Anti-dengue virus nonstructural protein 1 antibodies recognize protein disulfide isomerase on platelets and inhibit platelet aggregation

Cheng, Hsien Jen; Lei, Huan Yao; Lin, Chiou Feng; Luo, Yueh Hsia; Wan, Shu; Liu, Hsiao Sheng; Yeh, Trai Ming; Lin, Yee Shin

doi:10.1016/j.molimm.2009.08.033

Cited by 85 publications

(83 citation statements)

References 49 publications

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“…39,40 Furthermore, NS1 relates to thrombocytopenia because anti-NS1 antibodies have been suggested to cross-react with a platelet antigen. 41,42 The current study provides evidence that platelets can independently synthesize NS1. Because NS1 may be retained by the infected cell membrane, it is conceivable that direct viral antigen production may impact platelet clearance by immune complex formation.…”

Section: Discussionmentioning

confidence: 53%

Dengue virus binding and replication by platelets

Simon

Sutherland

Pryzdial

2015

Blood

148

161

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Key Points• Platelets replicate and produce infectious DENV.• DENV binds directly to platelets using DC-SIGN and heparan sulfate proteoglycan as primary receptors.Dengue virus (DENV) infection causes ∼200 million cases of severe flulike illness annually, escalating to life-threatening hemorrhagic fever or shock syndrome in ∼500 000. Although thrombocytopenia is typical of both mild and severe diseases, the mechanism triggering platelet reduction is incompletely understood. As a probable initiating event, direct purified DENV-platelet binding was followed in the current study by quantitative reverse transcription-polymerase chain reaction and confirmed antigenically. Approximately 800 viruses specifically bound per platelet at 37°C. Fewer sites were observed at 25°C, the blood bank storage temperature (∼350 sites), or 4°C, known to attenuate virus cell entry (∼200 sites). Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and heparan sulfate proteoglycan were implicated as coreceptors because only the combination of anti-DC-SIGN and lowmolecular-weight heparin prevented binding. Interestingly, at 37°C and 25°C, platelets replicated the positive sense single-stranded RNA genome of DENV by up to ∼4-fold over 7 days. Further time course experiments demonstrated production of viral NS1 protein, which is known to be highly antigenic in patient serum. The infectivity of DENV intrinsically decayed in vitro, which was moderated by plateletmediated generation of viable progeny. This was shown using a transcription inhibitor and confirmed by freeze-denatured platelets being incapable of replicating the DENV genome. For the first time, these data demonstrate that platelets directly bind DENV saturably and produce infectious virus. Thus, expression of antigen encoded by DENV is a novel consideration in the pathogen-induced thrombocytopenia mechanism. These results furthermore draw attention to the possibility that platelets may produce permissive RNA viruses in addition to DENV. (Blood. 2015;126(3):378-385)

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Section: Discussionmentioning

confidence: 53%

Dengue virus binding and replication by platelets

Simon

Sutherland

Pryzdial

2015

Blood

148

161

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“…Antibodies induced by molecular mimicry between DENV and human proteins can cross-react with platelets, coagulation factors, and endothelial cells. These autoantibodies may contribute to thrombocytopenia, abnormal coagulation and fibrinolysis, and endothelial damage in DHF/DSS patients, causing hemorrhage (16,18,32,44). However, other factors, such as proinflammatory cytokines and secreted NS1, may also contribute to the development of hemorrhage during the acute stage of DENV infection (37,(45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mimicry between Dengue Virus and Coagulation Factors Induces Antibodies To Inhibit Thrombin Activity and Enhance Fibrinolysis

Chuang

Lin

Liu

et al. 2014

J Virol

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Dengue virus (DENV) is the most common cause of viral hemorrhagic fever, and it may lead to life-threating dengue hemorrhagic fever and shock syndrome (DHF/DSS). Because most cases of DHF/DSS occur in patients with secondary DENV infection, anti-DENV antibodies are generally considered to play a role in the pathogenesis of DHF/DSS. Previously, we have found that antithrombin antibodies (ATAs) with both antithrombotic and profibrinolytic activities are present in the sera of dengue patients. However, the mechanism by which these autoantibodies are induced is unclear. In this study, we demonstrated that antibodies induced by DENV immunization in mice and rabbits could bind to DENV antigens as well as to human thrombin and plasminogen (Plg). The binding of anti-DENV antibodies to thrombin and Plg was inhibited by preadsorption with DENV nonstructural protein 1. In addition, affinity-purified ATAs from DENV-immunized rabbit sera could inhibit thrombin activity and enhance Plg activation both in vitro and in vivo. Taken together, our results suggest that molecular mimicry between DENV and coagulation factors can induce the production of autoantibodies with biological effects similar to those of ATAs found in dengue patients. These coagulation-factor cross-reactive anti-DENV antibodies can interfere with the balance of coagulation and fibrinolysis, which may lead to the tendency of DHF/DSS patients to bleed. IMPORTANCE Dengue virus (DENV) infection is the most common mosquito-borne viral disease in tropical and subtropical areas. Over 50million DENV infection cases develop each year, and more than 2.5 billion people are at risk of dengue-induced hemorrhagic fever and shock syndrome. Currently, there is no vaccine or drug treatment for DENV. In the present study, we demonstrated that DENV immunization could induce thrombin and plasminogen (Plg) cross-reactive antibodies, which were able to inhibit thrombin activity and enhance Plg activation. These results suggest that molecular mimicry between DENV antigens, thrombin, and Plg may elicit antibodies that disturb hemostasis. The selection of appropriate candidate antigens for use in DENV vaccines should prevent these potentially dangerous autoimmune responses.

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“…This has been implicated in DENV entry into endothelial cells [38•]. Besides its important role in the endoplasmic reticulum, it has been detected on the cell surface of lymphocytes [39], platelets [40,41], and endothelial cells [38•]. PDI has been implicated in entry of several viruses such as polyomavirus [42], New Castle disease virus [43], and the human immunodeficiency virus [39,44,45].…”

Section: Dengue Virus Receptors In Human Cellsmentioning

confidence: 99%

Dengue Virus Cellular Receptors and Tropism

et al. 2014

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Viral entry into host cells primordially defines tropism and represents an attractive target to counteract infection either by antiviral agents or by immune mediated mechanisms. Research on Dengue virus entry presents interesting challenges. Whatever the mechanism dengue virus exploits to gain entry into cells, this had to be evolutionarily conserved, so that it is now present in arthropod and human cells. Until now, dengue cellular receptors were not completely unraveled. However, we have clues about the key steps dengue virus is relying on. Initially a group of factors that interact with the virus through carbohydrate interaction assure its adherence and further contact with a protein receptor complex, which is held together thanks to its special interaction with cell membrane lipidic platforms. This interaction may be so intimate that it may trigger not only viral entry through receptormediated endocytosis, but also activation of cell signaling pathways that the virus is going to subvert to its advantage.

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Anti-dengue virus nonstructural protein 1 antibodies recognize protein disulfide isomerase on platelets and inhibit platelet aggregation

Cited by 85 publications

References 49 publications

Dengue virus binding and replication by platelets

Dengue virus binding and replication by platelets

Molecular Mimicry between Dengue Virus and Coagulation Factors Induces Antibodies To Inhibit Thrombin Activity and Enhance Fibrinolysis

Dengue Virus Cellular Receptors and Tropism

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