Dengue virus and antiplatelet autoantibodies synergistically induce haemorrhage through Nlrp3-inflammasome and FcγRIII.
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.
Te-Sheng
TS
Lien
Der-Shan
DS
Sun
Chia-Ming
CM
Chang
Cheng-Yeu
CY
Wu
Ming-Shen
MS
Dai
Hao
H
Chan
Wen-Sheng
WS
Wu
Shu-Hui
SH
Su
You-Yen
YY
Lin
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.
Hsin-Hou
HH
Chang
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology*; D003716:Dengue Virus / Q000472:pathogenicity*; D005260:Female; D006470:Hemorrhage / Q000276:immunology* / Q000821:virology; D058847:Inflammasomes / Q000276:immunology*; D007375:Interleukin-1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017452:Receptors, IgG / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D019595:Severe Dengue / Q000276:immunology / Q000821:virology; D013925:Thromboplastin / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism
D000914:Antibodies, Viral; D001323:Autoantibodies; D002352:Carrier Proteins; C485700:Fcgr3 protein, mouse; D058847:Inflammasomes; D007375:Interleukin-1; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017452:Receptors, IgG; D011994:Recombinant Proteins; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D013925:Thromboplastin
Autoantibody; Fcγ receptor III; Nlrp3 inflammasome; Shwartzman reaction; Toll like receptor 3; dengue virus