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Thromb Haemost 2015; 113(05): 1060-1070
DOI: 10.1160/TH14-07-0637
Blood Cells, Inflammation and Infection
Schattauer GmbH

Dengue virus and antiplatelet autoantibodies synergistically induce haemorrhage through Nlrp3-inflammasome and FcүRIII

Te-Sheng Lien   †
1   Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan
,
Der-Shan Sun   †
1   Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan
2   Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
,
Chia-Ming Chang
3   Department of Biochemistry, Tzu-Chi University, Hualien, Taiwan
,
Cheng-Yeu Wu
4   Center for Molecular and Clinical Immunology, Chang Gung University, Gueishan, Taoyuan, Taiwan
,
Ming-Shen Dai
5   Division of Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
,
Hao Chan
2   Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
,
Wen-Sheng Wu
6   Department of Laboratory Medicine and Biotechnology, Tzu-Chi University, Hualien, Taiwan
,
Shu-Hui Su
1   Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan
2   Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
,
You-Yen Lin
2   Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
,
Hsin-Hou Chang
1   Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan
2   Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
7   Center for Vascular Medicine, Tzu-Chi University, Hualien, Taiwan
› Author Affiliations Financial support: This work is supported by research funding from National Science Council (98–2320-B-320–004MY3, 101–2320-B-320–004-MY3 to HHC) and Tzu-Chi University (TCIRP98001, TCIRP101001 to HHC, DSS, WSW, and SHS) and Chang Gung Memorial Hospital (CLRPD1A0012 to CYW).
Further Information

Publication History

Received: 29 July 2014

Accepted after major revision: 06 January 2015

Publication Date:
24 November 2017 (online)

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Summary

Dengue haemorrhagic fever (DHF) typically occurs during secondary infections with dengue viruses (DENVs). Although it is generally accepted that antibody-dependent enhancement is the primary reason why patients with secondary infection are at an increased risk of developing DHF, a growing body of evidence shows that other mechanisms, such as the elicitation of antiplatelet autoantibodies by DENV nonstructural protein NS1, also play crucial roles in the pathogenesis of DHF. In this study, we developed a “two-hit” model of secondary DENV infection to examine the respective roles of DENV (first hit) and antiplatelet Igs (second hit) on the induction of haemorrhage. Mice were first exposed to DENV and then exposed to antiplatelet or anti-NS1 Igs 24 hours later. The two-hit treatment induced substantial haemorrhage, coagulopathy, and cytokine surge, and additional treatment with antagonists of TNF-α, IL-1, caspase-1, and FcүRIII ameliorated such effects. In addition, knockout mice lacking the Fcү receptor III, Toll-like receptor 3, and inflammasome components Nlrp3 and caspase-1 exhibited considerably fewer pathological alterations than did wild type controls. These findings may provide new perspectives for developing feasible approaches to treat patients with DHF.

Keywords

Autoantibody - dengue virus - Fcे receptor III - Nlrp3 inflammasome - Toll like receptor 3 - Shwartzman reaction

† These authors share equal contribution.


 

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