Abstract
Dengue virus (DV) infection is the most prevalent mosquito-borne viral disease and its manifestation has been shown to be contributed in part by the host immune responses. In this study, pathogen recognition receptors, Toll-like receptor (TLR) 2 and TLR6 were found to be up-regulated in DV-infected human PBMC using immunofluorescence staining, flow cytometry and Western blot analyses. Using ELISA, IL-6 and TNF-α, cytokines downstream of TLR2 and TLR6 signaling pathways were also found to be up-regulated in DV-infected PBMC. IL-6 and TNF-α production by PBMC were reduced when TLR2 and TLR6 were blocked using TLR2 and TLR6 neutralizing antibodies during DV infection. These results suggested that signaling pathways of TLR2 and TLR6 were activated during DV infection and its activation contributed to IL-6 and TNF-α production. DV NS1 protein was found to significantly increase the production of IL-6 and TNF-α when added to PBMC. The amount of IL-6 and TNF-α stimulated by DV NS1 protein was reduced when TLR2 and TLR6 were blocked, suggesting that DV NS1 protein is the viral protein responsible for the activation of TLR2 and TLR6 during DV infection. Secreted alkaline phosphatase (SEAP) reporter assay was used to further confirm activation of TLR2 and TLR6 by DV NS1 protein. In addition, DV-infected and DV NS1 protein-treated TLR6-/- mice have higher survivability compared to DV-infected and DV NS1 protein-treated wild-type mice. Hence, activation of TLR6 via DV NS1 protein could potentially play an important role in the immunopathogenesis of DV infection.
Highlights
Dengue virus (DV) is a member of the Flavivirus genus of the Flaviviridae family
IL-6 and TNF-α production by peripheral blood mononuclear cells (PBMC) were reduced when TLR2 and TLR6 were blocked using TLR2 and TLR6 neutralizing antibodies during DV infection. These results suggested that signaling pathways of TLR2 and TLR6 were activated during DV infection and its activation contributed to IL-6 and TNF-α production
We found that dengue NS1 protein activates TLR2 and TLR6, leading to increase proinflammatory cytokine production
Summary
Dengue virus (DV) is a member of the Flavivirus genus of the Flaviviridae family. Dengue virus is a positive-sense, single-stranded RNA virus and it has four distinct serotypes (DV1 to 4). Dengue virus genome encodes for a single polyprotein that consists of 3 structural proteins (capsid, premembrane and envelope) that form the physical structure of the virus particle and 7 non-structural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5) which are necessary for the replication of the virus. Dengue is a mosquito-borne viral disease transmitted through a human-to-mosquito-tohuman transmission cycle typically by the Aedes mosquitoes: Aedes aegypti and Aedes albopictus. DV infection remains the most prevalent mosquito-borne viral disease and the geographical regions at risk are continually growing due to globalisation and climate change [6]. It is estimated that 100 million cases of dengue infection occur worldwide each year with 2.5 billion people at risk [7,8,9]. No effective treatment and vaccine are available for DV infection
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