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1.
Chandima Jeewandara Thiruni N. Adikari Laksiri Gomes Samitha Fernando R. H. Fernando M. K. T. Perera Dinuka Ariyaratne Achala Kamaladasa Maryam Salimi Shamini Prathapan Graham S. Ogg Gathsaurie Neelika Malavige 《PLoS neglected tropical diseases》2015,9(4)
Background
Although antibody responses to dengue virus (DENV) in naturally infected individuals have been extensively studied, the functionality of DENV specific memory T cell responses in relation to clinical disease severity is incompletely understood.Methodology/Principal findings
Using ex vivo IFNγ ELISpot assays, and by determining cytokines produced in ELISpot supernatants, we investigated the functionality of DENV-specific memory T cell responses in a large cohort of individuals from Sri Lanka (n=338), who were naturally infected and were either hospitalized due to dengue or had mild or sub clinical dengue infection. We found that T cells of individuals with both past mild or sub clinical dengue infection and who were hospitalized produced multiple cytokines when stimulated with DENV-NS3 peptides. However, while DENV-NS3 specific T cells of those with mild/sub clinical dengue infection were more likely to produce only granzyme B (p=0.02), those who were hospitalized were more likely to produce both TNFα and IFNγ (p=0.03) or TNFα alone.We have also investigated the usefulness of a novel T cell based assay, which can be used to determine the past infecting DENV serotype. 92.4% of DENV seropositive individuals responded to at least one DENV serotype of this assay and none of the seronegatives responded. Individuals who were seronegative, but had received the Japanese encephalitis vaccine too made no responses, suggesting that the peptides used in this assay did not cross react with the Japanese encephalitis virus.Conclusions/significance
The types of cytokines produced by DENV-specific memory T cells appear to influence the outcome of clinical disease severity. The novel T cell based assay, is likely to be useful in determining the past infecting DENV serotype in immune-epidemiological studies and also in dengue vaccine trials. 相似文献2.
Malavige GN Rostron T Rohanachandra LT Jayaratne SD Fernando N De Silva AD Liyanage M Ogg G 《PloS one》2011,6(6):e20581
Background
HLA class I and class II alleles have been shown to be associated with the development of dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) in different populations. However, the majority of studies have been based on limited numbers of patients. In this study we aimed to investigate the HLA-class I and class II alleles that are positively and negatively associated with the development of DSS in a cohort of patients with DHF and also the alleles associated with development of DHF during primary dengue infections in a Sri Lankan population.Methodology/Principal Findings
The allele frequencies of HLA class I and class II alleles were compared in 110 patients with DHF and 119 individuals from the population who had never reported a symptomatic dengue infection at the time of recruitment. We found that HLA-A*31 (corrected P = 0.01) and DRB1*08 (corrected P = 0.009) were associated with susceptibility to DSS when infected with the dengue virus, during secondary dengue infection. The frequency of DRB1*08 allele was 28.7 times higher than in the normal population in patients with DSS. HLA-A*31 allele was increased 16.6 fold in DHF who developed shock when compared to those who did not develop shock. A*24 (corrected P = 0.03) and DRB1*12 (corrected P = 0.041) were strongly associated with the development of DHF during primary dengue infection.Conclusions/Significance
These data suggest that certain HLA alleles confer susceptibility/protection to severe dengue infections. As T cell epitope recognition depend on the HLA type of an individual, it would be now important to investigate how epitope specific T cells associate with primary and secondary dengue infections and in severe dengue infections. 相似文献3.
Gathsaurie Neelika Malavige Li-Chieh Huang Maryam Salimi Laksiri Gomes S. D. Jayaratne Graham S. Ogg 《PloS one》2012,7(11)
Background
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.Methodology/Principal Findings
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.Conclusions/Significance
Our data suggest that serum IL-10, TNFα and TGFβ differentially associate with dengue disease severity. 相似文献4.
Gathsaurie Neelika Malavige Louise Jones S. D. Kamaladasa A. Wijewickrama S. L. Seneviratne Antony P. Black Graham S. Ogg 《PloS one》2008,3(11)
Background
In Sri Lanka, varicella zoster virus (VZV) is typically acquired during adulthood with significant associated disease morbidity and mortality. T cells are believed to be important in the control of VZV replication and in the prevention of reactivation. The relationship between viral load, disease severity and cellular immune responses in primary VZV infection has not been well studied.Methodology
We used IFNγ ELISpot assays and MHC class II tetramers based on VZV gE and IE63 epitopes, together with quantitative real time PCR assays to compare the frequency and phenotype of specific T cells with virological and clinical outcomes in 34 adult Sri Lankan individuals with primary VZV infection.Principal Findings
Viral loads were found to be significantly higher in patients with moderate to severe infection compared to those with mild infection (p<0.001) and were significantly higher in those over 25 years of age (P<0.01). A significant inverse correlation was seen between the viral loads and the ex vivo IFNγ ELISpot responses of patients (P<0.001, r = −0.85). VZV-specific CD4+ T cells expressed markers of intermediate differentiation and activation.Conclusions
Overall, these data show that increased clinical severity in Sri Lankan adults with primary VZV infection associates with higher viral load and reduced viral specific T cell responses. 相似文献5.
