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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.


 

  • References

  • 1 Simmons CP, Farrar JJ, Nguyen VV. et al. Dengue. N Engl J Med 2012; 366: 1423-1432.
    CrossrefPubMedGoogle Scholar
  • 2 Gubler DJ. Dengue and dengue haemorrhagic fever. Clin Microbiol Rev 1998; 11: 480-496.
    CrossrefPubMedGoogle Scholar
  • 3 Halstead SB. Pathogenesis of dengue: challenges to molecular biology. Science 1988; 239: 476-481.
    CrossrefPubMedGoogle Scholar
  • 4 Sun DS, King CC, Huang HS. et al. Antiplatelet autoantibodies elicited by dengue virus non-structural protein 1 cause thrombocytopenia and mortality in mice. J Thromb Haemost 2007; 05: 2291-2299.
    CrossrefPubMedGoogle Scholar
  • 5 Falconar AKI. The dengue virus nonstructural-1 protein (NS1) generates antibodies to common epitopes on human blood clotting, integrin/adhesion proteins and binds to human endothelium cells: potential implications in haemorrhagic fever pathogenesis. Arch Virol 1997; 142: 897-916.
    CrossrefPubMedGoogle Scholar
  • 6 Chang HH, Shyu HF, Wang YM. et al. Facilitation of Cell Adhesion by Immobilized Dengue Viral Nonstructural Protein 1 (NS1): Arginine-Glycine-Aspartic Acid Structural Mimicry within the Dengue Viral NS1 Antigen. J Infect Dis 2002; 186: 743-751.
    CrossrefPubMedGoogle Scholar
  • 7 Lin CF, Wan SW, Chen MC. et al. Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model. Lab Invest 2008; 88: 1079-1089.
    CrossrefPubMedGoogle Scholar
  • 8 Oishi K, Inoue S, Cinco MT. et al. Correlation between increased platelet-associated IgG and thrombocytopenia in secondary dengue virus infections. J Med Virol 2003; 71: 259-264.
    CrossrefPubMedGoogle Scholar
  • 9 Saito M, Oishi K, Inoue S. et al. Association of increased platelet-associated immunoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections. Clin Exp Immunol 2004; 138: 299-303.
    CrossrefPubMedGoogle Scholar
  • 10 Wills BA, Oragui EE, Stephens AC. et al. Coagulation abnormalities in dengue haemorrhagic Fever: serial investigations in 167 Vietnamese children with Dengue shock syndrome. Clin Infect Dis 2002; 35: 277-285.
    CrossrefPubMedGoogle Scholar
  • 11 Halstead SB. Dengue. Lancet 2007; 370: 1644-1652.
    CrossrefPubMedGoogle Scholar
  • 12 WHO. Dengue: guidelines for diagnosis, treatment, prevention and control. New ed Geneva, World Health Organisation 2009; Chapter 1 and 2 11-28.
    PubMedGoogle Scholar
  • 13 Andre P, Hartwell D, Hrachovinova I. et al. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci USA 2000; 97: 13835-13840.
    CrossrefPubMedGoogle Scholar
  • 14 Brozna JP. Shwartzman reaction. Semin Thromb Hemost 1990; 16: 326-332.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Gross O, Thomas CJ, Guarda G. et al. The inflammasome: an integrated view. Immunol Rev 2011; 243: 136-151.
    CrossrefPubMedGoogle Scholar
  • 16 Wu MF, Chen ST, Yang AH. et al. CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages. Blood 2013; 121: 95-106.
    CrossrefPubMedGoogle Scholar
  • 17 Hottz ED, Lopes JF, Freitas C. et al. Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation. Blood 2013; 122: 3405-3414.
    CrossrefPubMedGoogle Scholar
  • 18 Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 2008; 08: 34-47.
    CrossrefPubMedGoogle Scholar
  • 19 Schmidt RE, Gessner JE. Fc receptors and their interaction with complement in autoimmunity. Immunol Lett 2005; 100: 56-67.
    CrossrefPubMedGoogle Scholar
  • 20 Chang HH, Kau JH, Lo SJ. et al. Cell-adhesion and morphological changes are not sufficient to support anchorage-dependent cell growth via non-integrin-mediated attachment. Cell Biol Int 2003; 27: 123-133.
    CrossrefPubMedGoogle Scholar
  • 21 Kuida K, Lippke JA, Ku G. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 1995; 267: 2000-2003.
    CrossrefPubMedGoogle Scholar
  • 22 Alexopoulou L, Holt AC, Medzhitov R. et al. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413: 732-738.
    CrossrefPubMedGoogle Scholar
  • 23 Martinon F, Petrilli V, Mayor A. et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-241.
    CrossrefPubMedGoogle Scholar
  • 24 Thomas L, Verlaeten O, Cabie A. et al. Influence of the dengue serotype, previous dengue infection, and plasma viral load on clinical presentation and outcome during a dengue-2 and dengue-4 co-epidemic. Am J Trop Med Hyg 2008; 78: 990-998.
    PubMedGoogle Scholar
  • 25 Huang HS, Sun DS, Lien TS. et al. Dendritic cells modulate platelet activity in IVIg-mediated amelioration of ITP in mice. Blood 2010; 116: 5002-5009.
