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Thromb Haemost 2016; 115(03): 646-656
DOI: 10.1160/th15-06-0498
Blood Cells, Inflammation and Infection
Schattauer GmbH

Anti-dengue virus nonstructural protein 1 antibodies contribute to platelet phagocytosis by macrophages

Shu-Wen Wan   †
1   Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
2   Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
,
Yi-Wen Yang   †
2   Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
,
Ya-Ting Chu
2   Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
,
Chiou-Feng Lin
1   Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
3   Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan
,
Chih-Peng Chang
1   Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
2   Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
,
Trai-Ming Yeh
1   Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
4   Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
,
Robert Anderson
5;   Departments of Microbiology & Immunology and Pediatrics, and Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, Canada
,
Yee-Shin Lin
1   Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
2   Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
› Author Affiliations Financial support: This work was supported by Grants NSC101–2321-B006–002, NSC102–2325-B-006–006 and MOST103–2325-B-006–010 from The Ministry of Science and Technology, Taiwan.
Further Information

Publication History

Received: 18 June 2015

Accepted after major revision: 30 October 2015

Publication Date:
20 March 2018 (online)

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Summary

Thrombocytopenia is an important clinical manifestation of dengue disease. The hypotheses concerning the pathogenesis of thrombocytopenia include decreased production and increased destruction or consumption of platelets. We previously suggested a mechanism of molecular mimicry in which antibodies (Abs) directed against dengue virus (DENV) nonstructural protein 1 (NS1) cross-react with platelets. Furthermore, several lines of evidence show activation of endothelial cells (ECs) and macrophages are related to dengue disease severity. Previous studies also suggested that Ab-opsonised platelets facilitate the engulfment of platelets by macrophages. Here we show that TNF-α-activated ECs upregulate adhesion molecule expression to enhance the binding of platelets and macrophages and lead to anti-DENV NS1 Ab-mediated platelet phagocytosis. We further demonstrate that the interaction between macrophages and TNF-α-activated ECs requires binding of FcγR with the Fc region of platelet-bound anti-DENV NS1 Abs. Importantly, the binding of anti-DENV NS1 Abs to platelets did not interfere with platelet adhesion to ECs. The adhesion molecules ICAM-1 and β3 integrin expressed on ECs as well as the FcγR expressed on macrophages were critical in anti-DENV NS1 Ab-mediated platelet phagocytosis on activated ECs. Moreover, anti-DENV NS1 Abs dramatically enhanced platelet engulfment by macrophages in a murine model of DENV infection. Our study provides evidence for a novel role for anti-DENV NS1 Abs in the pathogenesis of thrombocytopenia in dengue disease by enhancing platelet phagocytosis by macrophages.

Keywords

Dengue virus - nonstructural protein 1 - platelet phagocytosis

† These authors contributed equally.


Supplementary Material

 

  • References

  • 1 Bhatt S, Gething PW, Brady OJ. et al. The global distribution and burden of dengue. Nature 2013; 496: 504-507.
    CrossrefPubMedGoogle Scholar
  • 2 Guzman MG, Harris E. Dengue. Lancet 2015; 385: 453-465.
    CrossrefPubMedGoogle Scholar
  • 3 Chuansumrit A. Chaiyaratana W Haemostatic derangement in dengue haemor-rhagic fever. Thromb Res 2014; 133: 10-16.
    CrossrefPubMedGoogle Scholar
  • 4 Wang S, He R, Patarapotikul J. et al. Antibody-enhanced binding of dengue-2 virus to human platelets. Virology 1995; 213: 254-257.
    CrossrefPubMedGoogle Scholar
  • 5 Funahara Y, Ogawa K, Fujita N. et al. Three possible triggers to induce throm-bocytopenia in dengue virus infection. Southeast Asian J Trop Med Public Health 1987; 18: 351-355.
    PubMedGoogle Scholar
  • 6 Saito M, Oishi K, Inoue S. et al. Association of increased platelet-associated im-munoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections. Clin Exp Immunol 2004; 138: 299-303.
    CrossrefPubMedGoogle Scholar
  • 7 de Castro RA, de Castro JA, Barez MY. et al. Thrombocytopenia associated with dengue haemorrhagic fever responds to intravenous administration of anti-D (Rh0-D) immune globulin. Am J Trop Med Hyg 2007; 76: 737-742.
    PubMedGoogle Scholar
  • 8 Lin CF, Lei HY, Liu CC. et al. Generation of IgM anti-platelet autoantibody in dengue patients. J Med Virol 2001; 63: 143-149.
    CrossrefPubMedGoogle Scholar
  • 9 Lin CF, Lei HY, Liu CC. et al. Patient and mouse antibodies against dengue virus nonstructural protein 1 cross-react with platelets and cause their dysfunction or depletion. Am J Infect Dis 2008; 4: 69-75.
    CrossrefPubMedGoogle Scholar
  • 10 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; 5: 2291-2299.
    CrossrefPubMedGoogle Scholar
  • 11 Butthep P, Bunyaratvej A, Bhamarapravati N. Dengue virus and endothelial cell: a related phenomenon to thrombocytopenia and granulocytopenia in dengue haemorrhagic fever. Southeast Asian J Trop Med Public Health 1993; 24 (Suppl. 01) 246-249.
    PubMedGoogle Scholar
  • 12 Krishnamurti C, Peat RA, Cutting MA. et al. Platelet adhesion to dengue-2 virus-infected endothelial cells. Am J Trop Med Hyg 2002; 66: 435-441.
    CrossrefPubMedGoogle Scholar
  • 13 Anderson R, Wang S, Osiowy C. et al. Activation of endothelial cells via antibody-enhanced dengue virus infection of peripheral blood monocytes. J Virol 1997; 71: 4226-4232.
    PubMedGoogle Scholar
  • 14 van Gils JM, Zwaginga JJ, Hordijk PL. Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J Leukoc Biol 2009; 85: 195-204.
    CrossrefPubMedGoogle Scholar
  • 15 Kirton CM, Nash GB. Activated platelets adherent to an intact endothelial cell monolayer bind flowing neutrophils and enable them to transfer to the endothe-lial surface. J Lab Clin Med 2000; 136: 303-313.
    CrossrefPubMedGoogle Scholar
  • 16 Kuijper PH, Gallardo Torres HI, Houben LA. et al. P-selectin and MAC-1 mediate monocyte rolling and adhesion to ECM-bound platelets under flow conditions. J Leukoc Biol 1998; 64: 467-473.
    CrossrefPubMedGoogle Scholar
  • 17 Vijayalakshmi AM, Ganesh VR. Haemophagocytic syndrome associated with dengue haemorrhagic fever. Indian Pediatr 2009; 46: 545.
    PubMedGoogle Scholar
  • 18 Tan LH, Lum LC, Omar SF, Kan FK. Haemophagocytosis in dengue: comprehensive report of six cases. J Clin Virol 2012; 55: 79-82.
    CrossrefPubMedGoogle Scholar
  • 19 Pal P, Giri PP, Ramanan AV. Dengue associated haemophagocytic lymphohis-tiocytosis: a case series. Indian Pediatr 2014; 51: 496-497.
    PubMedGoogle Scholar
  • 20 Fisman DN. Haemophagocytic syndromes and infection. Emerg Infect Dis 2000; 6: 601-608.
    CrossrefPubMedGoogle Scholar
  • 21 Janka GE, Lehmberg K. Haemophagocytic syndromes-an update. Blood Rev 2014; 28: 135-142.
    CrossrefPubMedGoogle Scholar
  • 22 Lei HY. Transient haemophagocytic activity in dengue immunopathogenesis. J Formos Med Assoc 2009; 108: 595-598.
    CrossrefPubMedGoogle Scholar
  • 23 Onlamoon N, Noisakran S, Hsiao HM. et al. Dengue virus-induced haemorrhage in a nonhuman primate model. Blood 2010; 115: 1823-1834.
