Therapeutic Targeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19

Overview

Journal Front Pharmacol

Date 2021 Jun 24

PMID 34163359

Citations 7

Authors

Clarissa S Santoso

Zhaorong Li

Jaice T Rottenberg

Xing Liu

Vivian X Shen

Juan I Fuxman Bass

Affiliations

Soon will be listed here.

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.

Citing Articles

A Machine Learning Approach to Identify Potential miRNA-Gene Regulatory Network Contributing to the Pathogenesis of SARS-CoV-2 Infection.

Das R, Sinnarasan V, Paul D, Venkatesan A Biochem Genet. 2023; 62(2):987-1006.

PMID: 37515735 DOI: 10.1007/s10528-023-10458-x.

A digital nanoplasmonic microarray immunosensor for multiplexed cytokine monitoring during CAR T-cell therapy from a leukemia tumor microenvironment model.

Ma B, Liu X, Zhang Z, Ma C, Chand R, Patwardhan S Biosens Bioelectron. 2023; 230:115247.

PMID: 37023552 PMC: 10103176. DOI: 10.1016/j.bios.2023.115247.

The use of bioinformatics methods to identify the effects of SARS-CoV-2 and influenza viruses on the regulation of gene expression in patients.

Sun Z, Ke L, Zhao Q, Qu J, Hu Y, Gao H Front Immunol. 2023; 14:1098688.

PMID: 36911695 PMC: 9992716. DOI: 10.3389/fimmu.2023.1098688.

Single-Cell Gene Expression Analysis Revealed Immune Cell Signatures of Delta COVID-19.

Shaymardanov A, Antonova O, Sokol A, Deinichenko K, Kazakova P, Milovanov M Cells. 2022; 11(19).

PMID: 36230912 PMC: 9563974. DOI: 10.3390/cells11192950.

Differential gene expression profiling reveals potential biomarkers and pharmacological compounds against SARS-CoV-2: Insights from machine learning and bioinformatics approaches.

Hoque M, Sarkar M, Khan M, Hossain M, Hasan M, Rahman M Front Immunol. 2022; 13:918692.

PMID: 36059456 PMC: 9429819. DOI: 10.3389/fimmu.2022.918692.

References

Cronstein B, Kimmel S, Levin R, Martiniuk F, Weissmann G . A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1992; 89(21):9991-5. PMC: 50263. DOI: 10.1073/pnas.89.21.9991. View

Ren X, Wen W, Fan X, Hou W, Su B, Cai P . COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell. 2021; 184(7):1895-1913.e19. PMC: 7857060. DOI: 10.1016/j.cell.2021.01.053. View

Meltzer D, Best T, Zhang H, Vokes T, Arora V, Solway J . Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Netw Open. 2020; 3(9):e2019722. PMC: 7489852. DOI: 10.1001/jamanetworkopen.2020.19722. View

Gandhi R, Lynch J, Del Rio C . Mild or Moderate Covid-19. N Engl J Med. 2020; 383(18):1757-1766. DOI: 10.1056/NEJMcp2009249. View

Santoso C, Li Z, Lal S, Yuan S, Gan K, Agosto L . Comprehensive mapping of the human cytokine gene regulatory network. Nucleic Acids Res. 2020; 48(21):12055-12073. PMC: 7708076. DOI: 10.1093/nar/gkaa1055. View

Wolock S, Lopez R, Klein A . Scrublet: Computational Identification of Cell Doublets in Single-Cell Transcriptomic Data. Cell Syst. 2019; 8(4):281-291.e9. PMC: 6625319. DOI: 10.1016/j.cels.2018.11.005. View

Stebbing J, Sanchez Nievas G, Falcone M, Youhanna S, Richardson P, Ottaviani S . JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Sci Adv. 2020; 7(1). PMC: 7775747. DOI: 10.1126/sciadv.abe4724. View

LORD K, Abdollahi A, Liebermann D . Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation. Mol Cell Biol. 1993; 13(2):841-51. PMC: 358967. DOI: 10.1128/mcb.13.2.841-851.1993. View

Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S . SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181(2):271-280.e8. PMC: 7102627. DOI: 10.1016/j.cell.2020.02.052. View

10.

Nizet V, Johnson R . Interdependence of hypoxic and innate immune responses. Nat Rev Immunol. 2009; 9(9):609-17. PMC: 4343208. DOI: 10.1038/nri2607. View

11.

Bae M, Kim S, Jeong J, Lee Y, Kim H, Kim S . Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1. Oncol Rep. 2006; 15(6):1557-62. View

12.

Olagnier D, Farahani E, Thyrsted J, Blay-Cadanet J, Herengt A, Idorn M . SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun. 2020; 11(1):4938. PMC: 7532469. DOI: 10.1038/s41467-020-18764-3. View

13.

Horby P, Lim W, Emberson J, Mafham M, Bell J, Linsell L . Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2020; 384(8):693-704. PMC: 7383595. DOI: 10.1056/NEJMoa2021436. View

14.

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

15.

Lee D, Gardner R, Porter D, Louis C, Ahmed N, Jensen M . Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014; 124(2):188-95. PMC: 4093680. DOI: 10.1182/blood-2014-05-552729. View

16.

Singh S, Aggarwal B . Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem. 1995; 270(42):24995-5000. DOI: 10.1074/jbc.270.42.24995. View

17.

Morse C, Tabib T, Sembrat J, Buschur K, Trejo Bittar H, Valenzi E . Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. Eur Respir J. 2019; 54(2). PMC: 8025672. DOI: 10.1183/13993003.02441-2018. View

18.

Jain A, Chaurasia R, Sengar N, Singh M, Mahor S, Narain S . Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Sci Rep. 2020; 10(1):20191. PMC: 7677378. DOI: 10.1038/s41598-020-77093-z. View

19.

Samaddar A, Gadepalli R, Nag V, Misra S . The Enigma of Low COVID-19 Fatality Rate in India. Front Genet. 2020; 11:854. PMC: 7399343. DOI: 10.3389/fgene.2020.00854. View

20.

Lin Y, Hsu C, Liao Y, Chou M, Tang C . The CCL2/CCR2 axis enhances vascular cell adhesion molecule-1 expression in human synovial fibroblasts. PLoS One. 2012; 7(11):e49999. PMC: 3503714. DOI: 10.1371/journal.pone.0049999. View