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

Te-Sheng Lien; Der-Shan Sun; Chia-Ming Chang; Cheng-Yeu Wu; Ming-Shen Dai; Hao Chan; Wen-Sheng Wu; Shu-Hui Su; You-Yen Lin; Hsin-Hou Chang

doi:10.1160/TH14-07-0637

Thrombosis and Haemostasis, Table of Contents

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

Authors

Te-Sheng Lien^†

¹Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan
Der-Shan Sun^†

¹Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan

²Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
Chia-Ming Chang

³Department of Biochemistry, Tzu-Chi University, Hualien, Taiwan
Cheng-Yeu Wu

⁴Center for Molecular and Clinical Immunology, Chang Gung University, Gueishan, Taoyuan, Taiwan
Ming-Shen Dai

⁵Division of Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
Hao Chan

²Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
Wen-Sheng Wu

⁶Department of Laboratory Medicine and Biotechnology, Tzu-Chi University, Hualien, Taiwan
Shu-Hui Su

¹Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan

²Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
You-Yen Lin

²Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
Hsin-Hou Chang

¹Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan

²Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan

⁷Center for Vascular Medicine, Tzu-Chi University, Hualien, Taiwan

Abstract

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

Full Text

References

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