Coinfecting prion strains compete for a limiting cellular resource.
Prion strain interference can influence the emergence of a dominant strain from a mixture; however, the mechanisms underlying prion strain interference are poorly understood. In our model of strain interference, inoculation of the sciatic nerve with the drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent prior to superinfection with the hyper (HY) strain of TME can completely block HY TME from causing disease. We show here that the deposition of PrP(Sc), in the absence of neuronal loss or spongiform change, in the central nervous system corresponds with the ability of DY TME to block HY TME infection. This suggests that DY TME agent-induced damage is not responsible for strain interference but rather prions compete for a cellular resource. We show that protein misfolding cyclic amplification (PMCA) of DY and HY TME maintains the strain-specific properties of PrP(Sc) and replicates infectious agent and that DY TME can interfere, or completely block, the emergence of HY TME. DY PrP(Sc) does not convert all of the available PrP(C) to PrP(Sc) in PMCA, suggesting the mechanism of prion strain interference is due to the sequestering of PrP(C) and/or other cellular components required for prion conversion. The emergence of HY TME in PMCA was controlled by the initial ratio of the TME agents. A higher ratio of DY to HY TME agent is required for complete blockage of HY TME in PMCA compared to several previous in vivo studies, suggesting that HY TME persists in animals coinfected with the two strains. This was confirmed by PMCA detection of HY PrP(Sc) in animals where DY TME had completely blocked HY TME from causing disease.
Shikiya
Ronald A
RA
Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
Ayers
Jacob I
JI
Schutt
Charles R
CR
Kincaid
Anthony E
AE
Bartz
Jason C
JC
D000818:Animals; D006224:Cricetinae; D008907:Mink; D018620:PrPSc Proteins / Q000472:pathogenicity; D017096:Prion Diseases / Q000635:transmission*; D011328:Prions / Q000008:administration & dosage / Q000472:pathogenicity*; D017510:Protein Folding; D012584:Sciatic Nerve / Q000473:pathology; D013045:Species Specificity
D018620:PrPSc Proteins; D011328:Prions