Abstract
COVID-19 affects vulnerable populations including elderly individuals and patients with cancer. Natural Killer (NK) cells and innate-immune TRAIL suppress transformed and virally-infected cells. ACE2, and TMPRSS2 protease promote SARS-CoV-2 infectivity, while inflammatory cytokines IL-6, or G-CSF worsen COVID-19 severity. We show MEK inhibitors (MEKi) VS-6766, trametinib and selumetinib reduce ACE2 expression in human cells. In some human cells, remdesivir increases ACE2-promoter luciferase-reporter expression, ACE2 mRNA and protein, and ACE2 expression is attenuated by MEKi. In serum-deprived and stimulated cells treated with remdesivir and MEKi we observed correlations between pRB, pERK, and ACE2 expression further supporting role of proliferative state and MAPK pathway in ACE2 regulation. We show elevated cytokines in COVID-19-(+) patient plasma (N = 9) versus control (N = 11). TMPRSS2, inflammatory cytokines G-CSF, M-CSF, IL-1α, IL-6 and MCP-1 are suppressed by MEKi alone or with remdesivir. We observed MEKi stimulation of NK-cell killing of target-cells, without suppressing TRAIL-mediated cytotoxicity. Pseudotyped SARS-CoV-2 virus with a lentiviral core and SARS-CoV-2 D614 or G614 SPIKE (S) protein on its envelope infected human bronchial epithelial cells, small airway epithelial cells, or lung cancer cells and MEKi suppressed infectivity of the pseudovirus. We show a drug class-effect with MEKi to stimulate NK cells, inhibit inflammatory cytokines and block host-factors for SARS-CoV-2 infection leading also to suppression of SARS-CoV-2-S pseudovirus infection of human cells. MEKi may attenuate SARS-CoV-2 infection to allow immune responses and antiviral agents to control disease progression.
Highlights
Coronavirus 2 (SARS-CoV-2) infection progresses to a rapidly lethal adult respiratory distress syndrome (ARDS) associated with high mortality especially among the elderly or those with multiple comorbid conditions [1,2,3,4,5]
Based on prior literature that SARS coronavirus SPIKE protein through angiotensin converting enzyme 2 (ACE2) can activate MAPK signaling [39], we hypothesized that MEK inhibitors (MEKi) may inhibit SARS-CoV-2 cellular effects
Our approach was to evaluate candidate small molecules for their effects on SARS-CoV-2 infectivity factors such as ACE2, and TMPRSS2 expression while monitoring their impact on host immune suppressors of viral infection (Natural Killer cells and TNF-related apoptosis-inducing ligand (TRAIL)-mediated cell killing) and cytokine release that has been correlated with COVID-19 disease severity
Summary
Coronavirus 2 (SARS-CoV-2) infection progresses to a rapidly lethal adult respiratory distress syndrome (ARDS) associated with high mortality especially among the elderly or those with multiple comorbid conditions [1,2,3,4,5]. The lethality of SARS-CoV-2, the causative agent for the COVID-19 disease, involves a fulminant cytokine storm with bilateral lung infiltrates observed on chest X-rays and CT scans [9]. It has become clear that COVID-19 disease involves multiple organ systems including pulmonary, neurological, renal, hematological and gastrointestinal systems, among others [10,11,12,13,14,15]. Current therapeutic approaches include a number of agents such as anti-inflammatory agents that block IL-6, steroids, anti-viral agents, convalescent serum and alpha receptor blockers [17,18,19,20,21]. There are ongoing approaches for drug discovery and drug repurposing [22, 23]
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