Platelet Apoptosis and Apoptotic Platelet Clearance by Macrophages in Secondary Dengue Virus Infections

Alonzo, Maria T.G.; Lacuesta, Talitha Lea; Dimaano, Efren M.; Kurosu, Takeshi; Suarez, Lady Anne C.; Mapua, Cynthia A.; Akeda, Yukihiro; Matias, Ronald R.; Kuter, David J.; Nagata, Shinji; Natividad, Filipinas F.; Oishi, Kazunori

doi:10.1093/infdis/jis180

Cited by 75 publications

(75 citation statements)

References 34 publications

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“…4H). Notably, various factors could enhance MP shedding from platelets during the acute phase of DENV infection, such as platelet activation (48), platelet apoptosis (49), and direct infection of platelets by DENV (50). Indeed, a small number of circulating AnV ϩ CD41a ϩ MPs carried DENV E and NS1 antigens, similar to the findings for infected cell-derived MPs, as demonstrated in our in vitro model of DENV infection.…”

Section: Discussionsupporting

confidence: 83%

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Punyadee

Mairiang

Thiemmeca

et al. 2015

J Virol

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Shedding of microparticles (MPs) is a consequence of apoptotic cell death and cellular activation. Low levels of circulating MPs in blood help maintain homeostasis, whereas increased MP generation is linked to many pathological conditions. Herein, we investigated the role of MPs in dengue virus (DENV) infection. Infection of various susceptible cells by DENV led to apoptotic death and MP release. These MPs harbored a viral envelope protein and a nonstructural protein 1 (NS1) on their surfaces. Ex vivo analysis of clinical specimens from patients with infections of different degrees of severity at multiple time points revealed that MPs generated from erythrocytes and platelets are two major MP populations in the circulation of DENV-infected patients. Elevated levels of red blood cell-derived MPs (RMPs) directly correlated with DENV disease severity, whereas a significant decrease in platelet-derived MPs was associated with a bleeding tendency. Removal by mononuclear cells of complement-opsonized NS1-anti-NS1 immune complexes bound to erythrocytes via complement receptor type 1 triggered MP shedding in vitro, a process that could explain the increased levels of RMPs in severe dengue. These findings point to the multiple roles of MPs in dengue pathogenesis. They offer a potential novel biomarker candidate capable of differentiating dengue fever from the more serious dengue hemorrhagic fever. IMPORTANCEDengue is the most important mosquito-transmitted viral disease in the world. No vaccines or specific treatments are available. Rapid diagnosis and immediate treatment are the keys to achieve a positive outcome. Dengue virus (DENV) infection, like some other medical conditions, changes the level and composition of microparticles (MPs), tiny bag-like structures which are normally present at low levels in the blood of healthy individuals. This study investigated how MPs in culture and patients' blood are changed in response to DENV infection. Infection of cells led to programmed cell death and MP release. In patients' blood, the majority of MPs originated from red blood cells and platelets. Decreased platelet-derived MPs were associated with a bleeding tendency, while increased levels of red blood cell-derived MPs (RMPs) correlated with more severe disease. Importantly, the level of RMPs during the early acute phase could serve as a biomarker to identify patients with potentially severe disease who require immediate care. E ach year, up to 390 million people are infected by dengue virus (DENV), the most significant mosquito-borne virus of the Flaviviridae family, posing serious socioeconomic and health burdens globally (1). Four serotypes of viruses (DENV serotype 1 [DENV-1], DENV-2, DENV-3, and DENV-4) are transmitted to humans by Aedes mosquitoes to establish both endemic and epidemic transmission cycles primarily in tropical and subtropical countries (1). Although the majority of DENV infections in humans are subclinical, a small fraction of infected individuals develops clinical symptoms ranging from a self-...

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Section: Discussionsupporting

confidence: 83%

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Punyadee

Mairiang

Thiemmeca

et al. 2015

J Virol

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“…Whether there are settings in which platelet apoptosis induced by an infectious agent does contribute to thrombocytopenia is yet to be established, but there is evidence to support the idea. Platelets from dengue virus-infected patients exhibit increased signs of apoptosis 58 , as do platelets exposed to Helicobacter pylori in vitro 59 . Perhaps most compelling is recent work demonstrating that Escherichia coli and Staphylococcus aureus isolates from sepsis patients induce features of apoptosis in platelets in vitro, including the calpain-mediated degradation of BCL-X L 60 .…”

Section: Discussionmentioning

confidence: 99%

Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways

et al. 2014

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“…A previous study has reported increased platelet-monocyte aggregation in patients with dengue (14). The phagocytosis of apoptotic platelets from DENV-infected patients by macrophages has also been shown (15). Although interaction with activated platelets and recognition of apoptotic bodies have recognized roles in immunomodulation of mononuclear cells (10, 11, 16), the role played by activated and apoptotic platelets in the modulation of monocyte responses during DENV infection has not been addressed.…”

Section: Introductionmentioning

confidence: 99%

Platelet Activation and Apoptosis Modulate Monocyte Inflammatory Responses in Dengue

Hottz

Medeiros-de-Moraes

Vieira‐de‐Abreu

et al. 2014

The Journal of Immunology

127

150

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Background Dengue is the most prevalent human arbovirus disease in the world. Dengue infection has a large spectrum of clinical manifestations from self-limited febrile illness to severe syndromes accompanied by bleeding and shock. Thrombocytopenia and vascular leak with altered cytokine profiles in plasma are features of severe dengue. Although monocytes have been recognized as important sources of cytokines in dengue, the contributions of platelet-monocyte interactions to inflammatory responses in dengue have not been addressed. Patients/Methods Patients with dengue were investigated for platelet-monocyte aggregate formation and markers of monocyte activation. Platelet-induced cytokine responses by monocytes and underlying mechanisms were also investigated in vitro. Results We observed increased levels of platelet-monocyte aggregates in blood samples from patients with dengue, especially patients with thrombocytopenia and increased vascular permeability. Moreover, the exposure of monocytes from healthy volunteers to platelets from patients with dengue induced the secretion of the cytokines IL-1β, IL-8, IL-10 and MCP-1, while the exposure to platelets from healthy volunteers only induced the secretion of MCP-1. In addition to the well-established modulation of monocyte cytokine responses by activated platelets through P-selectin binding, we found that interaction of monocytes with apoptotic platelets mediate IL-10 secretion through phosphatidylserine recognition in platelet-monocyte aggregates. Moreover, IL-10 secretion required platelet-monocyte contact but not phagocytosis. Conclusions Together, our results demonstrate that activated and apoptotic platelets aggregate with monocytes during dengue infection and signal specific cytokine responses that may contribute to the pathogenesis of dengue.

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Platelet Apoptosis and Apoptotic Platelet Clearance by Macrophages in Secondary Dengue Virus Infections

Abstract: UMIN000004835.

Cited by 75 publications

References 34 publications

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways

Platelet Activation and Apoptosis Modulate Monocyte Inflammatory Responses in Dengue

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