The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner.
The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner.
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DOI：
10.3390/v13061062
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发表时间：
2021-06-03
期刊：
影响因子：
--
通讯作者：
Kehn-Hall K
中科院分区：
文献类型：
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作者：
Callahan V;Hawks S;Crawford MA;Lehman CW;Morrison HA;Ivester HM;Akhrymuk I;Boghdeh N;Flor R;Finkielstein CV;Allen IC;Weger-Lucarelli J;Duggal N;Hughes MA;Kehn-Hall K
严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）是一种高传染性RNA病毒，是2019年冠状病毒病（COVID-19）大流行的病原体。重症COVID-19患者可能出现急性肺损伤（ALI）或急性呼吸窘迫综合征（ARDS），需要机械通气。SARS-CoV-2诱导的肺部并发症的主要特征包括导致“细胞因子风暴”的促炎趋化因子和细胞因子的过度表达。在目前的研究中，Calu-3人肺上皮细胞的炎症状态被表征为免疫刺激趋化因子CXCL9、CXCL10和CXCL11的转录显著升高。此外，观察到细胞因子IL-6、TNFα和IFN-γ的基因表达增加。在感染了SARS-CoV-2的人转基因血管紧张素转换酶2 （ACE2）小鼠的肺中，也能诱导CXCL9、CXCL10、IL-6和IFN-γ的转录。为了阐明SARS-CoV-2感染细胞中趋化因子上调的细胞信号通路，研究人员使用了靶向关键信号激酶的小分子抑制剂。AKT抑制剂GSK690693可显著降低CXCL9、CXCL10和CXCL11基因表达对SARS-CoV-2感染的响应。来自COVID-19阳性个体的样本也显示出CXCL9、CXCL10和CXCL11转录本以及AKT通路转录本的显著增加。目前的研究阐明了减少趋化因子诱导的潜在途径特异性靶点，这些趋化因子可能通过过度炎症导致SARS-CoV-2发病。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a ‘cytokine storm.’ In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.
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影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
4.8
作者：
Jiang, TY;Qiu, Y
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影响因子：
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Yen, Hui-Ling
影响因子：
5.4
作者：
Chen, Jun;Lau, Yuk Fai;Subbarao, Kanta
通讯作者：
Subbarao, Kanta
DOI：
10.3791/52065
发表时间：
2014-11-04
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Baer A;Kehn-Hall K
通讯作者：
Kehn-Hall K