Nature Medicine 11, 731 - 739 (2005)
Published online: 26 June 2005; | doi:10.1038/nm1265
There is a Corrigendum (December 2005) associated with this Article.
Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinasesPatrick M Reeves1, 2, Bettina Bommarius2, Sarah Lebeis1, 2, Shannon McNulty1, 2, Jens Christensen3, Alyson Swimm2, Ann Chahroudi4, Rahul Chavan4, Mark B Feinberg4, Darren Veach5, William Bornmann6, Melanie Sherman2 & Daniel Kalman21
Microbiology and Molecular Genetics Graduate Program, Emory University School of Medicine, 615 Michael Street, Whitehead Research Building #144, Atlanta, Georgia
30322, USA. 2
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Whitehead Research Building #144, Atlanta, Georgia
30322, USA. 3
Institute of Public Health, NANEA at Department of Epidemiology, University of Aarhus, Vennelyst Boulevard 6, DK-8000
Aarhus C, Denmark. 4
The Emory Vaccine Center, Emory University School of Medicine, 954 Gatewood Road NE, Atlanta, Georgia
30322, USA. 5
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York
10021, USA. 6
Organic Chemistry Section, M.D. Anderson Cancer Center, University of Texas, Unit 603, P.O. Box 301402, Houston, Texas
77030-1402, USA.
Correspondence should be addressed to Daniel Kalman dkalman@emory.edu The Poxviridae family members vaccinia and variola virus enter mammalian cells, replicate outside the nucleus and produce virions that travel to the cell surface along microtubules, fuse with the plasma membrane and egress from infected cells toward apposing cells on actin-filled membranous protrusions. We show that cell-associated enveloped virions (CEV) use Abl- and Src-family tyrosine kinases for actin motility, and that these kinases act in a redundant fashion, perhaps permitting motility in a greater range of cell types. Additionally, release of CEV from the cell requires Abl- but not Src-family tyrosine kinases, and is blocked by STI-571 (Gleevec), an Abl-family kinase inhibitor used to treat chronic myelogenous leukemia in humans. Finally, we show that STI-571 reduces viral dissemination by five orders of magnitude and promotes survival in infected mice, suggesting possible use for this drug in treating smallpox or complications associated with vaccination. This therapeutic approach may prove generally efficacious in treating microbial infections that rely on host tyrosine kinases, and, because the drug targets host but not viral molecules, this strategy is much less likely to engender resistance compared to conventional antimicrobial therapies.
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