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Nonlytic viral spread enhanced by autophagy components.

Sara Whitney Bird1, Nathaniel D Maynard2, Markus W Covert2

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Proceedings of the National Academy of Sciences of the United States of America
|August 27, 2014
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Autophagy pathway components enable nonlytic cell-to-cell spread of poliovirus, bypassing cell lysis. Stimulating autophagy accelerates viral spread and increases pathogenicity, suggesting this mechanism is vital for viral pathogenesis.

Keywords:
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Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Cell-to-cell spread of cytoplasmic components, including viruses, typically requires cell lysis.
  • Unconventional secretion pathways can mediate extracellular delivery of cytoplasmic molecules, bypassing the classical secretory pathway.
  • Autophagy pathway components are implicated in the unconventional secretion of cytoplasmic signaling proteins.

Purpose of the Study:

  • To demonstrate nonlytic cell-to-cell spread of poliovirus, distinguishing it from lysis-dependent release.
  • To investigate the role of the autophagy pathway in mediating this nonlytic intercellular viral transfer.
  • To assess the impact of autophagy modulation on poliovirus spread and pathogenicity.

Main Methods:

  • Quantitative time-lapse microscopy to observe viral spread in real-time without lysis.
  • siRNA-mediated depletion of autophagy protein LC3 to assess its role in viral transfer.
  • Pharmacological stimulation of the autophagy pathway to evaluate its effect on viral spread and pathogenicity in vivo.

Main Results:

  • Demonstrated infectious cytoplasmic material spread between cells in the absence of detectable cell lysis.
  • siRNA depletion of LC3 significantly reduced nonlytic intercellular viral transfer.
  • Autophagy pathway stimulation led to accelerated viral spread in tissue culture and increased pathogenicity in mouse models.

Conclusions:

  • Components of the autophagy pathway are essential for the unconventional secretion of infectious poliovirus in the absence of cell lysis.
  • This nonlytic intercellular spread mechanism, mediated by autophagy, is likely utilized by other nonenveloped viruses for pathogenesis.
  • Autophagy modulation represents a potential target for controlling viral spread and disease progression.