PT  - JOURNAL ARTICLE
AU  - Lanlan Zhou
AU  - Kelsey Huntington
AU  - Shengliang Zhang
AU  - Lindsey Carlsen
AU  - Eui-Young So
AU  - Cassandra Parker
AU  - Ilyas Sahin
AU  - Howard Safran
AU  - Suchitra Kamle
AU  - Chang-Min Lee
AU  - Chun Geun Lee
AU  - Jack A. Elias
AU  - Kerry S. Campbell
AU  - Mandar T. Naik
AU  - Walter J. Atwood
AU  - Emile Youssef
AU  - Jonathan A. Pachter
AU  - Arunasalam Navaraj
AU  - Attila A. Seyhan
AU  - Olin Liang
AU  - Wafik S. El-Deiry
TI  - Natural Killer cell activation, reduced ACE2, TMPRSS2, cytokines G-CSF, M-CSF and SARS-CoV-2-S pseudovirus infectivity by MEK inhibitor treatment of human cells
AID  - 10.1101/2020.08.02.230839
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.02.230839
4099  - http://biorxiv.org/content/early/2020/09/02/2020.08.02.230839.short
4100  - http://biorxiv.org/content/early/2020/09/02/2020.08.02.230839.full
AB  - 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.Competing Interest StatementE.Y. and J.A.P. are employees and stockholders of Verastem Oncology. None of the other co-authors have relevant disclosures for this work.