Genome-wide bioinformatic analyses predict key host and viral factors in SARS-CoV-2 pathogenesis

Ferrarini, Mariana Galvão; A, Lal; Rebollo, Rita; Gruber, Andreas J.; Guarracino, Andrea; Gonzalez, Itziar Martinez; Floyd, Taylor; Oliveira, Daniel Siqueira de; Shanklin, Justin; Beausoleil, Ethan; Pusa, Taneli; Pickett, Brett E.; Aguiar‐Pulido, Vanessa

doi:10.1038/s42003-021-02095-0

Cited by 36 publications

(21 citation statements)

References 129 publications

(155 reference statements)

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“…3 ) contribute to innate immune evasion by sequestering dsRNA, causing epitope masking. Alternatively, Alpha may induce less endogenous dsRNA production from the expression of transposable elements that can contribute PAMPs to innate immune sensing 15 – 17 .…”

Section: Alpha Shows Reduced Interferon Inductionmentioning

confidence: 99%

Evolution of enhanced innate immune evasion by SARS-CoV-2

Thorne

Bouhaddou

Reuschl

et al. 2021

Nature

255

272

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The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6—all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.

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Section: Alpha Shows Reduced Interferon Inductionmentioning

confidence: 99%

Evolution of enhanced innate immune evasion by SARS-CoV-2

Thorne

Bouhaddou

Reuschl

et al. 2021

Nature

255

272

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“…Other hub-high traffic genes in this module, such as BTAF1 ( 216 ), EZH2 ( 346 ), NPM1 ( 347 ), TPT1 ( 151 , 269 , 348 ), LDHA ( 217 , 268 ), PTPRC ( 189 ), SOS1 ( 349 , 350 ), DDX5 ( 351 , 352 ), BCL10 ( 162 , 353 ), EEF1B2 ( 354 ), CALM1 ( 344 ), EIF4A2 , EIF4B ( 336 , 355 , 356 ), EEF1A1 ( 269 , 354 ), HNRNPA1 ( 228 , 347 ), and IFNG ( 8 , 357 , 358 ), have important roles in development/inhibition of COVID-19. Overexpression of SARS-CoV-2 ORF6 caused HNRNPA1 nuclear accumulation, subverting the host mRNA export system and reducing nucleus size ( 359 ).…”

Section: Discussionmentioning

confidence: 99%

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

et al. 2021

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BackgroundThe recent emergence of COVID-19, rapid worldwide spread, and incomplete knowledge of molecular mechanisms underlying SARS-CoV-2 infection have limited development of therapeutic strategies. Our objective was to systematically investigate molecular regulatory mechanisms of COVID-19, using a combination of high throughput RNA-sequencing-based transcriptomics and systems biology approaches.MethodsRNA-Seq data from peripheral blood mononuclear cells (PBMCs) of healthy persons, mild and severe 17 COVID-19 patients were analyzed to generate a gene expression matrix. Weighted gene co-expression network analysis (WGCNA) was used to identify co-expression modules in healthy samples as a reference set. For differential co-expression network analysis, module preservation and module-trait relationships approaches were used to identify key modules. Then, protein-protein interaction (PPI) networks, based on co-expressed hub genes, were constructed to identify hub genes/TFs with the highest information transfer (hub-high traffic genes) within candidate modules.ResultsBased on differential co-expression network analysis, connectivity patterns and network density, 72% (15 of 21) of modules identified in healthy samples were altered by SARS-CoV-2 infection. Therefore, SARS-CoV-2 caused systemic perturbations in host biological gene networks. In functional enrichment analysis, among 15 non-preserved modules and two significant highly-correlated modules (identified by MTRs), 9 modules were directly related to the host immune response and COVID-19 immunopathogenesis. Intriguingly, systemic investigation of SARS-CoV-2 infection identified signaling pathways and key genes/proteins associated with COVID-19’s main hallmarks, e.g., cytokine storm, respiratory distress syndrome (ARDS), acute lung injury (ALI), lymphopenia, coagulation disorders, thrombosis, and pregnancy complications, as well as comorbidities associated with COVID-19, e.g., asthma, diabetic complications, cardiovascular diseases (CVDs), liver disorders and acute kidney injury (AKI). Topological analysis with betweenness centrality (BC) identified 290 hub-high traffic genes, central in both co-expression and PPI networks. We also identified several transcriptional regulatory factors, including NFKB1, HIF1A, AHR, and TP53, with important immunoregulatory roles in SARS-CoV-2 infection. Moreover, several hub-high traffic genes, including IL6, IL1B, IL10, TNF, SOCS1, SOCS3, ICAM1, PTEN, RHOA, GDI2, SUMO1, CASP1, IRAK3, HSPA5, ADRB2, PRF1, GZMB, OASL, CCL5, HSP90AA1, HSPD1, IFNG, MAPK1, RAB5A, and TNFRSF1A had the highest rates of information transfer in 9 candidate modules and central roles in COVID-19 immunopathogenesis.ConclusionThis study provides comprehensive information on molecular mechanisms of SARS-CoV-2-host interactions and identifies several hub-high traffic genes as promising therapeutic targets for the COVID-19 pandemic.

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“…Although some studies have addressed TEs expression following SARS-CoV-2 infection 27,28 , none has considered the cell type and basal TE expression levels as important characteristics of their analysis.…”

Section: Introductionmentioning

confidence: 99%

Impaired activation of Transposable Elements in SARS-CoV-2 infection

Sorek

Meshorer

Schlesinger

2021

Preprint

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Transposable elements (TEs) are induced in response to viral infections. TEs induction triggers a robust and durable interferon (IFN) response, providing a host defense mechanism. Still, the connection between SARS-CoV-2 IFN response and TEs remained unexplored. Here, we analyzed TE expression changes in response to SARS-CoV-2 infection in different human cellular models. We find that compared to other viruses, which cause global upregulation of TEs, SARS-CoV-2 infection results in a significantly milder TE response in both primary lung epithelial cells and in iPSC-derived lung alveolar type 2 cells. In general, we observe that TE activation correlates with, and precedes, the induction of IFN-related genes, suggesting that the failure to activate TEs may be the reason for the weak IFN response. Moreover, we identify two variables which explain most of the observed diverseness in immune responses: basal expression levels of TEs in the pre-infected cell, and the viral load. Since basal TE levels increase with age, we propose that "TE desensitization" leads to age-related death from COVID19. This work provides a potential mechanistic explanation for SARS-CoV-2s success in its fight against the host immune system, and suggests that TEs could be used as sensors or serve as potential drug targets for COVID-19.

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Genome-wide bioinformatic analyses predict key host and viral factors in SARS-CoV-2 pathogenesis

Cited by 36 publications

References 129 publications

Evolution of enhanced innate immune evasion by SARS-CoV-2

Evolution of enhanced innate immune evasion by SARS-CoV-2

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

Impaired activation of Transposable Elements in SARS-CoV-2 infection

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