tetano
Editor, Senior Moderator
Signal Transduct Target Ther
. 2021 Aug 18;6(1):308.
doi: 10.1038/s41392-021-00726-w.
HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19
Mingfu Tian[SUP] #[/SUP][SUP] 1 2 [/SUP], Weiyong Liu[SUP] #[/SUP][SUP] 3 [/SUP], Xiang Li[SUP] #[/SUP][SUP] 4 [/SUP], Peiyi Zhao[SUP] 5 [/SUP], Muhammad Adnan Shereen[SUP] 5 [/SUP], Chengliang Zhu[SUP] 6 [/SUP], Shanyu Huang[SUP] 5 [/SUP], Siyu Liu[SUP] 5 [/SUP], Xiao Yu[SUP] 4 [/SUP], Miaomiao Yue[SUP] 4 [/SUP], Pan Pan[SUP] 1 2 [/SUP], Wenbiao Wang[SUP] 2 [/SUP], Yongkui Li[SUP] 2 7 [/SUP], Xulin Chen[SUP] 2 7 [/SUP], Kailang Wu[SUP] 5 [/SUP], Zhen Luo[SUP] 8 9 [/SUP], Qiwei Zhang[SUP] 10 11 [/SUP], Jianguo Wu[SUP] 12 13 14 15 [/SUP]
Affiliations
Abstract
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.
. 2021 Aug 18;6(1):308.
doi: 10.1038/s41392-021-00726-w.
HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19
Mingfu Tian[SUP] #[/SUP][SUP] 1 2 [/SUP], Weiyong Liu[SUP] #[/SUP][SUP] 3 [/SUP], Xiang Li[SUP] #[/SUP][SUP] 4 [/SUP], Peiyi Zhao[SUP] 5 [/SUP], Muhammad Adnan Shereen[SUP] 5 [/SUP], Chengliang Zhu[SUP] 6 [/SUP], Shanyu Huang[SUP] 5 [/SUP], Siyu Liu[SUP] 5 [/SUP], Xiao Yu[SUP] 4 [/SUP], Miaomiao Yue[SUP] 4 [/SUP], Pan Pan[SUP] 1 2 [/SUP], Wenbiao Wang[SUP] 2 [/SUP], Yongkui Li[SUP] 2 7 [/SUP], Xulin Chen[SUP] 2 7 [/SUP], Kailang Wu[SUP] 5 [/SUP], Zhen Luo[SUP] 8 9 [/SUP], Qiwei Zhang[SUP] 10 11 [/SUP], Jianguo Wu[SUP] 12 13 14 15 [/SUP]
Affiliations
- PMID: 34408131
- DOI: 10.1038/s41392-021-00726-w
Abstract
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.