Dengue virus and antiplatelet autoantibodies synergistically induce haemorrhage through Nlrp3-inflammasome and FcүRIII

2015 ◽  
Vol 113 (05) ◽  
pp. 1060-1070 ◽  
Author(s):  
Chia-Ming Chang ◽  
Cheng-Yeu Wu ◽  
Ming-Shen Dai ◽  
Hao Chan ◽  
Wen-Sheng Wu ◽  
...  
Keyword(s):  
Nonstructural Protein ◽  
Secondary Infection ◽  
Denv Infection ◽  
Additional Treatment ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Caspase 1 ◽  
Secondary Infections ◽  
Increased Risk ◽  
Tnf Α

SummaryDengue haemorrhagic fever (DHF) typically occurs during secondary infections with dengue viruses (DENVs). Although it is generally accepted that antibody-dependent enhancement is the primary reason why patients with secondary infection are at an increased risk of developing DHF, a growing body of evidence shows that other mechanisms, such as the elicitation of antiplatelet autoantibodies by DENV nonstructural protein NS1, also play crucial roles in the pathogenesis of DHF. In this study, we developed a “two-hit” model of secondary DENV infection to examine the respective roles of DENV (first hit) and antiplatelet Igs (second hit) on the induction of haemorrhage. Mice were first exposed to DENV and then exposed to antiplatelet or anti-NS1 Igs 24 hours later. The two-hit treatment induced substantial haemorrhage, coagulopathy, and cytokine surge, and additional treatment with antagonists of TNF-α, IL-1, caspase-1, and FcүRIII ameliorated such effects. In addition, knockout mice lacking the Fcү receptor III, Toll-like receptor 3, and inflammasome components Nlrp3 and caspase-1 exhibited considerably fewer pathological alterations than did wild type controls. These findings may provide new perspectives for developing feasible approaches to treat patients with DHF.

scholarly journals The role of Toll-like receptor 4 in apoptosis of brain tissue after induction of intracerebral hemorrhage

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Xiaowei Fei ◽  
Yeting He ◽  
Jia Chen ◽  
Weitao Man ◽  
Chen Chen ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Knockout Mice ◽  
Neuronal Apoptosis ◽  
Inflammatory Factors ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Tnf Α ◽  
Apoptotic Effect

Abstract Background Inflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis. Methods We performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1β and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant. Results TLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1β and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice. Conclusions We conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1β and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.

Mechanism of Toll-like receptor 4 on chronic post-thoracotomy pain via caspase-1 activation

2020 ◽  
Vol 17 ◽  
Author(s):  
Zhonghua Hu ◽  
Juan Liao ◽  
Fan Zhang ◽  
Wenxiang Qing ◽  
Rili Yu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Intrathecal Injection ◽  
Underlying Mechanism ◽  
Mechanical Hyperalgesia ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Caspase 1 ◽  
Tnf Α ◽  
Tlr4 Agonist ◽  
Tlr4 Antagonist

Objective: Post-operative chronic post-thoracotomy pain (CPTP) has been linked to restrictions in mobility and daily activities. However, its potential causes and optimal therapy have not been well characterized. Here, the purpose of this study was to investigate the role of Toll-like receptor 4 (TLR4) in CPTP rats and its underlying mechanism. Methods: Initially, rat models of CPTP were established. Then, the mechanical withdrawal threshold (MWT) was measured after intrathecal injection of TLR4 antagonist (LPS-RS), TLR4 agonist (LPS-PG), or caspase-1 inhibitor (Ac-YVAD-CMK) in CPTP rats. Levels of TNF-α, IL-6 and IL-1β in the spinal dorsal horn (SDH) were measured by ELISA. TLR4 and caspase-1 were located by immunofluorescence double staining. TLR4 and caspase-1 levels were assessed by qRT-PCR and Western blot. Results: TLR4 and caspase-1 were up-regulated in SDH of CPTP rats. Compared with Sham and non-CPTP groups, MWT was effectively decreased while TNF-α, IL-6 and IL-1β in SDH were increased in CPTP group. Moreover, intrathecal injection of TLR4 antagonist or caspase-1 inhibitor significantly elevated MWT expression and reduced levels of TNF-α, IL-6 and IL-1β in SDH. Additionally, high expression of TLR4 promoted mechanical hyperalgesia and inflammatory response, while intrathecal injection of a mixture of caspase-1 inhibitor and TLR4 agonist reversed the alleviation of caspase-1 inhibitor on the mechanical hyperalgesia and inflammatory response. TLR4 and caspase-1 were co-located in neurons. Conclusion: TLR4 aggravated CPTP in rats by mediating activation of caspase-1 in SDH.

