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AAV exploits subcellular stress associated with inflammation, endoplasmic reticulum expansion, and misfolded proteins in models of cystic fibrosis

  • 0Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America. rjs@med.unc.edu
Plos Pathogens +

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June 1, 2011

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June 1, 2011

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View abstract on PubMed

Summary

This summary is machine-generated.

Cellular stress, particularly from misfolded proteins like those in cystic fibrosis (CF), enhances adeno-associated virus (AAV) infection by exploiting the secretory pathway. This highlights how a stressed cellular environment impacts viral susceptibility.

Area Of Science

  • Virology
  • Cell Biology
  • Genetics

Background

  • Cellular barriers normally prevent viral infections.
  • Cellular stress, including inflammation and misfolded proteins, may compromise these barriers.
  • Cystic Fibrosis (CF) is characterized by misfolded proteins, particularly ΔF508-CFTR.

Purpose Of The Study

  • To investigate if subcellular stress increases susceptibility to adeno-associated virus (AAV) infection using cystic fibrosis (CF) models.
  • To determine if misfolded proteins independently enhance AAV infection efficiency.

Main Methods

  • Human airway epithelium cultured at an air/liquid interface was exposed to CF lung supernatant to mimic stress.
  • Adeno-associated virus (AAV) infection efficiency was compared in cells expressing wild-type CFTR versus CFTR mutants (ΔF508-CFTR, G551D, D572N, 1410X).
  • Viral attachment and transgene expression were assessed; AAV trafficking and interactions with secretory pathway proteins were analyzed using siRNA knockdown.

Main Results

  • Inflammatory stimulus from CF lungs significantly enhanced AAV infection.
  • Cells expressing ΔF508-CFTR showed an order of magnitude higher AAV transduction efficiency compared to wild-type CFTR cells.
  • Misfolded proteins, not loss of CFTR activity, increased susceptibility; AAV exploited the secretory pathway, trafficking to the microtubule organizing center and interacting with ER/Golgi proteins.

Conclusions

  • A stressed subcellular environment, exemplified by misfolded proteins in CF, increases susceptibility to AAV infection.
  • Adeno-associated virus (AAV) exploits a compromised secretory system for efficient infection.
  • The findings underscore the significant impact of cellular stress on viral infection efficiency.

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