    CrossrefPubMedGoogle Scholar
  • 26 Subramaniam M, Frenette PS, Saffaripour S. et al. Defects in hemostasis in P-selectin- deficient mice. Blood 1996; 87: 1238-1242.
    PubMedGoogle Scholar
  • 27 WHO. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2 ed. World Health Organisation. 1997; Chapter 2 12-23.
    PubMedGoogle Scholar
  • 28 Iyngkaran N, Yadav M, Sinniah M. Augmented inflammatory cytokines in primary dengue infection progressing to shock. Singapore Med J 1995; 36: 218-221.
    PubMedGoogle Scholar
  • 29 Arias J, Valero N, Mosquera J. et al. Increased expression of cytokines, soluble cytokine receptors, soluble apoptosis ligand and apoptosis in dengue. Virology 2014; 452-453: 42-51.
    CrossrefPubMedGoogle Scholar
  • 30 Tsai TT, Chuang YJ, Lin YS. et al. An emerging role for the anti-inflammatory cytokine interleukin-10 in dengue virus infection. J Biomed Sci 2013; 20: 40.
    CrossrefPubMedGoogle Scholar
  • 31 Rachman A, Rinaldi I. Coagulopathy in dengue infection and the role of interleukin- 6. Acta Med Indon 2006; 38: 105-108.
    PubMedGoogle Scholar
  • 32 Tsai YT, Chang SY, Lee CN. et al. Human TLR3 recognizes dengue virus and modulates viral replication in vitro. Cell Microbiol 2009; 11: 604-615.
    CrossrefPubMedGoogle Scholar
  • 33 Belge KU, Dayyani F, Horelt A. et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol 2002; 168: 3536-3542.
    CrossrefPubMedGoogle Scholar
  • 34 Ziegler-Heitbrock L. The CD14+ CD16+ blood monocytes: their role in infection and inflammation. J Leukocyte Biol 2007; 81: 584-592.
    CrossrefPubMedGoogle Scholar
  • 35 Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol 2008; 26: 513-533.
    CrossrefPubMedGoogle Scholar
  • 36 Park-Min KH, Serbina NV, Yang W. et al. FcgammaRIII-dependent inhibition of interferon-gamma responses mediates suppressive effects of intravenous immune globulin. Immunity 2007; 26: 67-78.
    CrossrefPubMedGoogle Scholar
  • 37 Kliks SC, Nimmanitya S, Nisalak A. et al. Evidence that maternal dengue antibodies are important in the development of dengue haemorrhagic fever in infants. Am J Trop Med Hyg 1988; 38: 411-419.
    CrossrefPubMedGoogle Scholar
  • 38 Libraty DH, Acosta LP, Tallo V. et al. A prospective nested case-control study of Dengue in infants: rethinking and refining the antibody-dependent enhancement dengue haemorrhagic fever model. PLoS Med 2009; 06: e1000171.
    CrossrefPubMedGoogle Scholar
  • 39 Chen HC, Hofman FM, Kung JT. et al. Both virus and tumor necrosis factor alpha are critical for endothelium damage in a mouse model of dengue virus-induced haemorrhage. J Virol 2007; 81: 5518-5526.
    CrossrefPubMedGoogle Scholar
  • 40 Rothman AL. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 2011; 11: 532-543.
    CrossrefPubMedGoogle Scholar
  • 41 Halstead SB, Mahalingam S, Marovich MA. et al. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis 2010; 10: 712-722.
    CrossrefPubMedGoogle Scholar
  • 42 Scott RM, Nimmannitya S, Bancroft WH. et al. Shock syndrome in primary dengue infections. Am J Trop Med Hyg 1976; 25: 866-874.
    CrossrefPubMedGoogle Scholar
  • 43 Chao DY, Lin TH, Hwang KP. et al. 1998 dengue haemorrhagic fever epidemic in Taiwan. Emerg Infect Dis 2004; 10: 552-554.
    CrossrefPubMedGoogle Scholar
  • 44 Barnes WJ, Rosen L. Fatal haemorrhagic disease and shock associated with primary dengue infection on a Pacific island. Am J Trop Med Hyg 1974; 23: 495-506.
    CrossrefPubMedGoogle Scholar
  • 45 Marchette NJ, Halstead SB, Nash DR. et al. Recovery of dengue viruses from tissues of experimentally infected rhesus monkeys. Appl Microbiol 1972; 24: 328-333.
    PubMedGoogle Scholar
  • 46 Martina BE, Koraka P, Osterhaus AD. Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev 2009; 22: 564-581.
    CrossrefPubMedGoogle Scholar
  • 47 Halstead SB. Controversies in dengue pathogenesis. Paediat Internat Child Health 2012; 32 (Suppl. 01) 5-9.
    PubMedGoogle Scholar
  • 48 Irikura VM, Hirsch E, Hirsh D. Effects of interleukin-1 receptor antagonist overexpression on infection by Listeria monocytogenes. Infect Immun 1999; 67: 1901-1909.
    PubMedGoogle Scholar
  • 49 Dimaano EM, Saito M, Honda S. et al. Lack of efficacy of high-dose intravenous immunoglobulin treatment of severe thrombocytopenia in patients with secondary dengue virus infection. Am J Trop Med Hyg 2007; 77: 1135-1138.
    PubMedGoogle Scholar
  • 50 Rajapakse S. Intravenous immunoglobulins in the treatment of dengue illness. Transact Royal Soc Trop Med Hyg 2009; 103: 867-870.
    PubMedGoogle Scholar