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.

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

“…Imatinib has been shown to reduce vaccinia virus replication. 31 In contrast, LCMV titers in the spleen 4 days after infection were comparable in imatinib-treated and nontreated mice. In addition, imatinib did not impair LCMV replication in vitro in MC57-infected cells (S.M., unpublished results, August 2005).…”

Rho’ing in and out of cells

“…140,141 These CEV sit on the cell surface and induce an outside-in signaling cascade initiated by the viral B5 protein to locally activate Src and Abl family kinases, resulting in tyrosine phosphorylation of the viral integral membrane protein A36. [142][143][144][145][146][147][148] A36 phosphorylation triggers the recruitment of a signaling complex consisting of Grb2, Nck, WASP-interacting protein (WIP), N-WASP and Cdc42, a process that was recently shown to also depend on recruitment of clathrin. 144,[149][150][151][152][153][154][155][156][157] This signaling complex stimulates the actin-nucleating activity of the Arp2/3 complex, resulting in actin polymerization-driven propulsion of virus CEV particles to neighboring cells, thereby enhancing cell-to-cell spread of the virus (Fig.…”

Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules

“…Despite this success, there are looming concerns about its reemergence owing to the possible usage of variola virus as a bioterrorism agent, because a large percentage of the current human population is susceptible to smallpox (2). Thus, there is a need to further define the factors that influence variola virus virulence, pathogenesis, and control (3,4).…”