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

2016 ◽  
Vol 115 (03) ◽  
pp. 646-656 ◽  
Author(s):  
Ya-Ting Chu ◽  
Chiou-Feng Lin ◽  
Chih-Peng Chang ◽  
Trai-Ming Yeh ◽  
Robert Anderson ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Platelet Adhesion ◽  
Molecular Mimicry ◽  
Nonstructural Protein ◽  
Denv Infection ◽  
Dengue Disease ◽  
Nonstructural Protein 1 ◽  
Tnf Α ◽  
Β3 Integrin ◽  
Lines Of Evidence

SummaryThrombocytopenia 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.

scholarly journals Sialylated human milk oligosaccharides prevent intestinal inflammation by inhibiting toll like receptor 4/NLRP3 inflammasome pathway in necrotizing enterocolitis rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wenting Zhang ◽  
Jingqiu He-Yang ◽  
Wenjuan Tu ◽  
Xiaoying Zhou
Keyword(s):  
Membrane Potential ◽  
Human Milk ◽  
Nlrp3 Inflammasome ◽  
Interleukin 6 ◽  
Mitochondrial Membrane ◽  
Toll Like Receptor ◽  
Human Milk Oligosaccharides ◽  
Toll Like Receptor 4 ◽  
Caspase 1 ◽  
Tnf Α

Abstract Background Necrotizing enterocolitis (NEC) remains a fatal gastrointestinal disorder in neonates and has very limited therapeutic options. Sialylated human milk oligosaccharides (SHMOs) improve pathological changes in experimental NEC models. The objectives of this study were to investigate the involvement of NLRP3 inflammasome in NEC pathology and to explore the effects of SHMOs on toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB)/NLRP3 inflammatory pathway in experimental NEC. Methods The intestinal-tissue segments were collected from NEC infants, NLRP3 and caspase-1 positive cell were examined by immunohistochemistry. Newborn rats were hand-fed with formula containing or non-containing SHMOs (1500 mg/L) and exposed to hypoxia/cold stress to induce experimental NEC. The NEC pathological scores were evaluated; ileum protein expression of membrane TLR4 (mTLR4), inhibitor κB-α (IκB-α), NF-κB p65 subunit and phospho-NF-κB p65, as well as NLRP3 and caspase-1 were analyzed; ileum concentrations of interleukin-1β, interleukin-6, tumor necrosis factor-α (TNF-α) were also measured. Human colon epithelial Caco-2 cells were pre-treated with or without SHMOs and stimulated with TLR4 activator, lipopolysaccharide. Cell viabilities, mitochondrial membrane potential and supernatant matrix metalloprotease 2 (MMP-2) activities were analyzed. Results Increased frequencies of NLRP3 and caspase-1 positive cells were found in the lamina propria of damaged intestinal area of NEC neonates. SHMOs supplementation reduced NEC incidence and pathological damage scores of rats challenged with hypoxia/cold stress. Accumulation of interleukin-1β, interleukin-6 and TNF-α in NEC group were attenuated in SHMOs + NEC group. Protein expression of mTLR4, NLRP3 and caspase-1 were elevated, cytoplasmic IκB-α were reduced, nuclear phospho-NF-κB p65 were increased in the ileum of NEC rats. SHMOs supplementation ameliorated the elevation of mTLR4, NLRP3 and caspase-1, restored IκB-α in the cytoplasmic fraction and reduced phospho-NF-κB p65 in the nuclear fraction in the ileum of NEC rats. SHMOs pre-treatment improved Caco-2 cell viability, mitigated loss of mitochondrial membrane potential and modulated MMP-2 activities in the presence of lipopolysaccharide in-vitro. Conclusions This study provided clinical evidence of involvement of NLRP3 inflammasome in NEC pathology, and demonstrated the protective actions of SHMOs might be owing to the suppression of TLR4/NF-κB/NLRP3-mediated inflammation in NEC.

