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Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases

Patrick M Reeves1, Bettina Bommarius, Sarah Lebeis

  • 1Microbiology and Molecular Genetics Graduate Program, Emory University School of Medicine, 615 Michael Street, Whitehead Research Building #144, Atlanta, Georgia 30322, USA.

Nature Medicine
|June 28, 2005
PubMed

Insights

The drug Gleevec (STI-571) inhibits Abl-family kinases, crucial for poxvirus (Poxviridae) cell-to-cell spread. This discovery suggests Gleevec could treat smallpox and other viral infections by blocking viral dissemination.

Area of Science:

  • Virology
  • Cell Biology
  • Pharmacology

Background:

  • Poxviridae, including vaccinia and variola viruses, infect mammalian cells, replicating extranuclearly.
  • Virions egress from infected cells via actin-filled protrusions, utilizing host cell machinery for dissemination.

Purpose of the Study:

  • To investigate the role of Abl- and Src-family tyrosine kinases in poxvirus cell-associated enveloped virion (CEV) motility and release.
  • To evaluate the therapeutic potential of the Abl-family kinase inhibitor STI-571 (Gleevec) against poxvirus infections.

Main Methods:

  • Utilized cell-based assays to study CEV motility and release mechanisms.
  • Administered STI-571 to infected mice to assess its effect on viral dissemination and survival.

Main Results:

  • Abl- and Src-family tyrosine kinases are essential for CEV actin motility, acting redundantly.
  • CEV release from cells requires Abl-family kinases and is inhibited by STI-571.
  • STI-571 significantly reduced viral dissemination and improved survival rates in infected mice.

Conclusions:

  • Host Abl-family tyrosine kinases are critical targets for inhibiting poxvirus spread.
  • STI-571 demonstrates therapeutic potential for treating smallpox and potentially other microbial infections reliant on host kinases.
  • Targeting host kinases offers a strategy less prone to resistance development compared to conventional antimicrobial therapies.

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