Mouse STAT2 Restricts Early Dengue Virus Replication

Joseph Ashour, et al. 2010 Cell Host & Microbe 8:410–21

Speaker: Wan-Shan Chou (周琬軒)                             Time: 15:10~16:00, March 16, 2011

Commentator: Dr. Hsiao-Sheng Liu (劉校生 教授)   Place: Room 601

Abstract:

Based on WHO reports, dengue virus (DENV) infection causes about 50 to 100 million cases every year (1). However, no vaccine or effective antiviral drug is currently available. One of the primary obstacles on vaccine and drug development is the lack of robust animal model to test their efficacy. Mouse is highly resistant to the DENV infection. This resistance makes it difficult to develop mouse model for DENV infection. Previous studies indicated that type I interferon (IFN) plays a critical role in the resistance to DENV infection. Only STAT1 and STAT2 in STAT family are required for type I IFN signaling. Reports showed that STAT2 is a frequent target for degradation by viral protein. DENV NS5 is one of the viral proteins that binds to STAT2 protein and targets it for degradation (2). In the present study, the authors found that DENV NS5-mediated STAT2 degradation only occurred on human STAT2 (hSTAT2) but not on mouse STAT2 (mSTAT2) in both human and mouse cells. It suggests that NS5-mediated STAT2 degradation is species-specific, and such degradation does not require other host factors. The authors also found that NS5 recognizes the N-terminal region of hSTAT2 and associates with it, but there is still additional STAT2 specific sequence required for NS5 to mediate hSTAT2 degradation. Results demonstrated that mSTAT2 expression could inhibit virus production through an IFN-dependent manner both in human and mouse cells. Using STAT2 knockout mice, the authors proved that mSTAT2 is crucial for mouse to control DENV replication at the early stage both in vivo and in vitro. Taken together, this study demonstrates that mSTAT2 restricts early DENV replication in vivo. This restrictioncauses mouse resistant to DENV infection. It suggests that using the transgenic mouse technology could overcome this restriction, and it may help in the development of an immune-competent mouse model for DENV infection.

References:

1.      Deen, J. L., et al. 2006. The WHO dengue classification and case definitions: time for a reassessment. Lancet 368:170-3.

2.      Ashour, J., et al. 2009. NS5 of dengue virus mediates STAT2 binding and degradation. J. Virol. 83, 5408–18.