transforming-growth-factor-beta and Dengue

Increased serum and mRNA levels of cytokines in patients with dengue virus (DV) infection suggest that cytokines are one of the key factors in the pathogenesis of disease caused by this virus. Here, we tested 211 serum and 56 mRNA samples from an equal number of dengue cases to determine the levels of interleukin-8 (IL-8), interferon gamma (IFN-γ), interleukin-10 (IL-10) and transforming growth factor beta (TGF-β). A total 70 serum and 15 mRNA samples from healthy individual were also tested for cytokines and served as controls. Serum and mRNA levels of IL-8 were highest in the earlier days of dengue infection. IFNγ levels peaked one or two days before defervescence. Levels of IL-10 and TGF-β were highest later in dengue infection, and TGF-β levels peaked on the day of defervescence. Mean levels of IFNγ, TGF β and IL-10 were higher in samples from dengue cases, irrespective of severity, than in healthy controls. In contrast, the level of IL-8 was significantly higher in samples from severe dengue cases and lower in cases of dengue without warning signs than in healthy controls. Children (82.2 % of 101 paediatric cases) commonly had severe dengue illness. Samples that were positive for anti-DV IgG antibody had higher levels of IL-8 and TGF β. DV-2 infections were associated with severe dengue illness. IL-8 and IFNγ levels were higher in the presence of warning signs of severe dengue. Levels of IL-8, IL-10 and TGF β were independently associated with disease outcome. These data provide evidence of an association of IL-8, IFNγ, TGF β and IL-10 levels with the severity of dengue illness. Especially, IL-8 levels can be used as a predictor of severe DV infection.

Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Dengue; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Humans; Infant; Infant, Newborn; Interferon-gamma; Interleukin-10; Interleukin-8; Male; Real-Time Polymerase Chain Reaction; Severity of Illness Index; Transforming Growth Factor beta; Young Adult

Secondary heterologous dengue infection is a risk factor for severe disease manifestations because of the immune-enhancement phenomenon. Succeeding clinical infections are seldom reported, and the clinical course of tertiary and quaternary dengue infections is not clear. Cuba represents a unique environment to study tertiary/quaternary dengue infections in a population with known clinical and serologic dengue markers and no dengue endemicity. We took advantage of this exceptional epidemiologic condition to study the effect of primary, secondary, tertiary, and quaternary dengue infection exposure on the expression of pro-inflammatory and regulatory cytokines, critical in dengue infection pathogenesis, by using a dengue infection ex vivo model. Whereas secondary exposure induced a high cytokine response, we found a significantly lower expression of tumor necrosis factor-α, interferon-γ, interleukin-10, and tumor growth factor-β after tertiary and quaternary infectious challenge. Significant differences in expression of the cytokines were seen between the dengue immune profiles, suggesting that the sequence in which the immune system encounters serotypes may be important in determining the nature of the immune response to subsequent infections.

Topics: Adolescent; Adult; Antibodies, Neutralizing; Antigens, Viral; Cuba; Dengue; Dengue Virus; Epidemiologic Studies; Female; Humans; Inflammation; Interferon-gamma; Interleukin-10; Male; Middle Aged; Neutralization Tests; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Young Adult

The occurrence of dengue haemorrhagic fever (DHF) is thought to result from a complex interplay between the virus, host genetics and host immune factors. Existing published data are not consistent, in part related to relatively small sample sizes. We set out to determine possible associations between dengue virus (DEN-V) NS3 specific T cells and cytokine and chemokine levels and the pathogenesis of severe disease in a large cohort of individuals with DHF.. By using ex vivo IFNγ ELISpot assays we determined DENV-NS3 specific responses in patients with varying severity of DHF. Other cytokines produced by DENV-NS3 specific T cells were determined by using multiple bead array analysis (MBAA). We also determined the serum cytokine levels using MBAA, lymphocyte subsets and Annexin V expression of lymphocytes in patients with varying severity of DHF. Of the 112 DHF patients studied, 29 developed shock. Serum IL-10 and IP-10 levels positively and significantly correlated with T cell apoptosis while IL-10 levels inversely correlated with T cell numbers. In contrast, TGFß showed a very significant (P<0.0001) and positive correlation (Spearman's R = 0.65) with the platelet counts, consistent with platelet release. We found that whilst patients with severe dengue had lower total T cell numbers, the DV-NS3 specific T cells persisted and produced high levels of IFNγ but not TNFα, IL-3, IL-13, IL-2, IL-10 or IL-17.. Our data suggest that serum IL-10, TNFα and TGFβ differentially associate with dengue disease severity.

Topics: Adolescent; Adult; Aged; Chemokines; Cohort Studies; Cytokines; Dengue; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Interleukin-10; Lymphocyte Subsets; Male; Middle Aged; Peptides; Propidium; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha