Cellular and Cytokine Correlates of Severe Dengue Infection

Gathsaurie Neelika Malavige,Maryam Salimi,Graham S Ogg,Laksiri Gomes,Li-Chieh Huang,S D Jayaratne,Xia Jin

doi:10.1371/journal.pone.0050387

Abstract

BackgroundThe 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 FindingsBy 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/SignificanceOur data suggest that serum IL-10, TNFα and TGFβ differentially associate with dengue disease severity.

Highlights

Dengue viral infections (DVI) have become one of the most important mosquito borne viral infections in the world and represent one of the major emerging infectious diseases
We have investigated the possible associations between DEN-V NS3 specific T cells and cytokine and chemokine levels and the pathogenesis of severe disease in patients with acute dengue virus infection
We found that severe dengue was associated with a reduction of total T cells and an elevation of IL-10 and TNFa, which was not, produced by NS3-specific T cells

Summary

Introduction

Dengue viral infections (DVI) have become one of the most important mosquito borne viral infections in the world and represent one of the major emerging infectious diseases. It is estimated that 2.1 million cases of dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS) occur every year resulting in 21,000 deaths [1]. Infection with any of the four dengue viruses may cause a wide spectrum of clinical features from asymptomatic disease, an undifferentiated febrile illness, dengue fever, DHF and DSS [2]. Initial infection with a particular serotype is known as primary infection (PD), which is usually asymptomatic or results in mild disease manifestations, but severe disease can occur [3,4]. Subsequent infection with other serotypes (secondary dengue infections (SD)) carries an increased risk of more severe disease which can manifest in the form of DHF/DSS [4,5]. The occurrence of dengue haemorrhagic fever (DHF) is thought to result from a complex interplay between the virus, host genetics and host immune factors. 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

Methods

Results

Conclusion