STING strengthens host anti-hantaviral immunity through an interferon-independent pathway

Kerong Wang; Jian Zhang; Yongheng Yang; Yue Si; Ziqing Zhou; Xudong Zhu; Sushan Wu; He Liu; Hui Zhang; Liang Zhang; Linfeng Cheng; Wei Ye; Xin Lv; Yingfeng Lei; Xijing Zhang; Shilin Cheng; Lixin Shen; Fanglin Zhang; Hongwei Ma

doi:10.1016/j.virs.2023.06.006

August 2023

Citation: Kerong Wang, Jian Zhang, Yongheng Yang, Yue Si, Ziqing Zhou, Xudong Zhu, Sushan Wu, He Liu, Hui Zhang, Liang Zhang, Linfeng Cheng, Wei Ye, Xin Lv, Yingfeng Lei, Xijing Zhang, Shilin Cheng, Lixin Shen, Fanglin Zhang, Hongwei Ma. STING strengthens host anti-hantaviral immunity through an interferon-independent pathway .VIROLOGICA SINICA, 2023, 38(4) : 568-584. http://dx.doi.org/10.1016/j.virs.2023.06.006

STING strengthens host anti-hantaviral immunity through an interferon-independent pathway

Kerong Wang ^a,b ,
Jian Zhang ^b ,
Yongheng Yang ^b ,
Yue Si ^b ,
Ziqing Zhou ^b ,
Xudong Zhu ^b,c ,
Sushan Wu ^a,b ,
He Liu ^b ,
Hui Zhang ^b ,
Liang Zhang ^b ,
Linfeng Cheng ^b ,
Wei Ye ^b ,
Xin Lv ^b ,
Yingfeng Lei ^b ,
Xijing Zhang ^d ,
Shilin Cheng ^a,e ,
Lixin Shen ^{a
,,} ,
Fanglin Zhang ^{b
,,} ,
Hongwei Ma ^{b
,,}

a. College of Life Sciences, Northwest University, Xi'an 710069, China;
b. Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China;
c. College of Medicine, Yan'an University, Yan'an 716000, China;
d. Department of Anesthesiology & Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China;
e. Medical Genetics and Developmental Biology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China

Corresponding author: Lixin Shen, shenlx@nwu.edu.cn
Fanglin Zhang, flzhang@fmmu.edu.cn
Hongwei Ma, mahongwei0720@sina.com
Received Date: 08 December 2022
Accepted Date: 16 June 2023
Available online: 22 June 2023

Abstract

Hantaan virus (HTNV), the prototype virus of hantavirus, could escape innate immunity by restraining type I interferon (IFN) responses. It is largely unknown whether there existed other efficient anti-hantaviral tactics in host cells. Here, we demonstrate that the stimulator of interferon genes (STING) strengthens the host IFN-independent anti-hantaviral immunity. HTNV infection activates RIG-I through IRE1-XBP 1-mediated ER stress, which further facilitates the subcellular translocation and activation of STING. During this process, STING triggers cellular autophagy by interacting with Rab7A, thus restricting viral replication. To note, the anti-hantaviral effects of STING are independent of canonical IFN signaling. Additionally, neither application of the pharmacological antagonist nor the agonist targeting STING could improve the outcomes of nude mice post HTNV challenge in vivo. However, the administration of plasmids exogenously expressing the mutant C-terminal tail (ΔCTT) STING, which would not trigger the type I IFN responses, protected the nude mice from lethal HTNV infection. In summary, our research revealed a novel antiviral pathway through the RIG-I-STING-autophagy pathway, which offered novel therapeutic strategies against hantavirus infection.
- Hantaan virus (HTNV)
- , IRE1
- , RIG-I
- , STING
- , Autophagy
- , Innate immunity

Electronic Supplementary Material

10.1016j.virs.2023.06.006-ESM.docx
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