Gene Expression Profiling Reveals the Shared and Distinct Transcriptional Signatures in Human Lung Epithelial Cells Infected With SARS-CoV-2, MERS-CoV, or SARS-CoV: Potential Implications in Cardiovascular Complications of COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative virus for the current global pandemic known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 belongs to the family of single-stranded RNA viruses known as coronaviruses, including the MERS-CoV and SARS-CoV that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), respectively. These coronaviruses are associated in the way that they cause mild to severe upper respiratory tract illness. This study has used an unbiased analysis of publicly available gene expression datasets from Gene Expression Omnibus to understand the shared and unique transcriptional signatures of human lung epithelial cells infected with SARS-CoV-2 relative to MERS-CoV or SARS-CoV. A major goal was to discover unique cellular responses to SARS-CoV-2 among these three coronaviruses. Analyzing differentially expressed genes (DEGs) shared by the three datasets led to a set of 17 genes, suggesting the lower expression of genes related to acute inflammatory response (TNF, IL32, IL1A, CXCL1, and CXCL3) in SARS-CoV-2. This subdued transcriptional response to SARS-CoV-2 may cause prolonged viral replication, leading to severe lung damage. Downstream analysis of unique DEGs of SARS-CoV-2 infection revealed changes in genes related to apoptosis (NRP1, FOXO1, TP53INP1, CSF2, and NLRP1), coagulation (F3, PROS1, ITGB3, and TFPI2), and vascular function (VAV3, TYMP, TCF4, and NR2F2), which may contribute to more systemic cardiovascular complications of COVID-19 than MERS and SARS. The study has uncovered a novel set of transcriptomic signatures unique to SARS-CoV-2 infection and shared by three coronaviruses, which may guide the initial efforts in the development of prognostic or therapeutic tools for COVID-19.

Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19

“…Moreover, two recent publications demonstrated that infection of various lung epithelial cells with SARS-CoV-2 leads to decreased expression of the α 1 -, α 2 -, α 3 -, β 1 -, and β 3 -subunits of the Na,K-ATPase at the transcriptional level ( 48 , 49 ). Similar results were obtained in another study, which documented reduced gene expression of the Na,K-ATPase β 1 -subunit upon infection of human lung epithelial cells with SARS-CoV-2 ( 50 ). In addition, differential gene expression analysis of postmortem lung tissue samples from patients with COVID-19 revealed significant downregulation of gene expression of the Na,K-ATPase α 1 -subunit ( 48 ).…”

Transcriptional Profiling and Machine Learning Unveil a Concordant Biosignature of Type I Interferon-Inducible Host Response Across Nasal Swab and Pulmonary Tissue for COVID-19 Diagnosis

“…Thus, discovering the unique transcriptional feature of COVID-19 may supplement the diagnostic strategy of COVID-19, especially the signature of host response. Notably, SARS-CoV-2-induced changes of gene expressions has reported to potentially distinguish COVID-19 from other infections (e.g., MERS-CoV and SARS-CoV), in which IFN-I genes is involved in the unique biosignature in response to SARS-CoV-2 infection ( 32 ). However, ISGs can be triggered by various stimulators.…”

Clotting in COVID-19: Is It All in the Genes?

“…Finally, FitzGerald and colleagues showed that this prothrombotic response may be unique to SARS-CoV-2 and not shared by other respiratory viruses such as influenza A, which did not significantly alter the expression levels of genes involved in the coagulation pathway. Consistent with this notion, a recent study has shown a significant relationship of genes related to coagulation (e.g., F3, PROS1, ITGB3, and TFPI2 ) with SARS-CoV-2 but not to other human coronaviruses (e.g., Middle East Respiratory Syndrome coronavirus [MERS-CoV] and severe acute respiratory syndrome coronavirus [SARS-CoV]) ( 9 ). Together, these data suggest that SARS-CoV-2 coaxes a unique response in the epithelial cells and alveolar macrophages that leads to a prothrombotic milieu in the lungs, which can result in thrombosis in situ or pulmonary embolism in susceptible individuals (Figure 1 ).…”