Host mitochondrial transcriptome response to SARS-CoV-2 in multiple cell models and clinical samples

Brendan Miller, Ana Silverstein, Melanie Flores, Kevin Cao, Hiroshi Kumagai, Hemal H Mehta, Kelvin Yen, Su- Jeong Kim, Pinchas Cohen, Brendan Miller, Ana Silverstein, Melanie Flores, Kevin Cao, Hiroshi Kumagai, Hemal H Mehta, Kelvin Yen, Su- Jeong Kim, Pinchas Cohen

Abstract

SARS-CoV-2 induces a muted innate immune response compared to other respiratory viruses. Mitochondrial dynamics might partially mediate this effect of SARS-CoV-2 on innate immunity. Polypeptides encoded by open reading frames of SARS-CoV and SARS-CoV-2 have been shown to localize to mitochondria and disrupt Mitochondrial Antiviral Signaling (MAVS) protein signaling. Therefore, we hypothesized that SARS-CoV-2 would distinctly regulate the mitochondrial transcriptome. We analyzed multiple publicly available RNASeq data derived from primary cells, cell lines, and clinical samples (i.e., BALF and lung). We report that SARS-CoV-2 did not dramatically regulate (1) mtDNA-encoded gene expression or (2) MAVS expression, and (3) SARS-CoV-2 downregulated nuclear-encoded mitochondrial (NEM) genes related to cellular respiration and Complex I.

Conflict of interest statement

Pinchas Cohen is a consultant and stockholder of CohBar Inc. All other authors have no competing interests to declare.

Figures

Figure 1
Figure 1
Mitochondrial-gene expression after viral infection in primary cells (A), cell lines (B), and clinical samples (C). Colored genes indicate log twofold change with a padj < 0.2.
Figure 2
Figure 2
Principal component analysis of NEM expression data by primary cells (A), cell lines (B), and clinical samples (C).
Figure 3
Figure 3
Biological processes affected by NEM expression. Hierarchical clustering of all NEMs separate SARS-CoV-2, IAV, and IAVdNS1 (A). Top NEM biological processes by > 20% gene set enrichment (B). Top NEM biological processes by q value (C). Circos plot illustrating significant NEMs and interconnectedness among biological processes. (D) Heat map representing the top 10 GO enrichments.
Figure 4
Figure 4
Biological processes affected by NEM expression in cell lines. Hierarchical clustering of all NEMs separate SARS-CoV-2 from other viruses (A). Top NEM biological processes by > 20% gene set enrichment (B). Top NEM biological processes by q value. (C) Circos plot illustrating significant NEMs and interconnectedness among biological processes. (D) Heat map representing the top 10 GO enrichments.
Figure 5
Figure 5
Biological processes affected by NEM expression in clinical. Most significant (by qvalue) NEM-enriched biological processes (A, C) and corresponding genes in circos plot (B, D) with color representing log twofold change in BALF and lung, respectively.
Figure 6
Figure 6
SARS-CoV-2 does not induce downregulation of MAVS, whereas HPIV, RSV, and IAV downregulate MAVS across cell types (A). MAVS expression is inversely correlated with interferon response gene (B).

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Source: PubMed

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