ken; Whitman, Jeffrey D.; Ott, Mélanie; Conklin, Bruce R.; McDevitt, Todd C.

doi:10.1101/2020.08.25.265561

Cited by 78 publications

(97 citation statements)

References 62 publications

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“…Other studies demonstrated that SARS-CoV2 can enter and replicate within human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and induce cytotoxic effects that abolish cardiomyocyte beating [ 78 , 79 , 80 ]. SARS-CoV-2 enters cells by binding of the viral Spike protein (S) to the SARS-CoV2 receptor ACE2 and S priming by the serine protease TMPRSS2 [ 81 ].…”

Section: Macrophage Role In Cardiac Inflammation and Cardiac Dysfumentioning

confidence: 99%

“…SARS-CoV-2 enters cells by binding of the viral Spike protein (S) to the SARS-CoV2 receptor ACE2 and S priming by the serine protease TMPRSS2 [ 81 ]. Studies by Perez-Bermejo et al [ 80 ] examined the expression of ACE2 and TMPRSS2 in hiPSC-derived cardiomyocytes. ACE2 was expressed by the hiPSC-derived cardiomyocytes but not TMPRSS2.…”

Section: Macrophage Role In Cardiac Inflammation and Cardiac Dysfumentioning

confidence: 99%

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Role of Cardiac Macrophages on Cardiac Inflammation, Fibrosis and Tissue Repair

Lafuse

Wozniak

Rajaram

2020

Cells

225

175

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The immune system plays a pivotal role in the initiation, development and resolution of inflammation following insult or damage to organs. The heart is a vital organ which supplies nutrients and oxygen to all parts of the body. Heart failure (HF) has been conventionally described as a disease associated with cardiac tissue damage caused by systemic inflammation, arrhythmia and conduction defects. Cardiac inflammation and subsequent tissue damage is orchestrated by the infiltration and activation of various immune cells including neutrophils, monocytes, macrophages, eosinophils, mast cells, natural killer cells, and T and B cells into the myocardium. After tissue injury, monocytes and tissue-resident macrophages undergo marked phenotypic and functional changes, and function as key regulators of tissue repair, regeneration and fibrosis. Disturbance in resident macrophage functions such as uncontrolled production of inflammatory cytokines, growth factors and inefficient generation of an anti-inflammatory response or unsuccessful communication between macrophages and epithelial and endothelial cells and fibroblasts can lead to aberrant repair, persistent injury, and HF. Therefore, in this review, we discuss the role of cardiac macrophages on cardiac inflammation, tissue repair, regeneration and fibrosis.

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Section: Macrophage Role In Cardiac Inflammation and Cardiac Dysfumentioning

confidence: 99%

Section: Macrophage Role In Cardiac Inflammation and Cardiac Dysfumentioning

confidence: 99%

Role of Cardiac Macrophages on Cardiac Inflammation, Fibrosis and Tissue Repair

Lafuse

Wozniak

Rajaram

2020

Cells

225

175

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“…To investigate the possibility of viral integration into virus infected cells we analyzed published RNA-Seq data from SARS-CoV-2 -infected cells for evidence of chimeric transcripts, which would be indicative of viral integration into the genome and expression. Examination of these data sets [24][25][26][27][28][29][30] (Fig. S1a-b) revealed a substantial number of host-viral chimeric reads (Fig. 1a-c, S1c).…”

Section: Expression Of Viral-cellular Chimeric Transcripts In Infectementioning

confidence: 99%

SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome

Zhang

Richards

Khalil

et al. 2020

Preprint

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SummaryProlonged SARS-CoV-2 RNA shedding and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious1–14. Here we investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences might account for PCR-positive tests. In support of this hypothesis, we found chimeric transcripts consisting of viral fused to cellular sequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome. To experimentally corroborate the possibility of viral retro-integration, we describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed. Human endogenous LINE-1 expression was induced upon SARS-CoV-2 infection or by cytokine exposure in cultured cells, suggesting a molecular mechanism for SARS-CoV-2 retro-integration in patients. This novel feature of SARS-CoV-2 infection may explain why patients can continue to produce viral RNA after recovery and suggests a new aspect of RNA virus replication.

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“…These extrapulmonary manifestations include myocarditis, acute kidney injury, hepatocellular injury, gastrointestinal disease and increasing evidence for both PNS and CNS pathology 118,119 . There has been a rapid response from the stem cell field in engineering both 2D models and 3D organoids to study the tropism of SARS-CoV-2 in human gut enterocytes 120 and intestinal organoids 121,122 , cardiomyocytes [123][124][125] , kidney organoids 126 , liver organoids 124 , pancreatic endocrine cells 124 and, of course, lung organoids 127 .…”

Section: Models For Sars-cov-2 Infectionmentioning

confidence: 99%