Article

Dengue virus-reactive CD8+ T cells display quantitative and qualitative differences in their response to variant epitopes of heterologous viral serotypes.

Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, MA 01655, USA.
The Journal of Immunology (Impact Factor: 5.36). 04/2006; 176(5):2817-24. DOI: 10.4049/jimmunol.176.5.2817
Source: PubMed

ABSTRACT Reactivation of serotype cross-reactive CD8+ memory T lymphocytes is thought to contribute to the immunopathogenesis of dengue disease during secondary infection by a heterologous serotype. Using cytokine flow cytometry, we have defined four novel HLA-A*02-restricted dengue viral epitopes recognized by up to 1.5% of circulating CD8+ T cells in four donors after primary vaccination. All four donors had the highest cytokine response to the epitope NS4b 2353. We also studied the effect of sequence differences in heterologous dengue serotypes on dengue-reactive CD8+ memory T cell cytokine and proliferative responses. The D3 variant of a different NS4b epitope 2423 and the D2 variant of the NS4a epitope 2148 induced the largest cytokine response, compared with their respective heterologous sequences in all donors regardless of the primary vaccination serotype. Stimulation with variant peptides also altered the relative frequencies of the various subsets of cells that expressed IFN-gamma, TNF-alpha, MIP-1beta, and combinations of these cytokines. These results indicate that the prior infection history of the individual as well as the serotypes of the primary and heterologous secondary viruses influence the nature of the secondary response. These differences in the effector functions of serotype cross-reactive memory T cells induced by heterologous variant epitopes, which are both quantitative and qualitative, may contribute to the clinical outcome of secondary dengue infection.

0 Followers
 · 
42 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Detailed knowledge of dengue virus (DENV) cell mediated immunity is still limited. Herewe characterize CD8+ T lymphocytes recognizing 3 novel and 2 known nonstructural protein 3 peptide epitopes in DENV-infected dendritic cells. Three epitopes displayed high conservation (75 – 100%), compared to the others (0-50%). A hierarchy ranking based on magnitude and polyfunctionality of the antigen specific response showed that dominant epitopes were both highly conserved and cross-reactive against multiple DENV serotypes. These results are relevant to DENV pathogenesis and vaccine design.
    Clinical & Experimental Immunology 05/2014; DOI:10.1111/cei.12373 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dengue virus (DENV) infection associates with renal disorders. Patients with dengue hemorrhagic fever and acute kidney injury have a high mortality rate. Increased levels of cytokines may contribute to the pathogenesis of DENV-induced kidney injury. Currently, molecular mechanisms how DENV induces kidney cell injury has not been thoroughly investigated. Excessive cytokine production may involve in this process. Using human cytokine RT(2) Profiler PCR array, 14 genes including IP-10, RANTES, IL-8, CXCL-9 and MIP-1β were up-regulated more than 2folds in DENV-infected HEK 293 cells compared to that of mock-infected HEK 293 cells. In the present study, RANTES was suppressed by the NF-κB inhibitor, compound A (CpdA), in DENV-infected HEK 293 cells implying the role of NF-κB in RANTES expression. Chromatin immunoprecipitation (ChIP) assay showed that NF-κB binds more efficiently to its binding sites on the RANTES promoter in NS5-transfected HEK 293 cells than in HEK 293 cells expressing the vector lacking NS5. To further examine whether the NS5-activated RANTES promoter is mediated through NF-κB, the two NF-κB binding sites on the RANTES promoter were mutated and this promoter was coupled to the luciferase cDNA. The result showed that when both binding sites of NF-κB in the RANTES promoter were mutated, the ability of NS5 to induce the luciferase activity was significantly decreased. Therefore, DENV NS5 activates RANTES production by increasing NF-κB binding to its binding sites on the RANTES promoter. Copyright © 2014 Elsevier B.V. All rights reserved.
    Virus Research 12/2014; DOI:10.1016/j.virusres.2014.12.007 · 2.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dengue is a mosquito-borne viral disease of expanding geographical range and increasing incidence. The vast majority of dengue cases are children less than 15 years of age. Dengue causes a spectrum of illness from mild fever to severe disease with plasma leakage and shock. Infants and children with secondary heterologous dengue infections are most at risk for severe dengue disease. Laboratory diagnosis of dengue can be established within five days of disease onset by direct detection of viral components in serum. After day five, serologic diagnosis provides indirect evidence of dengue. Currently, no effective antiviral agents are available to treat dengue infection. Therefore, treatment remains supportive, with emphasis on close hematological monitoring, recognition of warning signs of severe disease and fluid-replacement therapy and/or blood transfusions when required. Development of a dengue vaccine is considered a high public health priority. A safe and efficacious dengue vaccine would also be important for travelers. This review highlights the current understanding of dengue in children, including its clinical manifestations, pathogenesis, diagnostic tests, management and prevention.
    Journal of Infection 11/2014; DOI:10.1016/j.jinf.2014.07.020 · 4.02 Impact Factor

Preview

Download
0 Downloads
Available from