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

• DOI: 10.1101/2020.08.02.230839
• Publication Date: 2020-08-04T03:55:22Z
• Authors: Lanlan Zhou; Kelsey Huntington; Shengliang Zhang; Lindsey Carlsen; Eui-Young So; Cassandra Parker; Ilyas Sahin; Howard Safran; Suchitra Kamle; Chang-Min Lee; Chun Geun Lee; Jack A. Elias; Kerry S. Campbell; Mandar T. Naik; Walter J. Atwood; Emile Youssef; Jonathan A. Pachter; Arunasalam Navaraj; Attila A. Seyhan; Olin Liang; Wafik S. El-Deiry
• Keywords: Infectivity; Trametinib

COVID-19 affects vulnerable populations including elderly individuals and patients with cancer. Natural Killer (NK) cells innate-immune TRAIL suppress transformed virally-infected cells. ACE2, TMPRSS2 protease promote SARS-CoV-2 infectivity, while inflammatory cytokines IL-6, or G-CSF worsen severity. We show MEK inhibitors (MEKi) VS-6766, trametinib selumetinib reduce ACE2 expression in human In some cells, remdesivir increases ACE2-promoter luciferase-reporter expression, mRNA protein, is attenuated by MEKi. serum-deprived stimulated treated MEKi we observed correlations between pRB, pERK, further supporting role of proliferative state MAPK pathway regulation. elevated COVID-19-(+) patient plasma (N=9) versus control (N=11). TMPRSS2, G-CSF, M-CSF, IL-1α, IL-6 MCP-1 are suppressed alone remdesivir. stimulation NK-cell killing target-cells, without suppressing TRAIL-mediated cytotoxicity. Pseudotyped virus a lentiviral core D614 G614 SPIKE (S) protein on its envelope infected bronchial epithelial small airway lung cancer infectivity the pseudovirus. drug class-effect to stimulate NK inhibit block host-factors for infection leading also suppression SARS-CoV-2-S pseudovirus may attenuate allow immune responses antiviral agents disease progression.