Activation of TLR2 and TLR6 by Dengue NS1 Protein and Its Implications in the Immunopathogenesis of Dengue Virus Infection

Jincheng Chen, Mary Mah-Lee Ng, Justin Jang Hann Chu

PLOS Pathogens. (2015)

Speaker: Po-Chun Chang (張博淳)              Time: 14:00~15:00 Dec 16, 2015

Commentator: Dr. Chia-Yi Yu (余佳益 老師)     Place: Room 601

Abstract:

        Dengue virus (DENV) is an arbovirus belonging to the family Flavivridae. It is a positive-sense single-stranded RNA virus and has envelope. When people infected by DENV develops symptoms like dengue fever or more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) which may lead to the death of patient. Accumulated studies indicate that patient’s immune system responses intricately are involved in occurrence of DHF or DSS [1]. Therefore, understanding of DENV immuonpathogenesis may help to find out the way to save patients’ lives in clinical. A previous study by the same team has shown that several genes involved in the toll-liked receptor (TLR) pathway including TLR6 were up-regulated during DENV infection in K562 cells [2]. TLR is one of pattern recognition receptors (PRR) which plays a key role in immune surveillance. In this study, authors want to investigate the role of TLR2 and TLR6 in dengue virus infection. At first, they used flow cytometry to find that TLR2 and TLR6 expression were up-regulated in DENV-infected human PBMC. They also found that IL-6 and TNF-a expression were significantly increased. They further used blocking antibody to confirm that the increase of cytokine production was via activation of TLR2 and TLR6. In addition, these responses were found to be signaled more than one day of post-infection. This indicates that viral replication is required. Further they found that compared to other DENV protein, nonstructural protein 1 (NS1) could induce significant expression of IL-6 and TNF-α. Responses of treatment by recombinant NS1 protein were similar to infection by DENV via TLR2 and TLR6. Authors used TLR6 knockout (TLR6^-/-) C57BL/6 mice to confirm the findings. They found that compared to wild-type mice, TLR6 knockout mice showed increase of survivability to DENV. Responses of murine peritioneal macrophage were similar as DENV-infected human PBMCs or NS1 protein treatment. According to these findings, authors concluded that DENV infects cells and replicates to up-regulate expression of TLR2 and TLR6. NS1 protein activates TLR2 and TLR6 to induce expression of IL-6 and TNF-a. These pro-inflammatory cytokines might be one of conditions to develop DHF. Regulating these conditions could possibly be one of the targets to get relieved from DHF and also reduce these responses to save lives.

References:

1.         Vaughn, D. W. et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. The Journal of infectious diseases 181, 2-9 (2000).

2.         Chen, J., Ng, M. M. & Chu, J. J. Molecular profiling of T-helper immune genes during dengue virus infection. Virology journal 5, 165 (2008).