scholarly journals Toll-Like Receptor 9 Modulates Macrophage Antifungal Effector Function during Innate Recognition of Candida albicans and Saccharomyces cerevisiae

2011 ◽  
Vol 79 (12) ◽  
pp. 4858-4867 ◽  
Author(s):  
Pia V. Kasperkovitz ◽  
Nida S. Khan ◽  
Jenny M. Tam ◽  
Michael K. Mansour ◽  
Peter J. Davids ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
Fungal Pathogens ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Tnf Α ◽  
Tlr9 Gene

ABSTRACTPhagocytic responses are critical for effective host defense against opportunistic fungal pathogens. Macrophages sample the phagosomal content and orchestrate the innate immune response. Toll-like receptor 9 (TLR9) recognizes unmethylated CpG DNA and is activated by fungal DNA. Here we demonstrate that specific triggering of TLR9 recruitment to the macrophage phagosomal membrane is a conserved feature of fungi of distinct phylogenetic origins, includingCandida albicans,Saccharomyces cerevisiae,Malassezia furfur, andCryptococcus neoformans. The capacity to trigger phagosomal TLR9 recruitment was not affected by a loss of fungal viability or cell wall integrity. TLR9 deficiency has been linked to increased resistance to murine candidiasis and to restriction of fungal growthin vivo. Macrophages lacking TLR9 demonstrate a comparable capacity for phagocytosis and normal phagosomal maturation compared to wild-type macrophages. We now show that TLR9 deficiency increases macrophage tumor necrosis factor alpha (TNF-α) production in response toC. albicansandS. cerevisiae, independent of yeast viability. The increase in TNF-α production was reversible by functional complementation of the TLR9 gene, confirming that TLR9 was responsible for negative modulation of the cytokine response. Consistently, TLR9 deficiency enhanced the macrophage effector response by increasing macrophage nitric oxide production. Moreover, microbicidal activity againstC. albicansandS. cerevisiaewas more efficient in TLR9 knockout (TLR9KO) macrophages than in wild-type macrophages. In conclusion, our data demonstrate that TLR9 is compartmentalized selectively to fungal phagosomes and negatively modulates macrophage antifungal effector functions. Our data support a model in which orchestration of antifungal innate immunity involves a complex interplay of fungal ligand combinations, host cell machinery rearrangements, and TLR cooperation and antagonism.

scholarly journals Primary infection with dengue or Zika virus does not affect the severity of heterologous secondary infection in macaques

2019 ◽  
Author(s):  
Meghan E. Breitbach ◽  
Christina M. Newman ◽  
Dawn M. Dudley ◽  
Laurel M. Stewart ◽  
Matthew T. Aliota ◽  
...  
Keyword(s):  
Zika Virus ◽  
Primary Infection ◽  
Rhesus Macaques ◽  
Secondary Infection ◽  
Denv Infection ◽  
The Other ◽  
Sample Type ◽  
Zikv Infection ◽  
Secondary Infections ◽  
Cynomolgus Macaques

