Acute dengue virus 2 infection in Gabonese patients is associated with an early innate immune response, including strong interferon alpha production

Becquart, Pierre; Wauquier, Nadia; Nkoghe, Dieudonné; Ndjoyi-Mbiguino, Angélique; Padilla, Cindy; Souris, Marc; Leroy, Eric M.

doi:10.1186/1471-2334-10-356

Cited by 58 publications

(51 citation statements)

References 67 publications

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“…In a study of a pediatric population with DHF, Srikiatkhachorn et al [6] also detected a rise in circulating VEGF in the early febrile and defervescent stages of Dengue infection, but not during the later convalescent stage. However, subsequent studies reported contradictory findings, as increased circulating VEGF concentrations were not observed during the early febrile and toxic stages in DHF, but lower VEGF concentrations were detected in patients with more severe Dengue infection [50]–[52]. Several underlying reasons may explain these differences, such as poor study design, small sample size, and the lack of a standardized collection methodology and storage of blood samples used for the measurement of VEGF.…”

Section: Discussionmentioning

confidence: 99%

Association of Mast Cell-Derived VEGF and Proteases in Dengue Shock Syndrome

et al. 2012

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BackgroundRecent in-vitro studies have suggested that mast cells are involved in Dengue virus infection. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEGFRs], tryptase, and chymase) and -related cytokines (IL-4, -9, and -17) between patients with differing severity of Dengue fever and healthy controls.Methodology/Principal FindingsThe study was performed at Children's Hospital No. 2, Ho Chi Minh City, and Vinh Long Province Hospital, Vietnam from 2002 to 2005. Study patients included 103 with Dengue fever (DF), Dengue hemorrhagic fever (DHF), and Dengue shock syndrome (DSS), as diagnosed by the World Health Organization criteria. There were 189 healthy subjects, and 19 febrile illness patients of the same Kinh ethnicity. The levels of mast cell-derived mediators and -related cytokines in plasma were measured by ELISA. VEGF and sVEGFR-1 levels were significantly increased in DHF and DSS compared with those of DF and controls, whereas sVEGFR-2 levels were significantly decreased in DHF and DSS. Significant increases in tryptase and chymase levels, which were accompanied by high IL-9 and -17 concentrations, were detected in DHF and DSS patients. By day 4 of admission, VEGF, sVEGFRs, and proteases levels had returned to similar levels as DF and controls. In-vitro VEGF production by mast cells was examined in KU812 and HMC-1 cells, and was found to be highest when the cells were inoculated with Dengue virus and human Dengue virus-immune serum in the presence of IL-9.ConclusionsAs mast cells are an important source of VEGF, tryptase, and chymase, our findings suggest that mast cell activation and mast cell-derived mediators participate in the development of DHF. The two proteases, particularly chymase, might serve as good predictive markers of Dengue disease severity.

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Section: Discussionmentioning

confidence: 99%

Association of Mast Cell-Derived VEGF and Proteases in Dengue Shock Syndrome

et al. 2012

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“…However, it has been shown that the timing of Th1 cytokine (IFN-␥, IL-10, sIL-2R, and TNF-␤) responses varies by stage of disease in humans and whether the patient presents with DF or DHF (34). A more recent study of cytokines secreted by patients with primary DENV infections in Gabon showed that TNF-␣ levels are not significantly altered but IFN-␥ levels are much higher in adults and children (7). Humanized mice infected by mosquito bite reacted in a similar manner during primary infection, with very high levels of IFN-␥ (approximately 1/10 of that seen in humans) and sIL-2R␣ (approximately 1/2 of that seen in humans) (27,28), with both cytokines produced during the viremic phase.…”

Section: Tablementioning

confidence: 99%

Mosquito Bite Delivery of Dengue Virus Enhances Immunogenicity and Pathogenesis in Humanized Mice

