A 25 nm virion is the likely cause of transmissible spongiform encephalopathies.
The transmissible spongiform encephalopathies (TSEs) such as endemic sheep scrapie, sporadic human Creutzfeldt-Jakob disease (CJD), and epidemic bovine spongiform encephalopathy (BSE) may all be caused by a unique class of "slow" viruses. This concept remains the most parsimonious explanation of the evidence to date, and correctly predicted the spread of the BSE agent to vastly divergent species. With the popularization of the prion (infectious protein) hypothesis, substantial data pointing to a TSE virus have been largely ignored. Yet no form of prion protein (PrP) fulfills Koch's postulates for infection. Pathologic PrP is not proportional to, or necessary for infection, and recombinant and "amplified" prions have failed to produce significant infectivity. Moreover, the "wealth of data" claimed to support the existence of infectious PrP are increasingly contradicted by experimental observations, and cumbersome speculative notions, such as spontaneous PrP mutations and invisible strain-specific forms of "infectious PrP" are proposed to explain the incompatible data. The ability of many "slow" viruses to survive harsh environmental conditions and enzymatic assaults, their stealth invasion through protective host-immune defenses, and their ability to hide in the host and persist for many years, all fit nicely with the characteristics of TSE agents. Highly infectious preparations with negligible PrP contain nucleic acids of 1-5 kb, even after exhaustive nuclease digestion. Sedimentation as well as electron microscopic data also reveal spherical infectious particles of 25-35 nm in diameter. This particle size can accommodate a viral genome of 1-4 kb, sufficient to encode a protective nucleocapsid and/or an enzyme required for its replication. Host PrP acts as a cellular facilitator for infectious particles, and ultimately accrues pathological amyloid features. A most significant advance has been the development of tissue culture models that support the replication of many different strains of agent and can produce high levels of infectivity. These models provide new ways to rapidly identify intrinsic viral and strain-specific molecules so important for diagnosis, prevention, and fundamental understanding.
Manuelidis
Laura
L
Yale Medical School, New Haven, CT 06510, USA. laura.manuelidis@yale.edu
D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D008854:Microscopy, Electron; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D011328:Prions / Q000378:metabolism; D014771:Virion / Q000502:physiology* / Q000648:ultrastructure
D011328:Prions