Delay in onset of prion disease for the HY strain of transmissible mink encephalopathy as a result of prior peripheral inoculation with the replication-deficient DY strain

Abstract

We report that the replication-deficient DY strain of transmissible mink encephalopathy (TME) can delay disease caused by the pathogenic HY TME strain. In this study, competition between the HY and DY TME agents was investigated following superinfection of the sciatic nerve and peritoneal cavity. Initially, DY TME infection was examined in the absence of superinfection and it was found that inoculation into the brain and sciatic nerve resulted in prion disease and PrP Sc deposition in brain but not lymphoreticular tissues. Conversely, intraperitoneal inoculation of the DY TME agent did not result in clinical symptoms, DY TME agent replication or PrP Sc deposition 400-600 days after infection. These findings indicate that the DY TME agent does not replicate in secondary lymphoid organs and is non-pathogenic when neuroinvasion is dependent on prior infection of the lymphoreticular system. However, intraperitoneal inoculation of the DY TME agent at 60 days, but not at 30 days, prior to intraperitoneal inoculation of the HY TME agent resulted in an extension of the HY TME incubation period. Inoculation of the DY TME agent into the sciatic nerve at 60 days prior to intrasciatic nerve inoculation of the HY TME agent did not delay the incubation period of HY TME. The ability of the DY TME agent to delay HY TME infection following extraneural inoculation, but not neural infection, suggests that HY and DY TME agent competition can occur in a common replication site whose cellular location precedes infection of both the lymphoreticular and peripheral nervous systems.

Prion interference with multiple prion isolates

“…A 60 or 90 day interval between DY TME agent infection and HY TME agent superinfection resulted in all of the animals developing clinical signs of HY TME with Per os prion strain interference www.landesbioscience.com Prionnodes, which is the major site of extraneural HY TME agent replication. 11,21,26 The DY TME agent can interfere with the HY TME agent following intraperitoneal and per os infection, suggesting that the DY TME agent is replicating in other locations that are involved in HY TME agent neuroinvasion (Table 2). 11 Table 2 Clinical signs and incubation periods of hamsters per os inoculated with either the HY TME or DY TME agent, or per os co-infected with the DY TME agent 60, 90 or 120 days prior to superinfection of hamsters with the HY TME agent …”

“…10 Interference between other prion strains has been described in mice and hamsters using rodent-adapted strains of scrapie, TME, Creutzfeldt-Jacob disease and Gerstmannn-Sträussler-Scheinker syndrome following intracerebral, intraperitoneal, intravenous and sciatic nerve routes of inoculation. [10][11][12][13][14][15] We previously demonstrated the detection of PrP Sc from the long incubation period DY TME agent correlated with its ability to extend the incubation period or completely block the superinfecting short incubation period HY TME agent from causing disease and results in a reduction of HY PrP Sc levels following sciatic nerve inoculation. 12 However, it is not known if a single long incubation period agent (e.g., DY TME) can interfere with more than one short incubation period agent or if interference can occur by a natural route of infection.…”

“…Sciatic nerve inoculations were performed as previously described. 11,12 Briefly, hamsters were inoculated with 10 3.0 i.c. LD 50 of the DY TME agent or equal volume (2 μl of a 1% w/v brain homogenate) of uninfected brain homogenate 120 days prior to superinfection of the same sciatic nerve with either 10 4.6 i.c.…”

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases

“…The prion interference has been observed in vivo in mice and Syrian hamsters that were inoculated simultaneously or sequentially with two distinct strains of prions. [55][56][57][58] Since we observed no direct interaction between different conformers of PrP Sc in our in vitro mixing experiments with "pure" MM1 and MM2 sCJD prions, we concluded that the most likely explanation is competition for PrP C substrate or auxiliary molecule; however, the exact molecular mechanism of this phenomenon remains to be fully elucidated. 34 Cumulatively, the distinct particle size, conformational stability, and amplification rate of these prion subtypes argue for the frequent coexistence of different sCJD prions in the same host (Fig.…”

Prion Propagation: The Role of Protein Dynamics

“…137 In addition to positive interactions between prions, co-existence of multiple prion forms, whether they are different sequences or different variants of the same sequence, is often disfavored. For example, co-inoculation of mice with distinct PrP variants extends incubation timing; 138,139 140 These observations suggest a competition for some component common to the propagation pathways. One example of this idea is the competition between different variants of the same prion protein.…”