Chandima Jeewandara Laksiri Gomes N. Wickramasinghe Danuta Gutowska-Owsiak Dominic Waithe S. A. Paranavitane N. L. A. Shyamali Graham S. Ogg Gathsaurie Neelika Malavige 《PLoS neglected tropical diseases》2015,9(2)
Background
Although plasma leakage is the hallmark of severe dengue infections, the factors that cause increased vascular permeability have not been identified. As platelet activating factor (PAF) is associated with an increase in vascular permeability in other diseases, we set out to investigate its role in acute dengue infection.Materials and Methods
PAF levels were initially assessed in 25 patients with acute dengue infection to determine if they were increased in acute dengue. For investigation of the kinetics of PAF, serial PAF values were assessed in 36 patients. The effect of dengue serum on tight junction protein ZO-1 was determined by using human endothelial cell lines (HUVECs). The effect of dengue serum on and trans-endothelial resistance (TEER) was also measured on HUVECs.Results
PAF levels were significantly higher in patients with acute dengue (n = 25; p = 0.001) when compared to healthy individuals (n = 12). In further investigation of the kinetics of PAF in serial blood samples of patients (n = 36), PAF levels rose just before the onset of the critical phase. PAF levels were significantly higher in patients with evidence of vascular leak throughout the course of the illness when compared to those with milder disease. Serum from patients with dengue significantly down-regulated expression of tight junction protein, ZO-1 (p = 0.004), HUVECs. This was significantly inhibited (p = 0.004) by use of a PAF receptor (PAFR) blocker. Serum from dengue patients also significantly reduced TEER and this reduction was also significantly (p = 0.02) inhibited by prior incubation with the PAFR blocker.Conclusion
Our results suggest the PAF is likely to be playing a significant role in inducing vascular leak in acute dengue infection which offers a potential target for therapeutic intervention. 相似文献6.
Gathsaurie Neelika Malavige Chandima Jeewandara Azhar Ghouse Gayasha Somathilake Hasitha Tissera 《PLoS neglected tropical diseases》2021,15(8)
BackgroundDengue infections are on the rise in Sri Lanka and are spreading to all areas in the country. Here, we discuss the changes in dengue epidemiology in Sri Lanka in relation to changes in age distribution, changes in seroprevalence rates over time, and possible reasons contributing to such changes.Methods and findingsAlthough the incidence of dengue increased 20-fold from the year 2000 to 2012 and a further 3-fold from 2012 to 2019, this increase is not reflected in a similar increase in the age-stratified seropositivity rates for dengue. For instance, the annual seroconversion rates were 0.76% in 2013 and 0.91% in 2017. The annual seroconversion rates in the 6 to 17 age group were 1.5% per year in 2003, 3.9% in 2013, and 4.1% in 2017. In addition, although a 13-fold increase in dengue was seen in those who were <19 years of age, a 52.4-fold increase was seen in the 40- to 59-year age group. The case fatality rates (CFRs) have similarly changed, with 61.8% of deaths occurring in those <19 years of age in the year 2000, while in 2012 to 2018, the highest CFR were seen in those who were aged 20 to 39 years. Although there has been a marked increase in the number of cases, the vector densities did not change during a 4-year period. The proportion of adult individuals experiencing a secondary dengue infection has also remained between 65% and 75% between the years 2004 and 2018.ConclusionsA change in the ratio of symptomatic to asymptomatic infections can give rise to changes in the reported incidence of dengue. In order to take an appropriate policy decision in dengue control activities, it would be important to study the changes in virus serotypes, vector dispersion, and densities. Further, the contribution of the rise in metabolic diseases to an increase in the symptomatic as well as more severe infections due to dengue is explored. 相似文献
7.
Open reading frame 4 (ORF4) of varicella-zoster virus (VZV) encodes an immediate-early protein that is believed to be important for viral infectivity and establishing latency. Evidence suggests that VZV-specific T cells are crucial in the control of viral replication, but there are no data addressing the existence of potential ORF4 protein-specific CD4+ T cells. We tested the hypothesis that VZV ORF4 protein-specific CD4+ T cells could be identified and characterized within the peripheral blood of healthy immune donors following primary infection. Gamma interferon (IFN-gamma) immunosorbent assays were used to screen peripheral blood mononuclear cells obtained from healthy seropositive donors for responses to overlapping ORF4 peptides, viral lysate, and live vaccine. High frequencies of ORF4 protein-specific T cells were detected ex vivo in individuals up to 52 years after primary infection. Several immunogenic regions of the ORF4 protein were identified, including a commonly recognized epitope which was restricted through HLA-DRB1*07. Total ORF4 protein-specific responses comprised 19.7% and 20.7% of the total lysate and vaccine responses, respectively, and were dominated by CD4+ T cells. Indeed, CD4+ T cells were found to dominate the overall virus-specific IFN-gamma cellular immune response both ex vivo and after expansion in vitro. In summary, we have identified an ORF4 protein as a novel target antigen for persistent VZV-specific CD4+ T cells, with implications for disease pathogenesis and future vaccine development. 相似文献
8.
