HIF-1αpromotes virus replication and cytokine storm in H1N1 virus-induced severe pneumonia through cellular metabolic reprogramming  

作　　者：Xiaoxiao Meng Yong Zhu Wenyu Yang Jiaxiang Zhang Wei Jin Rui Tian Zhengfeng Yang Ruilan Wang 

机构地区：[1]Department of Critical Care Medicine,Shanghai General Hospital,Shanghai Jiaotong University,School of Medicine,Shanghai,201620,China [2]Precision Research Center for Refractory Diseases,Shanghai General Hospital,Shanghai Jiaotong University,School of Medicine,Shanghai,201620,China

出　　处：《Virologica Sinica》2024年第1期81-96,共16页中国病毒学（英文版）

基　　金：supported by a grant from the National Natural Science Foundation of China(No.82072210);the Shanghai Municipal Science and Technology Commission,China(No.20ZR1445200);the Chinese Federation of Public Health Foundation(GWLM202001);the Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai(No.GWV-10.1-XK25).

摘　　要：The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated.Here,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells.Specifically,HIF-1αprotein expression is upregulated after H1N1 infection.Deficiency of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in vivo.In addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in vitro.Mechanistically,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and lactate.Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses.Further analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/βproduction.In conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.

关 键 词：H1N1 Severe pneumonia Virus replication Hypoxia inducible factor-1α GLYCOLYSIS 

分 类 号：R373.21[医药卫生—病原生物学]