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Appraising the apoptotic mimicry model and the role of phospholipids for poxvirus entry

Jason P Laliberte1, Bernard Moss

  • 1Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3210, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 7, 2009
PubMed

Insights

Phosphatidylserine (PS) aids vaccinia virus (VACV) entry into cells, but other phospholipids can also facilitate infection. Virus entry involves macropinocytosis and a low-pH pathway, independent of apoptotic mimicry.

Area of Science:

  • Virology
  • Cell Biology
  • Biochemistry

Background:

  • Vaccinia virus (VACV) enters cells via membrane fusion or a pH-dependent endosomal pathway.
  • VACV virions contain phospholipids, including phosphatidylserine (PS), leading to a model of apoptotic mimicry for cell entry.
  • The exact mechanism and cellular receptors involved in VACV entry remain largely unidentified.

Purpose of the Study:

  • To evaluate the apoptotic mimicry model for VACV entry.
  • To investigate the role of phosphatidylserine (PS) and other phospholipids in VACV cell entry.
  • To identify the cellular uptake pathways utilized by VACV.

Main Methods:

  • Detergent-extracted VACV virions were reconstituted with various phospholipids, including different stereoisomers of PS and phosphatidylglycerol.
  • Infectivity and cell entry of reconstituted virions were assessed.
  • Inhibition studies were performed using a neutralizing monoclonal antibody against a virion surface protein and drugs like blebbistatin and bafilomycin A1.
  • Virus-cell binding assays were conducted.

Main Results:

  • The L-stereoisomer of PS reconstituted VACV infectivity, as did the non-biologically relevant D-stereoisomer of PS and phosphatidylglycerol.
  • Virus entry, regardless of the phospholipid used for reconstitution, was inhibited by a neutralizing antibody and specific drugs, indicating a common, specific uptake mechanism.
  • This mechanism involves macropinocytosis and a low-pH endocytic pathway.
  • While lipid-reconstituted and non-reconstituted virions bound equally to cells, phospholipid association correlated with restored infectivity.
  • Other phospholipids, not typically associated with apoptotic debris signaling, could also mediate virus entry.

Conclusions:

  • Phosphatidylserine (PS) plays a role in poxvirus entry, but it is not the sole phospholipid capable of mediating this process.
  • VACV entry is not strictly dependent on apoptotic mimicry, as other phospholipids can facilitate entry via similar pathways.
  • The findings suggest a conserved mechanism of VACV entry involving macropinocytosis and low-pH-dependent endocytosis, irrespective of the specific phospholipid mediating initial interaction.

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