Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases

Nature Medicine 11:732-739, 2005

Speaker：黃淑真                  Time：13:10~14:00; 2005/10/05

Commentator：陳舜華 老師         Room : 601

Abstract：

    Variola, a lethal virus in Poxviridae family, causes smallpox. Vaccinia, another  Poxviridae family member, serves as a vaccine for smallpox. In 1980, the World Health Organization declared that smallpox was eliminated as a result of successful vaccination campaigns. However, some individuals have not immunity against smallpox, because smallpox vaccine was ended in 1972 as well as the vaccination may produce serious side effect in immunosuppressed individuals¹, raising the possibility of outbreak again. It has been reposted when pox virons entry into the mammalian cell and replicate in juxtanuclear replication centers, cell-associated enveloped virus (CEV) releases from the cell directly or with the help of actin tails to form extracellular enveloped virus (EEV). Moreover, the mammalian tyrosine kinase c-Src was localized to virions and could posphorylate A36R, a vaccinia protein required for actin polymerization.² The authors demonstrate that actin motility requires Abl- and Src-family tyrosine kineses by using PD-166326 to inhibit actin motility and STI-571 (Gleevec), an inhibitor of Abl-family kinase, to block the release of infectious EEV³. All of the inhibitors could limit the spread of infection and increase the survival of vaccinia-infected mice. The results provide a more potent therapy against microbial infections which rely on host tyrosine kinases, and this therapeutic approach causes much less resistance comparing to conventional antimicrobial therapies.

References:

1. Amorosa, V.K. & Isaacs, S.N. Separate worlds set to collide: smallpox, vaccinia virus vaccination, and human immunodeficiency virus and acquired immunodeficiency syndrome. Clin. Infect. Dis. 37, 426−432 (2003).

2. Frischknecht, F. et al. Actin-based motility of vaccinia virus mimics receptor tyrosine kinase signalling. Nature 401, 926−929 (1999). 

3. Reeves, P.M. et al. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat. Med. 11, 731−739 (2005).