Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic
Bibliographic record
Abstract
Background The 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. Methods RNA-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. Results Based 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. Conclusion This 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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".