The available evidence suggests that plasma leakage in dengue hemorrhagic fever is caused by the action of circulating mediators on the vascular endothelium, and that the host immune response is a critical determinant of this response. We have been exploring the role of dengue virus-specific T lymphocytes in the immunopathogenesis of plasma leakage. Memory dengue virus-specific T cells induced during a primary dengue virus infection are reactivated by the heterologous viral serotype during a secondary infection to expand to high levels and produce a skewed cytokine profile. Investigations are underway to identify the immunologic profiles associated with increased or decreased risk for severe disease.
"Consistent with this hypothesis, antiviral activity that promotes viral clearance in a manner that depends on IFN-γ and TNF-α-producing T-cells directed at H-2Db-restricted epitopes (Friberg et al. 2011) may be responsible for the resistance of mice to primary infection by dengue virus. We suggested that a serial SS infection may mimic a severe primary dengue infection in which others have described a cytokine storm associated with a T-lymphocyte response, that is mostly responsible for the development of disease rather than protection against severe infection (Rothman 2009, Guabiraba et al. 2010). "
[Show abstract][Hide abstract] ABSTRACT: Because an enriched environment (EE) enhances T-cell activity and T-lymphocytes contribute to immunopathogenesis during heterologous dengue virus (DENV) infections, we hypothesised that an EE increases dengue severity. To compare single serotype (SS) and antibody-enhanced disease (AED) infections regimens, serial intraperitoneal were performed with DENV3 (genotype III) infected brain homogenate or anti-DENV2 hyperimmune serum followed 24 h later by DENV3 (genotype III) infected brain homogenate. Compared AED for which significant differences were detected between the EE and impoverished environmental (IE) groups (Kaplan-Meyer log-rank test, p = 0.0025), no significant differences were detected between the SS experimental groups (Kaplan-Meyer log-rank test, p = 0.089). Survival curves from EE and IE animals infected with the AED regimen were extended after corticoid injection and this effect was greater in the EE than in the IE group (Kaplan-Meyer log-rank test, p = 0.0162). Under the AED regimen the EE group showed more intense clinical signs than the IE group. Dyspnoea, tremor, hunched posture, ruffled fur, immobility, pre-terminal paralysis, shock and death were associated with dominant T-lymphocytic hyperplasia and presence of viral antigens in the liver and lungs. We propose that the increased expansion of these memory T-cells and serotype cross-reactive antibodies facilitates the infection of these cells by DENV and that these events correlate with disease severity in an EE.
Memórias do Instituto Oswaldo Cruz 12/2012; 107(8):1021-9. DOI:10.1590/S0074-02762012000800010 · 1.59 Impact Factor
"Epidemiological studies have shown an association between DHF/DSS and secondary DENV infection. Preexisting antibodies and cross reactive T cell responses induced by the primary infection is believed to exacerbate the disease during secondary infection [3,4]. Proinflammatory cytokines namely interleukin-8 (IL-8), tumor necrosis factor-α and interferon-γ and anti inflammatory cytokine IL-10 also contribute to dengue disease pathogenesis [5-11]. "
[Show abstract][Hide abstract] ABSTRACT: Altered plasma concentrations of vitamin D and mannose binding lectin (MBL), components of innate immunity, have been shown to be associated with the pathogenesis of viral infections. The objective of the present study was to find out whether plasma concentrations of MBL and vitamin D are different in patients with dengue fever (DF) and dengue hemorrhagic fever (DHF).
The plasma concentrations of vitamin D and MBL were assessed in 48 DF cases, 45 DHF cases and 20 apparently healthy controls using ELISA based methods. Vitamin D concentrations were found to be higher among both DF and DHF cases as compared to healthy controls (P < 0.005 and P < 0.001). Vitamin D concentrations were not different between DF and DHF cases. When the dengue cases were classified into primary and secondary infections, secondary DHF cases had significantly higher concentrations of vitamin D as compared to secondary DF cases (P < 0.050). MBL concentrations were not significantly different between healthy controls and dengue cases. MBL concentrations were observed to be lower in DHF cases as compared to DF cases (P < 0.050). Although MBL levels were not different DF and DHF cases based on immune status, the percentage of primary DHF cases (50%) having MBL levels lower than 500 ng/ml were less compared to primary DF cases (P = 0.038).
The present study suggests that higher concentrations of vitamin D might be associated with secondary DHF while deficiency of MBL may be associated with primary DHF.
"One study showed elevated IFN-α plasma levels shortly after symptom onset in DF children (Kurane et al. 1993). The severity of DENV infection seems to be due more to disproportionate inflammatory cytokine production than direct viral effects (Chaturvedi et al. 2007, Rothman 2009). Recently, a study was conducted in African DF patients infected during the first Gabonese DENV-2 outbreak in 2007. "
[Show abstract][Hide abstract] ABSTRACT: Dengue virus (DENV) and parvovirus B19 (B19V) infections are acute exanthematic febrile illnesses that are not easily differentiated on clinical grounds and affect the paediatric population. Patients with these acute exanthematic diseases were studied. Fever was more frequent in DENV than in B19V-infected patients. Arthritis/arthralgias with DENV infection were shown to be significantly more frequent in adults than in children. The circulating levels of interleukin (IL)-1 receptor antagonist (Ra), CXCL10/inducible protein-10 (IP-10), CCL4/macrophage inflammatory protein-1 beta and CCL2/monocyte chemotactic protein-1 (MCP-1) were determined by multiplex immunoassay in serum samples obtained from B19V (37) and DENV-infected (36) patients and from healthy individuals (7). Forward stepwise logistic regression analysis revealed that circulating CXCL10/IP-10 tends to be associated with DENV infection and that IL-1Ra was significantly associated with DENV infection. Similar analysis showed that circulating CCL2/MCP-1 tends to be associated with B19V infection. In dengue fever, increased circulating IL-1Ra may exert antipyretic actions in an effort to counteract the already increased concentrations of IL-1β, while CXCL10/IP-10 was confirmed as a strong pro-inflammatory marker. Recruitment of monocytes/macrophages and upregulation of the humoral immune response by CCL2/MCP-1 by B19V may be involved in the persistence of the infection. Children with B19V or DENV infections had levels of these cytokines similar to those of adult patients.
Memórias do Instituto Oswaldo Cruz 02/2012; 107(1):48-56. DOI:10.1590/S0074-02762012000100007 · 1.59 Impact Factor
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