Quantification of dengue virus specific T cell responses and correlation with viral load and clinical disease severity in acute dengue infection.

Dulharie T Wijeratne,Gathsaurie Neelika Malavige,Samitha Fernando,Chandima Jeewandara,Clare S Hardman,Ananda Wijewickrama,Anushka Ginneliya,Laksiri Gomes,Supun Samarasekara,Graham S Ogg,Sujan Shresta

doi:10.1371/journal.pntd.0006540

Dulharie T Wijeratne, Gathsaurie Neelika Malavige + Show 9 more

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https://doi.org/10.1371/journal.pntd.0006540

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Abstract

BackgroundIn order to understand the role of dengue virus (DENV) specific T cell responses that associate with protection, we studied their frequency and phenotype in relation to clinical disease severity and resolution of viraemia in a large cohort of patients with varying severity of acute dengue infection.Methodology/Principal findingsUsing ex vivo IFNγ ELISpot assays we determined the frequency of dengue viral peptide (DENV)-NS3, NS1 and NS5 responsive T cells in 74 adult patients with acute dengue infection and examined the association of responsive T cell frequency with the extent of viraemia and clinical disease severity. We found that total DENV-specific and DENV-NS3-specific T cell responses, were higher in patients with dengue fever (DF), when compared to those with dengue haemorrhagic fever (DHF). In addition, those with DF had significantly higher (p = 0.02) DENV-specific T cell responses on day 4 of infection compared to those who subsequently developed DHF. DENV peptide specific T cell responses inversely correlated with the degree of viraemia, which was most significant for DENV-NS3 specific T cell responses (Spearman’s r = -0.47, p = 0.0003). The frequency of T cell responses to NS1, NS5 and pooled DENV peptides, correlated with the degree of thrombocytopenia but had no association with levels of liver transaminases. In contrast, total DENV-IgG inversely correlated with the degree of thrombocytopenia and levels of liver transaminases.Conclusions/SignificanceEarly appearance of DENV-specific T cell IFNγ responses before the onset of plasma leakage, appears to associate with milder clinical disease and resolution of viraemia, suggesting a protective role in acute dengue infection.

Highlights

Dengue virus is the cause of the most common mosquito-borne viral infection worldwide, over half of the global population live in areas where there is intense dengue transmission putting them at risk of dengue infection [1]
In order to understand the role of dengue virus (DENV) specific T cell responses that associate with protection, we studied their frequency and phenotype in relation to clinical disease severity and resolution of viraemia in a large cohort of patients with varying severity of acute dengue infection
DENV peptide specific T cell responses inversely correlated with the degree of viraemia, which was most significant for DENV-NS3 specific T cell responses (Spearman’s r = -0.47, p = 0.0003)

Summary

Introduction

Dengue virus is the cause of the most common mosquito-borne viral infection worldwide, over half of the global population live in areas where there is intense dengue transmission putting them at risk of dengue infection [1]. DHF is defined by a transient increase in vascular permeability resulting in plasma leakage, with high fever, bleeding, thrombocytopenia and haemoconcentration, which can lead to shock (dengue shock syndrome (DSS))[2] It is not fully understood why some people develop more severe forms of the disease, with patient history, immunity, age, viral serotype, sub-strain and epidemiological factors all postulated to play a role [3]. It was highlighted during a recent summit to identify correlates of protection for dengue, that dengue virus (DENV) specific T cell immunity should be studied in more detail, in order to develop safe and effective dengue vaccines [4]. In order to understand the role of dengue virus (DENV) specific T cell responses that associate with protection, we studied their frequency and phenotype in relation to clinical disease severity and resolution of viraemia in a large cohort of patients with varying severity of acute dengue infection

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