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.
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.
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通过 MEK 抑制剂处理人体细胞，激活自然杀伤细胞，降低 ACE2、TMPRSS2、细胞因子 G-CSF、M-CSF 和 SARS-CoV-2-S 假病毒感染性。
DOI：
10.1101/2020.08.02.230839
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
You
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文献类型：
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作者：
Zhou,Lanlan;Huntington,Kelsey;Zhang,Shengliang;Carlsen,Lindsey;So,Eui-Young;Parker,Cassandra;Sahin,Ilyas;Safran,Howard;Kamle,Suchitra;Lee,Chang-Min;Lee,ChunGeun;Elias,JackA;Campbell,KerryS;Naik,MandarT;Atwood,WalterJ;You
新冠肺炎影响弱势人群，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。血管紧张素转换酶2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加重新冠肺炎的严重程度。我们发现MEK抑制剂(Meki)VS-6766、曲美替尼和赛鲁米替尼降低了人类细胞中ACE2的表达。在一些人细胞中，瑞代韦增加了ACE2启动子荧光素酶报告基因的表达，增加了ACE2mRNA和蛋白的表达，而Meki抑制了ACE2的表达。在去血清刺激的细胞中，我们观察到PRB、PERK和ACE2表达的相关性，进一步支持了增殖状态和MAPK通路在ACE2调控中的作用。我们发现新冠肺炎阳性患者(N=9)的血浆细胞因子水平高于对照组(N=11)。MPRSS2、炎症细胞因子G-CsF、M-Csf、IL-1α、IL-6和MCP-1可被Meki单用或联合瑞士德韦抑制。我们观察到Meki刺激NK细胞对靶细胞的杀伤作用，而不抑制TRAIL介导的细胞毒作用。以慢病毒为核心的伪型SARS-CoV-2病毒及其包膜上的D614或G614刺突蛋白(S)感染人支气管上皮细胞、小气道上皮细胞或肺癌细胞，Meki抑制该假病毒的感染性。我们发现Meki具有刺激NK细胞、抑制炎性细胞因子和阻断SARS-CoV-2感染宿主因子的药物等级效应，从而抑制SARS-CoV-2-S假病毒对人类细胞的感染。Meki可能会减弱SARS-CoV-2的感染，使免疫反应和抗病毒药物控制疾病的进展。
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.