Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases.
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.
Microbiology and Molecular Genetics Graduate Program, Emory University School of Medicine, 615 Michael Street, Whitehead Research Building #144, Atlanta, Georgia 30322, USA.
Patrick M
PM
Reeves
Bettina
B
Bommarius
Sarah
S
Lebeis
Shannon
S
McNulty
Jens
J
Christensen
Alyson
A
Swimm
Ann
A
Chahroudi
Rahul
R
Chavan
Mark B
MB
Feinberg
Darren
D
Veach
William
W
Bornmann
Melanie
M
Sherman
Daniel
D
Kalman
D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001549:Benzamides; D002478:Cells, Cultured; D005260:Female; D000068877:Imatinib Mesylate; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010879:Piperazines / Q000494:pharmacology*; D011212:Poxviridae / Q000187:drug effects / Q000472:pathogenicity*; D011213:Poxviridae Infections / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D015996:Survival Rate; D014615:Vaccinia / Q000188:drug therapy / Q000401:mortality; D014616:Vaccinia virus / Q000378:metabolism; D014771:Virion / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000199:Actins; D001549:Benzamides; C473352:PD 166326; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases