SARS-CoV-2 Switches 'on' MAPK and NFκB Signaling via the Reduction of Nuclear DUSP1 and DUSP5 Expression

Swati Goel; Fatemeh Saheb Sharif-Askari; Narjes Saheb Sharif Askari; Bushra Madkhana; Ahmad Munzer Alwaa; Bassam Mahboub; Adel M Zakeri; Elaref Ratemi; Rifat Hamoudi; Qutayba Hamid; Rabih Halwani

doi:10.3389/fphar.2021.631879

SARS-CoV-2 Switches 'on' MAPK and NFκB Signaling via the Reduction of Nuclear DUSP1 and DUSP5 Expression

Front Pharmacol. 2021 Apr 20:12:631879. doi: 10.3389/fphar.2021.631879. eCollection 2021.

Authors

Swati Goel¹, Fatemeh Saheb Sharif-Askari¹, Narjes Saheb Sharif Askari¹, Bushra Madkhana¹, Ahmad Munzer Alwaa², Bassam Mahboub^{1

3}, Adel M Zakeri⁴, Elaref Ratemi⁵, Rifat Hamoudi^{1

2}, Qutayba Hamid^{1

2

6}, Rabih Halwani^{1

2

7}

Affiliations

¹ Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
² Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
³ Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates.
⁴ Department of Plant Production, Faculty of Agriculture and Food Sciences, King Saud University, Riyadh, Saudi Arabia.
⁵ Jubail- Industrial College, Department of Chemical and Process Engineering Technology, Jubail- Industrial City, Al Jubail, Saudi Arabia.
⁶ Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada.
⁷ Prince Abdullah Ben Khaled Celiac Disease Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia.

Abstract

Mitogen-activated protein kinases (MAPK) and NF-kappaB (NF-κB) pathway regulate many cellular processes and are essential for immune cells function. Their activity is controlled by dual-specificity phosphatases (DUSPs). A comprehensive analysis of publicly available gene expression data sets of human airway epithelial cells (AECs) infected with SARS-CoV-2 identified DUSP1 and DUSP5 among the lowest induced transcripts within these pathways. These proteins are known to downregulate MAPK and NF-κB pathways; and their lower expression was associated with increased activity of MAPK and NF-κB signaling and enhanced expression of proinflammatory cytokines such as TNF-α. Infection with other coronaviruses did not have a similar effect on these genes. Interestingly, treatment with chloroquine and/or non-steroidal anti-inflammatory drugs counteracted the SARS-CoV-2 induced reduction of DUSP1 and DUSP5 genes expression. Therapeutically, impeding this evasion mechanism of SARS-CoV-2 may help control the exaggerated activation of these immune regulatory pathways during a COVID-19 infection.

Keywords: COVID-19; DUSP1; DUSP5; MAPK; NFkB; SARS-CoV-2; chroloquine.