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.