An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts

Abstract

Rationale: While respiratory failure is a frequent and clinically significant outcome of COVID-19, cardiac complications are a common feature in hospitalized COVID-19 patients and are associated with worse patient outcomes. The cause of cardiac injury in COVID-19 patients is not yet known. Case reports of COVID-19 autopsy heart samples have demonstrated abnormal inflammatory infiltration of macrophages in heart tissues. Objective: Generate an immuno-cardiac co-culture platform to model macrophage-mediated hyper-inflammation in COVID-19 hearts and screen for drugs that can block the macrophage-mediated inflammation. Methods and Results: We systematically compared autopsy samples from non-COVID-19 donors and COVID-19 patients using RNA-seq and immunohistochemistry. We observed strikingly increased expression levels of CCL2 as well as macrophage infiltration in heart tissues of COVID-19 patients. We generated an immuno-cardiac co-culture platform containing human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) and macrophages. We found that macrophages induce increased reactive oxygen species (ROS) and apoptosis in CMs by secreting IL-6 and TNF-α after SARS-CoV-2 exposure. Using this immuno-cardiac co-culture platform, we performed a high content screen and identified ranolazine and tofacitinib as compounds that protect CMs from macrophage-induced cardiotoxicity. Conclusions: We established an immuno-host co-culture system to study macrophage-induced host cell damage following SARS-CoV-2 infection and identified FDA-approved drug candidates that alleviate the macrophage-mediated hyper-inflammation and cellular injury.

Post-mortem dissection of COVID-19: a pathogenic role for macrophages?

“…In keeping with this, high genotype-inferred pulmonary expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe disease, and numerous monocyte/macrophage chemotactic factors are elevated in blood, bronchoalveolar lavage fluid and whole lung tissue in COVID-19 [ 4 , 9 , 10 ]. These expanded macrophage populations are highly activated and with aberrant expression of key inflammation-associated molecules, often alongside expression of genes associated with tissue repair and fibrogenesis [ 2 , 11 , 12 ]. Interestingly, while epithelial cells are clearly the main viral target of SARS-CoV-2 infection, studies have reported viral S protein within macrophages [ 1 , 3 ].…”

Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injuries

“…To establish system level relevance of IL-1 β treated hCOs for modeling COVID-19 hearts, we performed RNA sequencing (RNAseq) on hCOs with/without IL-1 β treatment and compared their transcriptomic profiles to COVID-19 and healthy heart autopsy samples from publicly available datasets 38 . We first plotted the top differentially expressed genes (DEGs) for our IL-1β treated hCOs (compared to control hCOs) and the COVID-19 hearts (compared to healthy controls).…”

“…The R package, DESeq2 (v1.24.0) [doi: 10.1186/s13059-014-0550-8], was used to perform the differential gene expression analysis. Human in vivo myocardium samples containing healthy myocardium (n = 5) and myocardium from COVID infected patients 38 (n = 3) were retrieved on the National Institute of Health's Gene Expression Omnibus (GEO), GSE169241. Differential gene expression analysis was performed using Rstudio (v1.3.1093) (R language v3.6.1).…”

When stem cells meet COVID-19: recent advances, challenges and future perspectives

“…1 ). The main target cells for SARS-CoV-2 infection are ACE2-positive cells, such as type II alveolar epithelial (AT2) cells and resident alveolar macrophages in the lung, and the endothelial cells in the liver, kidney, hearts and intestines [ 16 – 20 ].

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