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HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19
Signal Transduction and Targeted Therapy ( IF 39.3 ) Pub Date : 2021-08-18 , DOI: 10.1038/s41392-021-00726-w
Mingfu Tian 1, 2 , Weiyong Liu 3 , Xiang Li 4 , Peiyi Zhao 5 , Muhammad Adnan Shereen 5 , Chengliang Zhu 6 , Shanyu Huang 5 , Siyu Liu 5 , Xiao Yu 4 , Miaomiao Yue 4 , Pan Pan 1, 2 , Wenbiao Wang 2 , Yongkui Li 2, 7 , Xulin Chen 2, 7 , Kailang Wu 5 , Zhen Luo 2, 7 , Qiwei Zhang 2, 7 , Jianguo Wu 1, 2, 6, 7
Affiliation  

Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major pathological feature of Coronavirus Disease 2019 (COVID-19) and a crucial determinant in COVID-19 prognosis. Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control. Here, we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α (HIF-1α) play key roles in the virus infection and pro-inflammatory responses. RNA sequencing shows that HIF-1α signaling, immune response, and metabolism pathways are dysregulated in COVID-19 patients. Clinical analyses indicate that HIF-1α production, inflammatory responses, and high mortalities occurr in elderly patients. HIF-1α and pro-inflammatory cytokines are elicited in patients and infected cells. Interestingly, SARS-CoV-2 ORF3a induces mitochondrial damage and Mito-ROS production to promote HIF-1α expression, which subsequently facilitates SARS-CoV-2 infection and cytokines production. Notably, HIF-1α also broadly promotes the infection of other viruses. Collectively, during SARS-CoV-2 infection, ORF3a induces HIF-1α, which in turn aggravates viral infection and inflammatory responses. Therefore, HIF-1α plays an important role in promoting SARS-CoV-2 infection and inducing pro-inflammatory responses to COVID-19.



中文翻译:

HIF-1α 促进 SARS-CoV-2 感染并加重对 COVID-19 的炎症反应

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 诱发的细胞因子风暴是 2019 年冠状病毒病 (COVID-19) 的主要病理特征,也是 COVID-19 预后的关键决定因素。了解 SARS-CoV-2 诱导的细胞因子风暴的潜在机制对于 COVID-19 的控制至关重要。在这里,我们确定 SARS-CoV-2 ORF3a 和宿主缺氧诱导因子-1α(HIF-1α)在病毒感染和促炎反应中起关键作用。RNA 测序显示 HIF-1α 信号、免疫反应和代谢途径在 COVID-19 患者中失调。临床分析表明,老年患者发生 HIF-1α 产生、炎症反应和高死亡率。HIF-1α 和促炎细胞因子在患者和受感染细胞中产生。有趣的是,SARS-CoV-2 ORF3a 诱导线粒体损伤和 Mito-ROS 产生以促进 HIF-1α 表达,从而促进 SARS-CoV-2 感染和细胞因子的产生。值得注意的是,HIF-1α 还广泛促进其他病毒的感染。总的来说,在 SARS-CoV-2 感染期间,ORF3a 诱导 HIF-1α,从而加剧病毒感染和炎症反应。因此,HIF-1α 在促进 SARS-CoV-2 感染和诱导对 COVID-19 的促炎反应中起着重要作用。

更新日期:2021-08-19
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