Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases Journal Article
| Authors: | Reeves, P. M.; Bommarius, B.; Lebeis, S.; McNulty, S.; Christensen, J.; Swimm, A.; Chahroudi, A.; Chavan, R.; Feinberg, M. B.; Veach, D.; Bornmann, W.; Sherman, M.; Kalman, D. |
| Article Title: | Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases |
| Abstract: | 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. |
| Keywords: | controlled study; survival rate; drug efficacy; nonhuman; pyridines; protein function; animal cell; mouse; mammalia; animals; mice; cells, cultured; imatinib; enzyme inhibition; animal experiment; animal model; mice, mutant strains; in vivo study; drug effect; abelson kinase; protein tyrosine kinase; chronic myeloid leukemia; pyrimidines; mice, inbred c57bl; animalia; protein kinase inhibitors; vaccinia virus; piperazines; actins; src-family kinases; cell motility; poxvirus; poxviridae; vaccinia; virus attenuation; variola virus; smallpox; virion; virus cell interaction; actin filament; proto-oncogene proteins c-abl; smallpox virus; poxvirus infection; poxviridae infections |
| Journal Title: | Nature Medicine |
| Volume: | 11 |
| Issue: | 7 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2005-07-01 |
| Start Page: | 731 |
| End Page: | 739 |
| Language: | English |
| DOI: | 10.1038/nm1265 |
| PUBMED: | 15980865 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 103" - "Export Date: 24 October 2012" - "CODEN: NAMEF" - "Source: Scopus" |
