Microbial Translocation Is Associated with Extensive Immune Activation in Dengue Virus Infected Patients with Severe Disease

Weg, Cornelia A. M. van de; Pannuti, Cláudio Sérgio; Araújo, Evaldo Stanislau Affonso de; Ham, Henk-Jan van den; Andeweg, Arno C.; Boas, Lucy S. Vilas; Félix, Alvina Clara; Carvalho, Karina I.; Matos, Andréia Manso de; Levi, José Eduardo; Romano, Camila Malta; Centrone, Cristiane C.; Rodrigues, Célia Luiza de Lima; Luna, Expedito; Gorp, Eric C. M. Van; Osterhaus, Albert D. M. E.; Martina, Benedict; Kallas, Esper G.

doi:10.1371/journal.pntd.0002236

Cited by 68 publications

(67 citation statements)

References 43 publications

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“…This cytokine has been shown to inhibit DENV-specific T cell responses as shown by ex vivo and in vitro models (38). Accordingly, patients with severe dengue present increased levels of IL-10 than patients with mild dengue (39)(40), and higher levels of IL-10 are observed in non-survivals than in survivals among severe dengue patients (41). …”

Section: Discussionmentioning

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

125

144

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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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Section: Discussionmentioning

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

125

144

View full text Add to dashboard Cite

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“…112 Interestingly, cytokines that are synthesized as a result of platelet-dependent signaling of monocytes, such as TNF-α, IL-1β, IL-8, and MCP-1, [116][117][118] are also recognized as important pathogenic factors in severe dengue. [119][120][121][122] The aggregation of activated platelets with themselves or with monocytes and neutrophils could lead to their sequestration in the microvasculature (Fig.1), as has been described in sepsis, [123][124][125] a condition that has many parallels to severe dengue. 126 Platelet activation and thrombocytopenia are considered ubiquitous in human septic syndromes, and sequestration of platelets in microvascular beds can induce vascular damage in part through deposition of fibrin.…”

Section: Platelet Interaction and Sequestration With Leukocytesmentioning

confidence: 99%

Emerging Concepts in Dengue Pathogenesis: Interplay between Plasmablasts, Platelets, and Complement in Triggering Vasculopathy

et al. 2014

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Dengue is a mosquito-borne disease caused by infection with dengue virus (DENV) that represents a serious and expanding global health threat. Most DENV infections are inapparent or produce mild and self-limiting illness; however a significant proportion results in severe disease characterized by vasculopathy and plasma leakage that may culminate in shock and death. The cause of dengue-associated vasculopathy is likely to be multifactorial but remains essentially unknown. Severe disease is manifest during a critical phase from 4 to 7 days after onset of symptoms, once the virus has disappeared from the circulation but before the peak of T-cell activation, suggesting that other factors mediate vasculopathy. Here, we present evidence for a combined role of plasmablasts, complement, and platelets in driving severe disease in DENV infection. Massive expansion of virus-specific plasmablasts peaks during the critical phase of infection, coincident with activation of complement and activation and depletion of platelets. We propose a step-wise model in which virus-specific antibodies produced by plasmablasts form immune complexes, leading to activation of complement and release of vasoactive anaphylatoxins. Platelets become activated through binding of complement- and antibody-coated virus, as well as direct binding of virus to DC-SIGN, leading to the release of inflammatory microparticles and cytokines and sequestration of platelets in the microvasculature. We suggest that the combined effects of anaphylatoxins, inflammatory microparticles, and platelet sequestration serve as triggers of vasculopathy in severe dengue.

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“…Based on these observations, it would be worthwhile to assess the effect of LPS on CHIKV pathogenesis in vivo . Moreover, given that increased levels of LPS in the blood have been found in several inflammatory diseases[48–50], such studies will inform us how co-microbial infections and/or how microbial translocation will influence host responses to CHIKV and ultimately disease progression. In addition, they are imperative to understanding whether pharmacological targeting of inflammatory mechanisms early in infection could serve as a strategy to prevent CHIKV-mediated arthralgia and arthritis, possibly, even without the necessity to decrease viral replication.…”

Section: Discussionmentioning

confidence: 99%

Rewiring PBMC responses to prevent CHIKV infection-specific monocyte subset redistribution and cytokine responses

Aguilar-Briseño

Silva

Moser

et al. 2020

Preprint

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19Infection with the mosquito-borne Chikungunya virus (CHIKV) causes acute or chronic 20 arthritis in humans. Inflammatory responses mediated by monocytes, the primary target 21 cells of CHIKV infection in the blood, are considered to play an important role in CHIKV 22 pathogenesis. A recent study revealed that the acute phase of CHIKV infection is 23 characterized by a monocyte-driven response, with an expansion of the intermediate 24 monocyte (IM) subset. In this study, we adopted a previously established in vitro model 25 of CHIKV infection in peripheral blood mononuclear cells, to elucidate the mechanism and 26 relevance of IM expansion in CHIKV replication and associated inflammatory responses. 27 Our data show that infectious but not replication-incompetent CHIKV increases the 28 frequency of IM and to a lesser extent, non-classical (NM) monocytes while reducing the 29 number of classical monocytes (CM). The increase of IM or NM frequency coincided with 30 the activation of inflammatory response and occurred in the absence of lymphocytes 31 implying that monocyte-derived cues are sufficient to drive this effect. Importantly, 32 priming of monocytes with LPS prevented expansion of IM and NM but had no effect on 33 viral replication. It did however alter CHIKV-induced cytokine signature. Taken together, 34 our data delineate the role of IM in CHIKV infection-specific innate immune responses 35 and provide insight for the development of therapeutic strategies that may focus on 36 rewiring monocyte immune responses to prevent CHIKV-mediated arthralgia and 37 arthritis. 38 39 Over the last decade, chikungunya virus (CHIKV) infection has affected millions of people 40 worldwide[1]. The vast majority of infected patients experience a febrile illness with 41 painful joints. A substantial number of these individuals, however, develop persistent 42 arthritis-like manifestations (12-49%)[1]. The exact mechanism underlying CHIKV-43 mediated pathogenesis is not completely understood, however, clinical and in vivo 44 studies describe local joint inflammation, infiltration of monocytes into the synovial 45 cavity and bone resorption due to increased osteoclast activity[1-3]. Monocytes 46 represent important cellular targets of CHIKV replication in the blood[4,5], and tissue 47 infiltrating monocytes and tissue-resident macrophages have been postulated to act as a 48 vehicles and a reservoir for chronic CHIKV RNA/antigens, respectively [6,7]. 49 As innate sentinels of their host, blood monocytes sense invading pathogens and 50 orchestrate innate immune responses to contain their spread as well as setting the scene 51 for the activation of adaptive immune responses[8]. Via a set of pathogen recognition 52 receptors (PRRs), monocytes are able to detect a variety of complex pathogen associated 53 molecular patterns (PAMPS). Engagement of PRRs triggers several cellular signaling 54 cascades resulting in cell differentiation, release of inflammatory mediators and/or 55 programmed cell death[8-10]. 56 Monocytes can be divi...

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Microbial Translocation Is Associated with Extensive Immune Activation in Dengue Virus Infected Patients with Severe Disease

Cited by 68 publications

References 43 publications

Platelet Activation and Apoptosis Modulate Monocyte Inflammatory Responses in Dengue

Platelet Activation and Apoptosis Modulate Monocyte Inflammatory Responses in Dengue

Emerging Concepts in Dengue Pathogenesis: Interplay between Plasmablasts, Platelets, and Complement in Triggering Vasculopathy

Rewiring PBMC responses to prevent CHIKV infection-specific monocyte subset redistribution and cytokine responses

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