Reeves Patrick M, Bommarius Bettina, Lebeis Sarah, McNulty Shannon, Christensen Jens, Swimm Alyson, Chahroudi Ann, Chavan Rahul, Feinberg Mark B, Veach Darren, Bornmann William, Sherman Melanie, Kalman Daniel
Microbiology and Molecular Genetics Graduate Program, Emory University School of Medicine, 615 Michael Street, Whitehead Research Building #144, Atlanta, Georgia 30322, USA.
Nat Med. 2005 Jul;11(7):731-9. doi: 10.1038/nm1265. Epub 2005 Jun 26.
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.
痘病毒科成员痘苗病毒和天花病毒进入哺乳动物细胞，在细胞核外复制，并产生沿着微管移动到细胞表面的病毒粒子，与质膜融合并从感染细胞释放到充满肌动蛋白的膜状突起上的相邻细胞。我们发现细胞相关包膜病毒粒子（CEV）利用Abl和Src家族酪氨酸激酶进行肌动蛋白运动，并且这些激酶以冗余方式起作用，这可能使更多类型的细胞能够进行运动。此外，CEV从细胞中释放需要Abl家族酪氨酸激酶而不是Src家族酪氨酸激酶，并且被用于治疗人类慢性粒细胞白血病的Abl家族激酶抑制剂STI-571（格列卫）所阻断。最后，我们表明STI-571将病毒传播减少了五个数量级，并提高了感染小鼠的存活率，这表明该药物可能用于治疗天花或与疫苗接种相关的并发症。这种治疗方法可能被证明在治疗依赖宿主酪氨酸激酶的微生物感染方面普遍有效，并且由于该药物靶向宿主而非病毒分子，与传统抗菌疗法相比，这种策略产生耐药性的可能性要小得多。
