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

Shu-Wen Wan; Yi-Wen Yang; Ya-Ting Chu; Chiou-Feng Lin; Chih-Peng Chang; Trai-Ming Yeh; Robert Anderson; Yee-Shin Lin

doi:10.1160/th15-06-0498

Thrombosis and Haemostasis, Table of Contents

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

Authors

Shu-Wen Wan^†

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Yi-Wen Yang^†

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Ya-Ting Chu

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Chiou-Feng Lin

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

³Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan
Chih-Peng Chang

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Trai-Ming Yeh

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

⁴Department 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

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Abstract

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

Full Text

References

References
1 Bhatt S, Gething PW, Brady OJ. et al. The global distribution and burden of dengue. Nature 2013; 496: 504-507.
2 Guzman MG, Harris E. Dengue. Lancet 2015; 385: 453-465.
3 Chuansumrit A. Chaiyaratana W Haemostatic derangement in dengue haemor-rhagic fever. Thromb Res 2014; 133: 10-16.
4 Wang S, He R, Patarapotikul J. et al. Antibody-enhanced binding of dengue-2 virus to human platelets. Virology 1995; 213: 254-257.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
17 Vijayalakshmi AM, Ganesh VR. Haemophagocytic syndrome associated with dengue haemorrhagic fever. Indian Pediatr 2009; 46: 545.
18 Tan LH, Lum LC, Omar SF, Kan FK. Haemophagocytosis in dengue: comprehensive report of six cases. J Clin Virol 2012; 55: 79-82.
19 Pal P, Giri PP, Ramanan AV. Dengue associated haemophagocytic lymphohis-tiocytosis: a case series. Indian Pediatr 2014; 51: 496-497.
20 Fisman DN. Haemophagocytic syndromes and infection. Emerg Infect Dis 2000; 6: 601-608.
21 Janka GE, Lehmberg K. Haemophagocytic syndromes-an update. Blood Rev 2014; 28: 135-142.
22 Lei HY. Transient haemophagocytic activity in dengue immunopathogenesis. J Formos Med Assoc 2009; 108: 595-598.
23 Onlamoon N, Noisakran S, Hsiao HM. et al. Dengue virus-induced haemorrhage in a nonhuman primate model. Blood 2010; 115: 1823-1834.
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.
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.
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.
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.
28 Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 2007; 7: 803-815.
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.
30 Boehm U, Klamp T, Groot M. et al. Cellular responses to interferon-γ. Annu Rev Immunol 1997; 15: 749-795.
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.
32 Fridman WH. Fc receptors and immunoglobulin binding factors. FASEB J 1991; 5: 2684-2690.
33 Fleit HB, Kobasiuk CD. The human monocyte-like cell line THP-1 expresses FcyRI and FcyRII. J Leukoc Biol 1991; 49: 556-565.
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.
35 van Hinsbergh VW. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol 2012; 34: 93-106.
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.
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.
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.
39 Cotran RS, Pober JS. Cytokine-endothelial interactions in inflammation, immunity, and vascular injury. J Am Soc Nephrol 1990; 1: 225-235.
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.
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.
42 Vervaeke P, Vermeire K, Liekens S. Endothelial dysfunction in dengue virus pathology. Rev Med Virol 2015; 25: 50-67.
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.
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.
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.

Supplementary Material

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