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
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.