Research Article: Functionality of Dengue Virus Specific Memory T Cell Responses in Individuals Who Were Hospitalized or Who Had Mild or Subclinical Dengue Infection

Date Published: April 13, 2015

Publisher: Public Library of Science

Author(s): 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, Alan L Rothman.

Abstract: BackgroundAlthough 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 findingsUsing 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/significanceThe 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.

Partial Text: Dengue viral infections are one of the most important emerging virus infections in the world [1] causing 390 million dengue infections annually, of which 96 million are clinically apparent [2][3]. 70% of infections occur in Asia and as a result of the high disease burden, dengue has been declared a priority infection by the WHO, UNICEF and World Bank [4]. Currently there are no effective antiviral drugs to treat acute infection, nor a licensed vaccine to prevent infection.

Of the 338 individuals who were recruited, 182 (53.8%) were females and 156 (46.1%) were males. The mean age was 39.86 (95% CI 35–44.72). 296/338 (87.6%) individuals were seropositive for dengue infection. 242/296 (81.8%) were considered to be have had a mild/subclinical past dengue infection, as they had never been hospitalized due to a febrile illness and therefore, are most likely to have had mild clinical disease or were asymptomatic. Of the 54 individuals who had been hospitalized due to a dengue infection, 8 (14.8%) had DF and 46 (85.2%) had DHF. The mean ages of those who were hospitalized due to dengue and who had mild/sub clinical dengue were similar (43.4 vs. 43.3 years) and the gender distribution of the two groups were similar (females 55.6% vs 53.3%).

Although DENV-specific T cells have been implicated in severe clinical disease [10, 12, 34, 35], more recent studies have shown that T cells are likely to have a protective role [13]. Extensive analysis of T cell responses by Weiskopf et al in individuals naturally infected with the DENV showed that the T cell responses of higher magnitude and which were multifunctional were directed towards HLA alleles associated with reduced disease susceptibility[13]. It was shown that DENV specific memory T cells of approximately 17% of naturally infected individuals produced 3 cytokines whereas approximately 50% were double positive. However, since the clinical disease severity in those who were naturally infected were not known in the study done by Weiskopf et al, in our study we aimed to determine the functionality of DENV-specific T cell responses in those with varying severity of past infection in a large cohort of naturally infected individuals.



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