Cellular and Cytokine Correlates of Severe Dengue Infection

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.

Viability and Functionality of Cryopreserved Peripheral Blood Mononuclear Cells in Pediatric Dengue

“…2A). The frequency of nonviable cells in children with dengue found here is consistent with previous reports that used propidium iodide and annexin V (29). The mechanisms by which DV induces cell death are not entirely clear and are dependent on the cellular type analyzed.…”

Dengue Infection in a Human Immunodeficiency Virus-1 Positive Patient Chronically Infected with Hepatitis B Virus in Western Mexico

“…20,21 Both IL-10 and TNF-α are strongly associated with severe dengue infection. 22 The HIV-1 viral loads in our patient remained at normal levels (< 40 HIV-1 RNA copies/mL) during DENV-1 infection and 6 months later. Watt and others 8 have reported a reduction in the HIV-1 viral load in an HIV-1-positive patient without HAART treatment who presented with dengue infection in Thailand, and demonstrated that HIV-1 replication was suppressed during the acute phase of the infection.…”

Expansion of highly activated invariant natural killer T cells with altered phenotype in acute dengue infection

“…They are known to play an important role in both acute [11] and chronic viral infections [14,28], including a recent report on their role in dengue infection [12]. Acute dengue is known to associate with a marked lymphopenia [29], especially with reduction of T cells due to massive T cell apoptosis [8,9]. We have also observed that DENV-specific IFN-g T cell responses are impaired during acute dengue, especially in those with more severe forms of dengue [7].…”

“…Our previous studies on T cell responses in acute dengue infection have shown that DENV-specific T cells have an impaired ability to produce cytokines such as interferon (IFN)-g and to degranulate [7]. In addition, T cells have been shown to undergo dramatic apoptosis in dengue infection [8,9]. Therefore, it would be crucial to examine the role of other immune cells that are capable of the rapid activation and production of large quantities of cytokines in the pathogenesis of acute dengue infection.…”