Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases

  • A Corrigendum to this article was published on 01 December 2005


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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Figure 1: Abl- and Src-family tyrosine kinases localize in vaccinia actin tails.
Figure 2: Vaccinia actin motility persists in cell lines lacking Abl- and Src-family kinases.
Figure 3: Redundant Abl- and Src-family tyrosine kinases are sufficient for vaccinia actin tail formation.
Figure 4: Redundant Abl- and Src-family tyrosine kinases are required for cell-to-cell spread.
Figure 5: Redundant Abl-family kinases are required for EEV release.
Figure 6: STI-571 reduces number of viral genomes and promotes survival in vaccinia-infected mice.


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The authors thank D. Kalman, D. Steinhauer, O. Weiner, J. Taunton and K. Saxe for discussions; A. Family, S. Staprans, N. Kozyr and R. Griffith for assistance and advice; B. Meyer and J. Wang for Abl cDNAs; T. Koleske for Abl1−/−Abl2−/− cells, Abl1 and Abl2 cells, and c-Arg-YFP cDNA; B. Moss and J. Yudell for α-TW2.3 mAb; R. Blasco for GFP-VV; C. Lowell for Src−/− cells, Src−/−Fyn−/− cells, and Src−/−Yes1−/− cells; G. Smith for α-IMV mAb; and L. Burleigh, D. Steinhauer, and C. Moran for commenting on the manuscript. The work was supported by US National Institutes of Health grant PO1 AI 46007 (to M.B.F.), and by grants from the University Research Council, Emory University, the Southeastern Regional Center for Excellence in Bioterrorism (SERCEB) Pilot Project Feasibility Award, grant R01-AI056067-01 from the N.I.A.I.D., and an award from the Emtech Biotechnology Foundation (all to D.K.).

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Correspondence to Daniel Kalman.

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Supplementary information

Supplementary Fig. 1

Protein sequences surrounding phosphorylation sites in VV A36R and enteropathogenic E. coli Tir. (PDF 53 kb)

Supplementary Fig. 2

Identification of VV-infected cells. (PDF 352 kb)

Supplementary Fig. 3

Effects of PD-166326 and STI-571. (PDF 339 kb)

Supplementary Fig. 4

Characterization of kinases sufficient for VV actin motility. (PDF 166 kb)

Supplementary Fig. 5

Abl-family kinases do not affect viral entry or replication. (PDF 356 kb)

Supplementary Fig. 6

Distinguishing the effects of Abl and Arg on EEV and IMV. (PDF 62 kb)

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