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.
Highlights
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]
Dengue viral infections cause severe clinical disease, the majority of individuals infected with the dengue virus (DENV) develop asymptomatic infection
We sought to investigate the function of DENV specific memory T cell responses in a large cohort (n = 338) of individuals who were naturally infected with the DENV but developed varying severity of clinical disease
Summary
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]. The main hurdle in developing a safe and effective vaccine has been our poor understanding of the complex nature of the protective immune response in acute dengue infection and the presence of four dengue virus (DENV) serotypes that are highly homologous[5]. DENV-specific, highly cross reactive T cells were believed to contribute to severe clinical disease [9,10,11], [12] more recent data suggest that T cell responses are likely to be protective [13, 14]. 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
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