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Coinfecting prion strains compete for a limiting cellular resource

Ronald A Shikiya1, Jacob I Ayers, Charles R Schutt

  • 1Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.

Journal of Virology
|March 19, 2010
PubMed

Insights

Prion strain interference, where one prion strain blocks another, occurs because prions compete for cellular resources, not due to damage. Protein misfolding cyclic amplification (PMCA) models this competition, showing strain interference is influenced by agent ratios.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Infectious Diseases

Background:

  • Prion strain interference influences disease progression but its mechanisms remain unclear.
  • Transmissible mink encephalopathy (TME) strains, drowsy (DY) and hyper (HY), provide a model to study this interference.
  • Previous studies suggest interference is linked to agent interactions within the host.

Purpose of the Study:

  • To elucidate the mechanisms of prion strain interference.
  • To investigate the role of PrP(Sc) deposition and cellular resource competition in blocking HY TME infection by DY TME.
  • To validate findings using protein misfolding cyclic amplification (PMCA).

Main Methods:

  • Inoculation of sciatic nerve with DY TME followed by HY TME in a mouse model.
  • Analysis of PrP(Sc) deposition in the central nervous system.
  • Application of PMCA to model prion strain interference in vitro.
  • Quantification of DY:HY TME ratios in PMCA and infected animals.

Main Results:

  • DY TME inoculation blocked HY TME disease without causing neuronal damage, indicating competition for cellular resources.
  • PMCA successfully replicated infectious agent and maintained strain-specific PrP(Sc) properties.
  • DY TME interfered with HY TME emergence in PMCA, with blockage dependent on the DY:HY ratio.
  • HY PrP(Sc) was detected in animals where DY TME blocked HY TME disease, suggesting HY TME persistence.

Conclusions:

  • Prion strain interference is mediated by competition for cellular resources, such as PrP(C), rather than agent-induced damage.
  • PMCA is a viable method for studying prion strain interference and the dynamics of prion conversion.
  • The ratio of competing prion strains is critical for determining the outcome of interference, with potential for subclinical persistence of the blocked strain.

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