AbstractZika virus (ZIKV) and dengue virus (DENV) are genetically and antigenically related flaviviruses that now co-circulate in much of the tropical and subtropical world. The rapid emergence of ZIKV in the Americas in 2015 and 2016, and its recent associations with Guillain-Barré syndrome, birth defects, and fetal loss have led to the hypothesis that DENV infection induces cross-reactive antibodies that influence the severity of secondary ZIKV infections. It has also been proposed that pre-existing ZIKV immunity could affect DENV pathogenesis. We examined outcomes of secondary ZIKV infections in three rhesus and fifteen cynomolgus macaques, as well as secondary DENV-2 infections in three additional rhesus macaques up to a year post-primary ZIKV infection. Although cross-binding antibodies were detected prior to secondary infection for all animals and cross-neutralizing antibodies were detected for some animals, previous DENV or ZIKV infection had no apparent effect on the clinical course of heterotypic secondary infections in these animals. All animals had asymptomatic infections and, when compared to controls, did not have significantly perturbed hematological parameters. Rhesus macaques infected with DENV-2 approximately one year after primary ZIKV infection had higher vRNA loads in plasma when compared with serum vRNA loads from ZIKV-naive animals infected with DENV-2, but a differential effect of sample type could not be ruled out. In cynomolgus macaques, the serotype of primary DENV infection did not affect the outcome of secondary ZIKV infection.Author summaryPre-existing immunity to one of the four DENV serotypes is known to increase the risk of severe disease upon secondary infection with a different serotype. Due to the antigenic similarities between ZIKV and DENV, it has been proposed that these viruses could interact in a similar fashion. Data from in vitro experiments and murine models suggests that pre-existing immunity to one virus could either enhance or protect against infection with the other. These somewhat contradictory findings highlight the need for immune competent animal models for understanding the role of cross-reactive antibodies in flavivirus pathogenesis. We examined secondary ZIKV or DENV infections in rhesus and cynomolgus macaques that had previously been infected with the other virus. We assessed the outcomes of secondary ZIKV or DENV infections by quantifying vRNA loads, clinical and laboratory parameters, body temperature, and weight for each cohort of animals and compared them with control animals. These comparisons demonstrated that within a year of primary infection, secondary infections with either ZIKV or DENV were similar to primary infections and were not associated with enhancement or reduction in severity of disease based on the outcomes that we assessed.

A simple mathematical model to describe antibody-dependent enhancement in heterologous secondary infection in dengue

2018 ◽  
Vol 36 (4) ◽  
pp. 411-438 ◽  
Author(s):  
Miller Cerón Gómez ◽  
Hyun Mo Yang
Keyword(s):  
Mathematical Model ◽  
Secondary Infection ◽  
Denv Infection ◽  
Severe Dengue ◽  
Asymptotically Stable ◽  
Effective Response ◽  
Antibody Dependent Enhancement ◽  
Secondary Infections ◽  
Initial Stage

Abstract We develop a mathematical model to describe the role of antibody-dependent enhancement (ADE) in heterologous secondary infections, assuming that antibodies specific to primary dengue virus (DENV) infection are being produced by immunological memory. The model has a virus-free equilibrium (VFE) and a unique virus-presence equilibrium (VPE). VFE is asymptotically stable when VPE is unstable; and unstable, otherwise. Additionally, there is an asymptotic attractor (not a fixed point) due to the fact that the model assumes unbounded increase in memory cells. In the analysis of the model, ADE must be accounted in the initial stage of infection (a window of time of few days), period of time elapsed from the heterologous infection until the immune system mounting an effective response against the secondary infection. We apply the results yielded by model to evaluate ADE phenomonon in heterologous DENV infection. We also associate the possible occurrence of severe dengue with huge viremia mediated by ADE phenomenon.

scholarly journals Intra-uterine Growth Restriction Downregulates the Hepatic Toll Like Receptor-4 Expression and Function

2005 ◽  
Vol 12 (1) ◽  
pp. 59-66 ◽  
Author(s):  
Ozlem Equils ◽  
Sapna Singh ◽  
Semra Karaburun ◽  
Daning Lu ◽  
Manikkavasagar Thamotharan ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Growth Restriction ◽  
Milk Intake ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Tlr4 Mrna ◽  
Increased Risk ◽  
Tnf Α ◽  
And Function

Maternal starvation is a significant cause of intrauterine growth restriction (IUGR) in the world and increases the risk of infection in the neonate. We examined the effect of maternal starvation on Toll like receptor (TLR)4 expression in hepatic, splenic and intestinal tissues obtained from the adult IUGR offspring of prenatal calorie restricted rats. The hepatic TLR4 protein concentration was undetectable in the IUGR rats that had restricted milk intake during the suckling period (SM/SP;n= 4,p< 0.05) as compared to the normal growth controls (CM/CP;n=4), and access to ad lib milk intake during the sucking period partially corrected the hepatic TLR4 expression (SM/CP;n= 4). IUGR had no effect on the splenic (n= 4) or intestinal (n= 4) TLR4 mRNA levels. In the liver, IUGR led to a 20% increase in baseline tumor necrosis factor (TNF)-α mRNA expression (p< 0.03) and a 70% increase in interleukin-1β (IL-1β) mRNA expression (p< 0.008) as compared to the control rats (CM/CP;n= 7). LPS-induced hepatic TNF-α release was significantly higher in SM/SP as compared to CM/CP. We propose that IUGR dysregulates TLR4 expression and function in the offspring, which may help explain the increased risk of Gram-negative sepsis and inflammatory diseases in this population.

