Disabling poxvirus pathogenesis by inhibition of Ab1-family tyrosine kinases (Nature Medicine, 11:731-739 , July 2005)

報告日期: 2005/09/20
報告時間: 17:10/18:00
報告學生: 張曉娟
講評老師: 陳舜華
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Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases

Nature Medicine 11:732-739, 2005

SpeakerChang, Hsaio-Chuan                    Time2005/09/20 17:10~18:00

CommentatorChen, Shun-Hua                                          Room602

Abstract

Smallpox, a dreaded disease with a fatality rate of 30 percent, caused by variola virus, was declared eliminated in 1979 after the vaccinating agent for variola virus was based on the related vaccinia virus.  Vaccinia virus and variola virus which belong to the Poxviridae family, replicate in the cytoplasm of infected mammalian cells.  In the virus life cycle, vaccinia virus could produce four different types of virions called intracellular mature virus (IMV), intracellular envelope virus (IEV), cell-associated enveloped virus (CEV), and extracellular envelope virus (EEV).  For dissemination between hosts, IMV is more suited than others because it is robust, stable and the most abundant form of virus at ambient temperature and desiccation.  Additionally, CEV either detach directly, or induce the formation of actin tails that drive CEV particle away from the cell on an actin-filled membrane protuberance and then detach; once detached, CEV form EEV.  CEV/EEV is important for cell-to-cell spread and the long-range dissemination of virus.  Previous reports suggest that the mammalian tyrosine kinase c-Src localizes to the phosporylated protein A36R1 of vaccinia virus that located in the IEV membrane and related to actin polymerization2 and virulence3.  In this paper, the authors verify that the Src- and Abl-family kinases co-localize to actin tail and virus virion.  They also infect cells lacking Src- and Abl-family kinases and the distribution of extranuclear replication centers, actin, and tyrosine kinases indicate that these tyrosine kinases influence the actin motility.  Moreover, they treat the inhibitors of those tyrosine kinases, such as PD-166326, PP2 and STI-571 to the above-mentioned cells to limit the release of infectious EEV.  Ultimately, the raise of mice survival rate and the reduction of virus genome number in vaccinia-infected mouse model indicate that the potential therapeutic apply to the inhibitor to treat a poxvirus infection in humans.

Reference

1. Frischknecht, F. et al. Nature 401:926–929 (1999).

2 Wolffe, E.J., Weisberg, A.S. & Moss, B. Virology 244:20–26 (1998).

3 Parkinson, J.E. & Smith, G.L. Virology 204:376–390 (1994).