Gathsaurie Neelika Malavige Chandima Jeewandara Ananda Wijewickrama Dumni Gunasinghe Sameera D. Mahapatuna Chathurika Gangani Vimalahan Vimalachandran Geethal Jayarathna Yashoda Perera Chandanie Wanigatunga Harsha Dissanayake Shamini Prathapan Eranga Narangoda Damayanthi Idampitiya Laksiri Gomes Samurdhi Wickramanayake Pramodth Sahabandu Graham S. Ogg 《PLoS neglected tropical diseases》2022,16(6)
BackgroundRupatadine was previously shown to reduce endothelial dysfunction in vitro, reduced vascular leak in dengue mouse models and to reduce the extent of pleural effusions and thrombocytopenia in patients with acute dengue. Therefore, we sought to determine the efficacy of rupatadine in reducing the incidence of dengue haemorrhagic fever (DHF) in patients with acute dengue.Methods and findingsA phase 2, randomised, double blind, placebo controlled clinical trial was carried out in patients with acute dengue in Sri Lanka in an outpatient setting. Patients with ≤3 days since the onset of illness were either recruited to the treatment arm of oral rupatadine 40mg for 5 days (n = 123) or the placebo arm (n = 126). Clinical and laboratory features were measured daily to assess development of DHF and other complications. 12 (9.7%) patients developed DHF in the treatment arm compared to 22 (17.5%) who were on the placebo although this was not significant (p = 0.09, relative risk 0.68, 95% CI 0.41 to 1.08). Rupatadine also significantly reduced (p = 0.01) the proportion of patients with platelet counts <50,000 cells/mm3 and significantly reduced (p = 0.04) persisting vomiting, headache and hepatic tenderness (p<0.0001) in patients. There was a significant difference in the duration of illness (p = 0.0002) although the proportion of individuals who required hospital admission in both treatment arms. Only 2 patients on rupatadine and 3 patients on the placebo developed shock, while bleeding manifestations were seen in 6 patients on rupatadine and 7 patients on the placebo.ConclusionsRupatadine appeared to be safe and well tolerated and showed a trend towards a reducing proportion of patients with acute dengue who developed DHF. Its usefulness when used in combination with other treatment modalities should be explored.Trial registrationInternational Clinical Trials Registration Platform: SLCTR/2017/024. 相似文献
9.
Gathsaurie Neelika Malavige Chandima Jeewandara K. M. Luckmaal Alles Maryam Salimi Laksiri Gomes Achala Kamaladasa S. D. Jayaratne Graham Stuart Ogg 《PLoS neglected tropical diseases》2013,7(9)
Background
Elevated IL-10 has been shown to be associated with severe dengue infection (DI). We proceeded to investigate the role of IL-10 in the pathogenesis of acute DI.Materials and methods
Ex vivo and cultured IFNγ ELISpot assays for dengue virus (DENV) NS3 protein and non dengue viral proteins were carried out in 26 patients with acute DI (16 with dengue haemorrhagic fever) and 12 healthy dengue seropositive individuals from Sri Lanka. DENV serotype specific (SS) responses were determined by using a panel of SS peptides.Results
Serum IL-10 level were significantly higher (p = 0.02) in those who did not have in vitro responses to DENV-SS peptides (mean 144.2 pg/ml) when compared to those who responded (mean 75.7 pg/ml). DENV-NS3 specific ex vivo IFNγ ELISpot responses were also significantly lower (p = 0.0001) in those who did not respond to DENV-SS peptides (mean 42 SFU/million PBMCs) when compared to those who responded to DENV-SS peptides (mean 1024 SFU/million PBMCs). Serum IL-10 levels correlated significantly (p = 0.03) and inversely (Spearmans R = −0.45) with ex vivo DENV-NS3 specific responses but not with ex vivo non DENV specific responses (Spearmans R = −014, p = 0.52). Blockage of IL-10 in vitro significantly increased (p = 0.04) the ex vivo IFNγ ELISpot DENV-NS3 specific responses but had no effect on responses to non DENV proteins.Conclusion
IL-10 appears to contribute to the pathogenesis of acute dengue infections by inhibiting DENV-specific T cell responses, which can be restored by blocking IL-10. 相似文献10.
Chandima Jeewandara Laksiri Gomes S. A. Paranavitane Mihiri Tantirimudalige Sumedha Sandaruwan Panapitiya Amitha Jayewardene Samitha Fernando R. H. Fernando Shamini Prathapan Graham S. Ogg Gathsaurie Neelika Malavige 《PloS one》2015,10(12)