Cox

Mota

Sukupolvi-Petty

et al. 2012

J Virol

184

205

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bDengue viruses (DENV) are transmitted to humans by the bite of Aedes aegypti or Aedes albopictus mosquitoes, with millions of infections annually in over 100 countries. The diseases they produce, which occur exclusively in humans, are dengue fever (DF) and dengue hemorrhagic fever (DHF). We previously developed a humanized mouse model of DF in which mice transplanted with human hematopoietic stem cells produced signs of DENV disease after injection with low-passage, wild-type isolates. Using these mice, but now allowing infected A. aegypti to transmit dengue virus during feeding, we observed signs of more severe disease (higher and more sustained viremia, erythema, and thrombocytopenia). Dengue fever (DF) in humans is characterized by fever, myalgia, arthralgia, abdominal pain, rash, low platelet counts (thrombocytopenia), and a viremia that begins 3 to 4 days after infection by mosquito bite. The more severe form of dengue, dengue hemorrhagic fever (DHF), usually presents as a second phase of disease, at the end of the fever stage, but with a sudden onset of plasma leakage that can result in hemoconcentration, pleural effusion, ascites, shock, hepatic failure, and encephalopathy. While this hemodynamic syndrome can resolve in 2 days, complete convalescence can take weeks to months (reviewed in reference 53). Moreover, ϳ5% of DHF patients die, usually from hypotensive shock, due to a delay in the recognition and treatment of the plasma leakage. Dengue virus (DENV)-induced disease has increased markedly due to the global spread of the virus and expansion of its mosquito vectors, and it is now the most important viral illness transmitted by insects (61). However, a clear understanding of the mechanisms leading to DF and DHF has been limited by several factors: (i) inadequate animal models of disease, with most knowledge being derived from clinical studies and in vitro experiments; (ii) the genetic diversity of DENV, with four different antigenic groups or serotypes and with humans potentially infected multiple times; and (iii) the relative risk of severe DENV disease, which is enhanced greatly by secondary infection with a heterologous serotype. The last factor has prompted the development of several models of immunopathogenesis (reviewed in reference 47) that have been difficult to evaluate experimentally, given the absence of reliable immunocompetent-animal models of human disease presenting with clinical signs of DHF after serial infection with wild-type viruses.We sought to produce an animal model of disease that could mimic the natural cycle of mosquito-human transmission with low-passage-number viruses from clinical samples, using human cells as targets of infection within a neutral background of nonsusceptible tissues (mouse) and using the appropriate species of mosquito vector, to evaluate the influence of biting/probing, virus delivery, and saliva proteins on DENV pathogenesis. Using humanized NOD/SCID/interleukin 2 receptor gamma (IL-2R␥)-null (hu-NSG) mice that had previously defined differences in th...

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“…IFN-γ, TNF-α, IL-1β, IL-6, and G-CSF have previously been reported to be elevated in serum of DV-infected patients (47,48). We found that ConA treatment also elevated serum levels of these proinflammatory molecules; and we were able to recapitulate the ConA effect by treating mice with recombinant G-CSF to recruit the MDL-1 + cells, as well as a low dose of IFN-γ, TNF-α, IL-1β, and IL-6 to prime the pathogenic cells.…”

Section: Figurementioning

confidence: 99%

Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice

Cheung¹,

Shen²,

Phillips³

et al. 2011

J. Clin. Invest.

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Systemic inflammatory response syndrome (SIRS) is a potentially lethal condition, as it can progress to shock, multi-organ failure, and death. It can be triggered by infection, tissue damage, or hemorrhage. The role of tissue injury in the progression from SIRS to shock is incompletely understood. Here, we show that treatment of mice with concanavalin A (ConA) to induce liver injury triggered a G-CSF-dependent hepatic infiltration of CD11b + Gr-1 + Ly6G + Ly6C + immature myeloid cells that expressed the orphan receptor myeloid DAP12-associated lectin-1 (MDL-1; also known as CLEC5A). Activation of MDL-1 using dengue virus or an agonist MDL-1-specific antibody in the ConA-treated mice resulted in shock. The MDL-1 + cells were pathogenic, and in vivo depletion of MDL-1 + cells provided protection. Triggering MDL-1 on these cells induced production of NO and TNF-α, which were found to be elevated in the serum of treated mice and required for MDL-1-induced shock. Surprisingly, MDL-1-induced NO and TNF-α production required eNOS but not iNOS. Activation of DAP12, DAP10, Syk, PI3K, and Akt was critical for MDL-1-induced shock. In addition, Akt physically interacted with and activated eNOS. Therefore, triggering of MDL-1 on immature myeloid cells and production of NO and TNF-α may play a critical role in the pathogenesis of shock. Targeting the MDL-1/Syk/PI3K/Akt/eNOS pathway represents a potential new therapeutic strategy to prevent the progression of SIRS to shock.

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Acute dengue virus 2 infection in Gabonese patients is associated with an early innate immune response, including strong interferon alpha production

Cited by 58 publications

References 67 publications

Association of Mast Cell-Derived VEGF and Proteases in Dengue Shock Syndrome

Association of Mast Cell-Derived VEGF and Proteases in Dengue Shock Syndrome

Mosquito Bite Delivery of Dengue Virus Enhances Immunogenicity and Pathogenesis in Humanized Mice

Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice

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