    CrossrefPubMedGoogle Scholar
  • 24 Chen MC, Lin CF, Lei HY. et al. Deletion of the C-terminal region of dengue virus nonstructural protein 1 (NS1) abolishes anti-NS1-mediated platelet dysfunction and bleeding tendency. J Immunol 2009; 183: 1797-1803.
    CrossrefPubMedGoogle Scholar
  • 25 Ades EW, Candal FJ, Swerlick RA. et al. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol 1992; 99: 683-690.
    CrossrefPubMedGoogle Scholar
  • 26 Huang KJ, Li SY, Chen SC. et al. Manifestation of thrombocytopenia in dengue-2-virus-infected mice. J Gen Virol 2000; 81: 2177-2182.
    CrossrefPubMedGoogle Scholar
  • 27 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
  • 28 Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 2007; 7: 803-815.
    CrossrefPubMedGoogle Scholar
  • 29 Flesch BK, Achtert G, Neppert J. Inhibition of monocyte and polymorphonu-clear granulocyte immune phagocytosis by monoclonal antibodies specific for FcyRI, II and III. Ann Hematol 1997; 74: 15-22.
    CrossrefPubMedGoogle Scholar
  • 30 Boehm U, Klamp T, Groot M. et al. Cellular responses to interferon-γ. Annu Rev Immunol 1997; 15: 749-795.
    CrossrefPubMedGoogle Scholar
  • 31 Hober D, Poli L, Roblin B. et al. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in dengue-infected patients. Am J Trop Med Hyg 1993; 48: 324-331.
    CrossrefPubMedGoogle Scholar
  • 32 Fridman WH. Fc receptors and immunoglobulin binding factors. FASEB J 1991; 5: 2684-2690.
    CrossrefPubMedGoogle Scholar
  • 33 Fleit HB, Kobasiuk CD. The human monocyte-like cell line THP-1 expresses FcyRI and FcyRII. J Leukoc Biol 1991; 49: 556-565.
    CrossrefPubMedGoogle Scholar
  • 34 Morikawa M, Harada N, Zeng H. et al. Induction of phosphatidylinositol-gly-can-linked FcyRIII in human monocytic THP-1 cells by transforming growth factor-β1 and retinoic acid. Immunol Lett 1992; 31: 105-110.
    CrossrefPubMedGoogle Scholar
  • 35 van Hinsbergh VW. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol 2012; 34: 93-106.
    CrossrefPubMedGoogle Scholar
  • 36 Sosothikul D, Seksarn P, Pongsewalak S. et al. Activation of endothelial cells, coagulation and fibrinolysis in children with Dengue virus infection. Thromb Haemost 2007; 97: 627-634.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Butthep P, Chunhakan S, Tangnararatchakit K. et al. Elevated soluble thrombo-modulin in the febrile stage related to patients at risk for dengue shock syndrome. Pediatr Infect Dis J 2006; 25: 894-897.
    CrossrefPubMedGoogle Scholar
  • 38 Pober JS, Lapierre LA, Stolpen AH. et al. Activation of cultured human endothe-lial cells by recombinant lymphotoxin: comparison with tumor necrosis factor and interleukin 1 species. J Immunol 1987; 138: 3319-3324.
    PubMedGoogle Scholar
  • 39 Cotran RS, Pober JS. Cytokine-endothelial interactions in inflammation, immunity, and vascular injury. J Am Soc Nephrol 1990; 1: 225-235.
    PubMedGoogle Scholar
  • 40 Wu SJ, Grouard-Vogel G, Sun W. et al. Human skin Langerhans cells are targets of dengue virus infection. Nat Med 2000; 6: 816-820.
    CrossrefPubMedGoogle Scholar
  • 41 Jessie K, Fong MY, Devi S. et al. Localisation of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridisation. J Infect Dis 2004; 189: 1411-1418.
    CrossrefPubMedGoogle Scholar
  • 42 Vervaeke P, Vermeire K, Liekens S. Endothelial dysfunction in dengue virus pathology. Rev Med Virol 2015; 25: 50-67.
    CrossrefPubMedGoogle Scholar
  • 43 Lien TS, Sun DS, Chang CM. et al. Dengue virus and antiplatelet autoantibodies synergistically induce haemorrhage through Nlrp3-inflammasome and FcyRIII. Thromb Haemost 2015; 113: 1060-1070.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 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
  • 45 Boonpucknavig S, Vuttiviroj O, Bunnag CN. et al. Demonstration of dengue antibody complexes on the surface of platelets from patients with dengue haemorrhagic fever. Am J Trop Med Hyg 1979; 28: 881-884.
    CrossrefPubMedGoogle Scholar