Severe fever with thrombocytopenia syndrome virus replicates in platelets and enhances platelet activation

Lei Fang; Sicong Yu; Xiaoxu Tian; Wanrong Fu; Lingxuan Su; Zhi Chen; Chunlan Yan; Ji He; Jin Hong; Wenwen Lian; Gangqiong Liu; Yanjun Zhang; Jiancang Zhou; Liang Hu

doi:10.1016/j.jtha.2023.02.006

Severe fever with thrombocytopenia syndrome virus replicates in platelets and enhances platelet activation

J Thromb Haemost. 2023 May;21(5):1336-1351. doi: 10.1016/j.jtha.2023.02.006. Epub 2023 Feb 13.

Authors

Lei Fang¹, Sicong Yu², Xiaoxu Tian³, Wanrong Fu³, Lingxuan Su⁴, Zhi Chen⁵, Chunlan Yan⁶, Ji He⁷, Jin Hong³, Wenwen Lian⁵, Gangqiong Liu³, Yanjun Zhang⁸, Jiancang Zhou⁹, Liang Hu¹⁰

Affiliations

¹ Department of Critical Care Medicine, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Centers for Disease Control and Prevention, Hangzhou, China; Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China.
² School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, China.
³ Department of Cardiology, Cardiovascular Center, Henan Key Laboratory of Hereditary, Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
⁴ Zhejiang Provincial Centers for Disease Control and Prevention, Hangzhou, China.
⁵ National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Hangzhou, China.
⁶ Department of Biophysics, College of Medicine, Zhejiang University, Hangzhou, China.
⁷ Blood Center of Zhejiang Province, Hangzhou, China.
⁸ Zhejiang Provincial Centers for Disease Control and Prevention, Hangzhou, China. Electronic address: yjzhang@cdc.zj.cn.
⁹ Department of Critical Care Medicine, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China. Electronic address: jiancangzhou@zju.edu.cn.
¹⁰ Department of Critical Care Medicine, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Department of Cardiology, Cardiovascular Center, Henan Key Laboratory of Hereditary, Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: fcchul@zzu.edu.cn.

PMID: 36792011
DOI: 10.1016/j.jtha.2023.02.006

Abstract

Background: Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) infection causes an emerging hemorrhagic fever in East Asia with a high mortality rate. Thrombocytopenia is a consistent feature of SFTS illness, but the mechanism remains elusive.

Objectives: We aimed to better understand the role of platelets in the pathophysiology of SFTSV infection, including the development of thrombocytopenia.

Methods: Using platelets from healthy volunteers and patients with SFTS, we evaluated the functional changes in platelets against SFTSV infection. We investigated the direct effect of glycoprotein VI on platelet-SFTSV interaction by quantitative real-time PCR, molecular docking, surface plasmon resonance spectrometry, flow cytometry, western blot, and platelet functional studies in vitro. Interactions of SFTSV and platelet-SFTSV complexes with macrophages were also determined by scanning electron microscope, quantitative real-time PCR, and flow cytometry.

Results: This study is the first to demonstrate that platelets are capable of harboring and producing SFTSV particles. Structural and functional studies found that SFTSVs bind platelet glycoprotein VI to potentiate platelet activation, including platelet aggregation, adenosine triphosphate release, spreading, clot retraction, coagulation, phosphatidylserine exposure, thrombus formation, and adherence. In vitro mechanistic studies highlighted that the interaction of platelets with human THP-1 cells promoted SFTSV clearance and suppressed cytokine production in macrophages. However, unwanted SFTSV replication in macrophages reciprocally aggravated SFTSV persistence in the circulation, which may contribute to thrombocytopenia and other complications during SFTSV infection.

Conclusion: These findings together highlighted the pathophysiological role of platelets in initial intrinsic defense against SFTSV infections, as well as intertwined processes with host immunity, which can also lead to thrombocytopenia and poor prognosis.

Keywords: GPVI; SFTSV; platelet activation; replication; thrombocytopenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blood Platelets
Bunyaviridae Infections* / complications
Humans
Molecular Docking Simulation
Platelet Activation
Severe Fever with Thrombocytopenia Syndrome* / complications
Thrombocytopenia* / complications

Supplementary concepts

SFTS phlebovirus