Suppression of Virus Specific Immune Responses by IL-10 in Acute Dengue Infection

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Abstract
Elevated IL-10 has been shown to be associated with severe dengue infection (DI). We proceeded to investigate the role of IL-10 in the pathogenesis of acute DI. Ex vivo and cultured IFNγ ELISpot assays for dengue virus (DENV) NS3 protein and non dengue viral proteins were carried out in 26 patients with acute DI (16 with dengue haemorrhagic fever) and 12 healthy dengue seropositive individuals from Sri Lanka. DENV serotype specific (SS) responses were determined by using a panel of SS peptides. Serum IL-10 level were significantly higher (p = 0.02) in those who did not have in vitro responses to DENV-SS peptides (mean 144.2 pg/ml) when compared to those who responded (mean 75.7 pg/ml). DENV-NS3 specific ex vivo IFNγ ELISpot responses were also significantly lower (p = 0.0001) in those who did not respond to DENV-SS peptides (mean 42 SFU/million PBMCs) when compared to those who responded to DENV-SS peptides (mean 1024 SFU/million PBMCs). Serum IL-10 levels correlated significantly (p = 0.03) and inversely (Spearmans R = −0.45) with ex vivo DENV-NS3 specific responses but not with ex vivo non DENV specific responses (Spearmans R = −014, p = 0.52). Blockage of IL-10 in vitro significantly increased (p = 0.04) the ex vivo IFNγ ELISpot DENV-NS3 specific responses but had no effect on responses to non DENV proteins. IL-10 appears to contribute to the pathogenesis of acute dengue infections by inhibiting DENV-specific T cell responses, which can be restored by blocking IL-10. Dengue viral infections have become one of the most important mosquito borne viral infections in the world and are one of the major emerging infectious diseases. The occurrence of dengue haemorrhagic fever is thought to result from a complex interplay between the virus, host genetics and host immune factors. Patients with more severe clinical disease have been shown to have higher serum IL-10 levels and IL-10 has also been shown to be associated with poorer disease outcome in other viral infections. Therefore, in this study, we proceeded to investigate the role of IL-10 in the pathogenesis of dengue infections and its effect on DENV-specific T cells. We found that both DENV- serotype-specific (SS) specific T cell responses and DENV-NS3 specific responses were impaired in patients with higher serum IL-10 levels. Serum IL-10 levels did not appear to have any effect on non dengue viral protein specific responses. IL-10 blockade significantly increased IFNγ production, in response to DENV-NS3 peptides but not to non dengue viral proteins in acute dengue infection. Therefore, our results suggest that IL-10 could be contributing to disease pathogenesis by inhibiting DENV-specific T cell responses.

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