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Thromb Haemost. 2015 May;113(5):1060-70. doi: 10.1160/TH14-07-0637. Epub 2015 Mar 5.

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

Author information

1
Hsin-Hou Chang, PhD, Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan, Republic of China, Tel.: +886 3 8565301 ext 2667, Fax: +886 3 8578386, E-mail: hhchang@mail.tcu.edu.tw.

Abstract

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 FcγRIII ameliorated such effects. In addition, knockout mice lacking the Fcγ 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; Fcγ receptor III; Nlrp3 inflammasome; Shwartzman reaction; Toll like receptor 3; dengue virus

PMID:
25740324
DOI:
10.1160/TH14-07-0637
[Indexed for MEDLINE]

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