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-1alpha, 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.

中文翻译：

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通过 MEK 抑制剂处理人体细胞，自然杀伤细胞活化，降低 ACE2、TMPRSS2、细胞因子 G-CSF、M-CSF 和 SARS-CoV-2-S 假病毒感染性。

COVID-19 影响弱势群体，包括老年人和癌症患者。自然杀伤 (NK) 细胞和先天免疫 TRAIL 抑制转化和病毒感染的细胞。ACE2 和 TMPRSS2 蛋白酶促进 SARS-CoV-2 的感染性，而炎性细胞因子 IL-6 或 G-CSF 会加重 COVID-19 的严重程度。我们展示了 MEK 抑制剂 (MEKi) VS-6766、曲美替尼和司美替尼可降低人类细胞中 ACE2 的表达。在一些人体细胞中，瑞德西韦会增加 ACE2 启动子荧光素酶报告基因、ACE2 mRNA 和蛋白质的表达，而 MEKi 会减弱 ACE2 的表达。在用 remdesivir 和 MEKi 处理的血清剥夺和刺激细胞中，我们观察到 pRB、pERK 和 ACE2 表达之间的相关性，进一步支持了增殖状态和 MAPK 通路在 ACE2 调节中的作用。我们显示 COVID-19-(+) 患者血浆 (N=9) 与对照 (N=11) 中的细胞因子升高。TMPRSS2、炎性细胞因子 G-CSF、M-CSF、IL-1α、IL-6 和 MCP-1 被 MEKi 单独或与 remdesivir 一起抑制。我们观察到 MEKi 刺激 NK 细胞杀死靶细胞，而不抑制 TRAIL 介导的细胞毒性。假型 SARS-CoV-2 病毒，其包膜上有慢病毒核心和 SARS-CoV-2 D614 或 G614 SPIKE (S) 蛋白，感染人支气管上皮细胞、小气道上皮细胞或肺癌细胞，MEKi 抑制假病毒的感染性. 我们展示了 MEKi 的药物类别效应，可刺激 NK 细胞、抑制炎性细胞因子和阻断 SARS-CoV-2 感染的宿主因子，从而抑制人类细胞的 SARS-CoV-2-S 假病毒感染。