scholarly journals Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Yu-Lei Gao ◽  
Jian-Hua Zhai ◽  
Yan-Fen Chai
Keyword(s):  
Molecular Mechanisms ◽  
Secondary Infection ◽  
Multiple Organ ◽  
Host Responses ◽  
Severe Condition ◽  
Caspase 1 ◽  
Recent Advances ◽  
Increased Risk ◽  
Life Threatening ◽  
Minimize Tissue Damage

Sepsis is recognized as a life-threatening organ dysfunctional disease that is caused by dysregulated host responses to infection. Up to now, sepsis still remains a dominant cause of multiple organ dysfunction syndrome (MODS) and death among severe condition patients. Pyroptosis, originally named after the Greek words “pyro” and “ptosis” in 2001, has been defined as a specific programmed cell death characterized by release of inflammatory cytokines. During sepsis, pyroptosis is required for defense against bacterial infection because appropriate pyroptosis can minimize tissue damage. Even so, pyroptosis when overactivated can result in septic shock, MODS, or increased risk of secondary infection. Proteolytic cleavage of gasdermin D (GSDMD) by caspase-1, caspase-4, caspase-5, and caspase-11 is an essential step for the execution of pyroptosis in activated innate immune cells and endothelial cells stimulated by cytosolic lipopolysaccharide (LPS). Cleaved GSDMD also triggers NACHT, LRR, and PYD domain-containing protein (NLRP) 3-mediated activation of caspase-1 via an intrinsic pathway, while the precise mechanism underlying GSDMD-induced NLRP 3 activation remains unclear. Hence, this study provides an overview of the recent advances in the molecular mechanisms underlying pyroptosis in sepsis.

scholarly journals Inflammatory signaling in dengue-infected platelets requires translation and secretion of nonstructural protein 1

2020 ◽  
Vol 4 (9) ◽  
pp. 2018-2031 ◽  
Author(s):  
Anna Cecíllia Quirino-Teixeira ◽  
Stephane Vicente Rozini ◽  
Giselle Barbosa-Lima ◽  
Diego Rodrigues Coelho ◽  
Pedro Henrique Carneiro ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Nonstructural Protein ◽  
Platelet Activating Factor ◽  
Denv Infection ◽  
Autocrine Loop ◽  
Extracellular Milieu ◽  
Caspase 1 ◽  
Nonstructural Protein 1 ◽  
Synergistic Activation ◽  
Inflammatory Phenotype

Abstract Emerging evidence identifies major contributions of platelets to inflammatory amplification in dengue, but the mechanisms of infection-driven platelet activation are not completely understood. Dengue virus nonstructural protein-1 (DENV NS1) is a viral protein secreted by infected cells with recognized roles in dengue pathogenesis, but it remains unknown whether NS1 contributes to the inflammatory phenotype of infected platelets. This study shows that recombinant DENV NS1 activated platelets toward an inflammatory phenotype that partially reproduced DENV infection. NS1 stimulation induced translocation of α-granules and release of stored factors, but not of newly synthesized interleukin-1β (IL-1β). Even though both NS1 and DENV were able to induce pro-IL-1β synthesis, only DENV infection triggered caspase-1 activation and IL-1β release by platelets. A more complete thromboinflammatory phenotype was achieved by synergistic activation of NS1 with classic platelet agonists, enhancing α-granule translocation and inducing thromboxane A2 synthesis (thrombin and platelet-activating factor), or activating caspase-1 for IL-1β processing and secretion (adenosine triphosphate). Also, platelet activation by NS1 partially depended on toll-like receptor-4 (TLR-4), but not TLR-2/6. Finally, the platelets sustained viral genome translation and replication, but did not support the release of viral progeny to the extracellular milieu, characterizing an abortive viral infection. Although DENV infection was not productive, translation of the DENV genome led to NS1 expression and release by platelets, contributing to the activation of infected platelets through an autocrine loop. These data reveal distinct, new mechanisms for platelet activation in dengue, involving DENV genome translation and NS1-induced platelet activation via platelet TLR4.

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