Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection.

Komudi Singh,Shahin Hassanzadeh,Yun-Ching Chen,Kim Han,Fayaz Seifuddin,Ilker Tunc,Jennifer T Judy,Michael N Sack,Mehdi Pirooznia

doi:10.3389/fgene.2021.599261

Abstract

Analyzing host cells' transcriptional response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will help delineate biological processes underlying viral pathogenesis. First, analysis of expression profiles of lung cell lines A549 and Calu3 revealed upregulation of antiviral interferon signaling genes in response to all three SARS-CoV-2, MERS-CoV, or influenza A virus (IAV) infections. However, perturbations in expression of genes involved in inflammatory, mitochondrial, and autophagy processes were specifically observed in SARS-CoV-2-infected cells. Next, a validation study in infected human nasopharyngeal samples also revealed perturbations in autophagy and mitochondrial processes. Specifically, mTOR expression, mitochondrial ribosomal, mitochondrial complex I, lysosome acidification, and mitochondrial fission promoting genes were concurrently downregulated in both infected cell lines and human samples. SARS-CoV-2 infection impeded autophagic flux either by upregulating GSK3B in lung cell lines or by downregulating autophagy genes, SNAP29, and lysosome acidification genes in human samples, contributing to increased viral replication. Therefore, drugs targeting lysosome acidification or autophagic flux could be tested as intervention strategies. Finally, age-stratified SARS-CoV-2-positive human data revealed impaired upregulation of chemokines, interferon-stimulated genes, and tripartite motif genes that are critical for antiviral signaling. Together, this analysis has revealed specific aspects of autophagic and mitochondrial function that are uniquely perturbed in SARS-CoV-2-infected host cells.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-coronavirus and the cause of the Coronavirus Disease 2019 (COVID-19) pandemic
Using the gene expression profiles of A549 and Calu3 cells infected with IAV or MERS-CoV, we concluded that perturbations in cytokine signaling and inflammation processes, downregulation of genes in the mitochondrial processes, and perturbation of autophagy were uniquely observed in novel coronavirus-infected cells
Consistent with the cell line data, DE genes from human data significantly annotated to inflammation, autophagy, and mitochondrial processes

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-coronavirus and the cause of the Coronavirus Disease 2019 (COVID-19) pandemic. COVID-19 presents as a wide range of clinical manifestations, ranging from asymptomatic to respiratory failure or multiorgan and systemic manifestations (Cascella et al, 2020; Ludwig and Zarbock, 2020; Wang C. et al, 2020; Zhu et al, 2020) This viral pneumonia outbreak caused by SARS-CoV2 was first identified in Wuhan, China, in December 2019 (Chan et al, 2020). Several drugs are currently under various phases of clinical trials, and management strategies include supportive medical care for existing cases and social distancing for prevention. Understanding this novel pathogen and the host response it elicits is crucial to combatting the emerging threat to public health

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