Prion replication without host adaptation during interspecies transmissions

Abstract

Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrPC) to selectively propagate optimized prion conformations from larger ensembles generated in the species of origin. Here we describe an alternate replicative process, termed nonadaptive prion amplification (NAPA), in which dominant conformers bypass this requirement during particular interspecies transmissions. To model susceptibility of horses to prions, we produced transgenic (Tg) mice expressing cognate PrPC. Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPCconversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPCwas similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPCfrom the species of prion origin, demonstrating that transmission barrier eradication of the originating prions was ephemeral and adaptation superficial in TgEq and TgD. Horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrPCalso failed to infect TgEq but retained tropism for wild-type mice. Concordant patterns of neuropathology and prion deposition in susceptible mice infected with NAPA prions and the corresponding prion of origin confirmed preservation of strain properties. The comparable responses of both prion types to guanidine hydrochloride denaturation indicated this occurs because NAPA precludes selection of novel prion conformations. Our findings provide insights into mechanisms regulating interspecies prion transmission and a framework to reconcile puzzling epidemiological features of certain prion disorders.

Dogs are resistant to prion infection, due to the presence of aspartic or glutamic acid at position 163 of their prion protein

“…Mw: Molecular weight amplification without adaptation to the new host but conserving its pathobiological features toward a host with the original cattle PrP C , similar to that described previously for other isolate-host combination such as scrapie in TgHorse mice. 21 The possible relevance of the negatively charged amino acid residue in position 163 of dog PrP to their resistance to prion infection was initially suspected from sequence alignment studies of the PRNP of several members of the canidae family with those of susceptible species. These studies revealed that feline PrP was the most similar in terms of amino acid sequence and as domestic cats are susceptible to at least three known prion strains (BSE, CWD, and CJD) 26,[44][45][46] the six amino acid difference between canine and feline PrP was studied in detail.…”

“…Reasons that might explain why species that have been experimentally proven susceptible to prion disease have never had naturally occurring cases reported. These include pigs, rabbits, mice, nonhuman primates, ferrets, and even horses where a transgenic mouse model with equine PrP was used …”

“…These include pigs, [12][13][14][15] rabbits, 16 mice, nonhuman primates, [17][18][19] ferrets, 20 and even horses where a transgenic mouse model with equine PrP was used. 21 Dogs are not included in this list for two reasons 1 ; experimentation on dogs using prions is very limited (for various reasons, including ethical constraints) and 2 no transgenic model has been generated. To date, no evidence exist that dogs can be infected naturally with prions, only theoretically using an in vitro assay that have, under extreme and specific conditions, succeeded in misfolding dog PrP C .…”

“…This is interpreted as a nonadaptive prion amplification (NAPA) phenomenon. 21 We have demonstrated that wild-type (WT) dog PrP C (with an aspartic acid in position 163) could be misfolded by BSE prions in vitro by PMCA and the resultant prions were infectious in TgBov mice (over expressing bovine PrP C ) 22,29 but there is still no evidence in vivo of PrP res propagation in dogs. This resistance to prion disease makes canids, particularly the domestic dog (Canis lupus familiaris), an interesting species to study as, although having been exposed to BSE contaminated feed like cats, no definitive field case has ever been published despite a few unconfirmed reports.…”

Molecular dynamics simulation of local structural models of PrPSc reveals how codon 129 polymorphism affects propagation of PrPSc

“…Therefore, conformations of M129-compatible PrP Sc and V129-compatible PrP Sc should be sufficiently different accordingly. Interestingly, the traits of V129-compatible PrP Sc are so stable that they are preserved through passages to M129-PrP-expressing individuals, without abbreviation of incubation periods on the secondary transmissions, i.e., no adaptation to M129-PrP [19][20][21], reminiscent of non-adaptive prion amplification, NAPA [22]. This was in contrast with ordinary species barriers accompanied by adaptation to the new host, e.g., transmission of Syrian hamster scrapie to Chinese hamsters [23].…”