Therapeutic Targeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19
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Abstract
Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription factors (TFs) for therapeutic targeting using approved drugs. We integrated a resource of TF-cytokine gene interactions with single-cell RNA-seq expression data from bronchoalveolar lavage fluid cells of COVID-19 patients. We found 581 significantly correlated interactions, between 95 TFs and 16 cytokines upregulated in the COVID-19 patients, that may contribute to pathogenesis of the disease. Among these, we identified 19 TFs that are targets of FDA approved drugs. We investigated the potential therapeutic effect of 10 drugs and 25 drugs combinations on inflammatory cytokine production, which revealed two drugs that inhibited cytokine production and numerous combinations that show synergistic efficacy in downregulating cytokine production. Further studies of these candidate repurposable drugs could lead to a therapeutic regimen to treat the CRS in COVID-19 patients.
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SciScore for 10.1101/2020.12.29.424728: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Signaling Pathways Project data acquisition and processing: A list of cytokines that were differentially expressed and upregulated in BALFs of COVID-19 patients compared to healthy controls was submitted to the Signaling Pathways Project Ominer web tool (42) on July 25, 2020. Signaling Pathways Projectsuggested: (Signaling Pathways Project, RRID:SCR_018412)Signaling Pathways Project Ominersuggested: NoneFresh or thawed PBMCs were pretreated with Acetaminophen (MiliporeSigma), Milip…SciScore for 10.1101/2020.12.29.424728: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Signaling Pathways Project data acquisition and processing: A list of cytokines that were differentially expressed and upregulated in BALFs of COVID-19 patients compared to healthy controls was submitted to the Signaling Pathways Project Ominer web tool (42) on July 25, 2020. Signaling Pathways Projectsuggested: (Signaling Pathways Project, RRID:SCR_018412)Signaling Pathways Project Ominersuggested: NoneFresh or thawed PBMCs were pretreated with Acetaminophen (MiliporeSigma), MiliporeSigmasuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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