Molecular Barriers to Zoonotic Transmission of Prions - Volume 20, Number 1—January 2014 - Emerging Infectious Disease journal - CDC
Volume 20, Number 1—January 2014
Molecular Barriers to Zoonotic Transmission of Prions
Marcelo A. Barria, Aru Balachandran, Masanori Morita, Tetsuyuki Kitamoto, Rona Barron, Jean Manson, Richard Knight, James W. Ironside, and Mark W. Head
Author affiliations: The University of Edinburgh, Edinburgh, Scotland, UK (M.A. Barria, R. Knight, J.W. Ironside, M.W Head);Canadian Food Inspection Agency, Ottawa, Ontario, Canada (A. Balachandran); Japan Blood Products Organization, Kobe, Japan (M. Morita); Tohoku University Graduate School of Medicine, Sendai, Japan (T. Kitamoto); University of Edinburgh, Easter Bush, Scotland, UK (R. Barron, J. Manson)
Prion diseases are rare fatal neurodegenerative conditions that affect humans and animals. The human diseases include Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Most cases of human prion disease are apparently spontaneously occurring (sporadic CJD [sCJD]) or are associated with mutations in the human prion protein gene, designated PRNP (genetic CJD, Gerstmann-Sträussler-Scheinker disease, or fatal familial insomnia). A small minority of cases are acquired by inadvertent human-to-human transmission during medical or surgical treatments (iatrogenic CJD).
In contrast, animal prion diseases are generally acquired. This applies to scrapie in sheep, transmissible mink encephalopathy, and chronic wasting disease (CWD) in deer and elk. No credible evidence exists of a link between scrapie and any human prion disease, despite the endemicity of scrapie in many parts of the world and the consequent likely human exposure to the scrapie agent, which has been attributed partly to a species barrier between sheep and humans. However, strong epidemiologic, pathologic, and molecular evidence does indicate that the epidemic of bovine spongiform encephalopathy (BSE), primarily in the United Kingdom during the 1980s, resulted in a zoonotic form of CJD termed variant CJD (vCJD). BSE/vCJD is the only known zoonotic prion disease strain.
After identification of BSE and vCJD, active surveillance for animal prion diseases in Europe and elsewhere has identified rare atypical prion diseases in sheep and cattle. These include Nor98 or atypical scrapie in sheep (1) and 2 prion diseases of cattle, bovine amyloidotic spongiform encephalopathy or L-type BSE (2) and H-type BSE (3), both of which have a pathology and epidemiology distinct from classical or C-type BSE (4). In addition to these new (or newly described) diseases of farmed sheep and cattle, CWD in cervids is an acquired, probably contagious disease that affects captive and free-ranging deer and elk populations primarily in North America (5).
Their distinctive epidemiology, clinical features, neuropathology, PrP biochemistry, and transmission characteristics suggest that scrapie, atypical scrapie, C-type BSE, H-type BSE, L-type BSE, and CWD represent distinct prion strains in their respective species (6,7). Within scrapie and CWD, natural strain variation also occurs. The prion hypothesis posits that the posttranslational conformational conversion of a host’s normal cellular prion protein (PrPC) by the abnormal form of the prion protein (PrPSc) is the fundamental event in prion disease pathogenesis and that PrPSc itself constitutes the infectious agent. It follows that an aspect of prion host range may be a species barrier operating at the molecular level that depends on compatibility between the PrPSc from 1 species and the PrPC from another. Similarities in the species-specific primary PRNP sequences may account for part of this effect, but prion strain and host PRNP polymorphic genotype, both of which probably find expression in the conformation of PrP, affect susceptibility in ways not yet fully understood.
A relatively simple empirical approach to assessing this molecular barrier is to use cell-free PrP conversion assay techniques (8,9) to determine the relative efficiency of PrP conversion using natural “seeds” from an infectious prion source from the brain of 1 species and a normal brain “substrate” from another species. We have previously reported the use of protein misfolding cyclic amplification (PMCA) as a model of cross-species prion transmission of C-type BSE in cattle and sheep to humans (10). Here we report a comparative study of the ability of sheep, cattle, and deer prions to convert normal human PrP in this same cell-free system.