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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
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 El-Deiry.
Affiliation
  • Lanlan Zhou; Brown University
  • Kelsey Huntington; Brown University
  • Shengliang Zhang; Brown University
  • Lindsey Carlsen; Brown University
  • Eui-Young So; Brown University
  • Cassandra Parker; Brown University
  • Ilyas Sahin; Brown University
  • Howard Safran; Brown University
  • Suchitra Kamle; Brown University
  • Chang-Min Lee; Brown University
  • Chun-Geun Lee; Brown University
  • Jack A. Elias; Brown University
  • Kerry S. Campbell; Fox Chase Cancer Center
  • Mandar T. Naik; Brown University
  • Walter J. Atwood; Brown University
  • Emile Youssef; Verastem
  • Jonathan A. Pachter; Verastem
  • Arunasalam Navaraj; Brown University
  • Attila A. Seyhan; Brown University
  • Olin Liang; Brown University
  • Wafik El-Deiry; Brown University
Preprint in English | bioRxiv | ID: ppbiorxiv-230839
Journal article
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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-1, 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.
License
cc_by_nc_nd
Full text: Available Collection: Preprints Database: bioRxiv Type of study: Prognostic study Language: English Year: 2020 Document type: Preprint
Full text: Available Collection: Preprints Database: bioRxiv Type of study: Prognostic study Language: English Year: 2020 Document type: Preprint
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