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Transmissible subacute spongiform encephalopathies
Biomed & Pharmacother 0 Elsevier, Paris
1999 ; 53 : l-2
Guest editorial
Transmissible subacute spongiform encephalopathies D. Dormont CEA, Service de Neurovirologie, Centre de Recherches du Service de Sante des armbes, Fontenay-au-Roses, France
Transmissiblesubacutespongifonn encephalopathies (TSE) are human and animal diseaseswhich can be experimentally transmitted: the first transmissionwas realisedin 1936by the two French veterinariansCuilIt and Chellesin Toulouse,via injection of an aliquot of brain homogenate derived from a naturally scrapieaffected animal into the central nervous system of healthy sheep,which developed experimental scrapie within 2 years. The samemethodology was used by Gajdusek and co-workers for the experimental transmission of Kuru and Creutzfeldt-Jakob diseasein the mid 1960s.Natural andexperimental TSEs have a long asymptomatic incubation period which can last in humansfor 40 years, although the clinical courseof the disease is usually short (6 weeks to 6 months in humans).Their clinical presentationis that of a neurological degeneration. Thesediseasesare characterisedby the accumulation of the host encodedprotein, the prion protein, or PrP The PrP is now well known, and in infected individuals accumulates under a pathological isoform (either PrP-resor PrP-SC)which resistsproteinaseK and proteinases,and is generally not metabolisedby the host cells. It then accumulates. This accumulation of a hydrophobic highly aggregableprotein is lethal for the neuronesin which it occurs. The differences between the normal isoform and the pathological isoform of the prion protein are not at the level of the amino acid sequence.The sequencesare the sameand differences can be evidencedonly at the level of the conformation. This is today the unique example in microbiology of a pathogenicity which is acquiredonly by a modification of the conformation of the protein: the normal isoform is mainly constituted of alpha helices, although there are strong indications that the pathological isoform has an excessof P-sheetstructures.Today, most of the scientific data support the fact that this protein under its
abnormal isoform is the infectious agent itself; in this “protein only hypothesis”, infectivity propagation occurs by transmission of abnormal conformation through direct contacts betweennormal and abnormal forms of PrP. This underlines the role of protein conformation in biological information, and the presence of different prion strainsthat can bederived in the same PrP genotype suggeststhat PrP can adopt several conformations that are stable and also be transmitted between speciesevent by oral route. The most frequent, although rare, TSE in humansis Creutzfeldt-Jakob disease(CJD), a severe dementia which can be recognised in three epidemiological forms. The first, which is the most frequent, is the sporadic fotm, which occurs in patients around the age 65 (90% of CJD casesare sporadic); somecasesof iatrogenie CJD have been reported in the literature and 510% are genetic dise&es.All three forms, including the genetic one, are transmissibleto animals. Transmissionof TSE can also occur betweenspecies: prions are capable of crossingthe speciesbarrier. For example, the CJD agentis capableof infecting monkey, guineapig, hamster,mouse,rat, sheep,goat, mink, ferret, and cat. The molecular determinant of the species barrier is the homology of the sequenceof the two PrP genesof the recipient and of the donor. Moreover, it has beendemonstratedthat mutationsoccurring in the open readingframe of the PrP geneareassociatedwith familial TSE in humans,andthat polymorphismsin this gene are associatedeither with susceptibility to TSE agent infection or with variations in incubation times. A doublecausality, “infectious” and genetic, of these diseasescan be derived from the various ideascurrently accepted. Indeed, transmissibility has been proven in natural situationssuch asthe outbreak of CreutzfeldtJakob diseasesamongchildren treated with extractive growth hormone,and the recent surgeof a new disease
2
D. Domont
decimating British cattle, the bovine spongiform subacute encephalopathy, or “‘mad cow disease”. This double causality has a number of consequences, one of them of paramount importance: although it is difficult to assessthe risk at the individual level, their transmissibility requires a strict compliance to security regulations in the preparation of biological products for therapeutic use. This is reinforced by the fact that prions resist all procedures that usually inactivate microorganisms. On the other hand, the appearance of the bovine spongiform encephalopathy in the United Kingdom demonstrates that, in particular conditions, TSE may be epidemic and induce consequences on both economic and animal health levels. The main problem in TSE is the subclinical phase during which amplification can occur through many passages in the same host species. We know that there were TSE “epidemics” in the past in sheep, humans and cattle which were related to intra-
specific recycling of prions via food and use of drugs of biological origin. The description of a new variant of Creutzfeldt-Jakob disease in the United Kingdom and in France since 1996 has raised the question of a potential pathogenicity of the BSE agent for humans; this hypothesises is unfortunately supported by all the scientific data that have been accumulated since 1996, and one has to consider now that BSE is transmissible to man. Nevertheless, it is today too early to estimate the future number of new variant cases that may appear within and outside of the U.K. The intrication of transmissible agent and host genetic in TSE is remarkable, and does not have any equivalent in the field of infectious diseases. For this reason, and because TSEs are degenerative diseases wherein molecular mechanisms might be close to those of Alzheimer’s disease and normal ageing, “prions” (or TSA) are the most exciting research domain in modem biology.
1999 ; 53 : l-2
Guest editorial
Transmissible subacute spongiform encephalopathies D. Dormont CEA, Service de Neurovirologie, Centre de Recherches du Service de Sante des armbes, Fontenay-au-Roses, France
Transmissiblesubacutespongifonn encephalopathies (TSE) are human and animal diseaseswhich can be experimentally transmitted: the first transmissionwas realisedin 1936by the two French veterinariansCuilIt and Chellesin Toulouse,via injection of an aliquot of brain homogenate derived from a naturally scrapieaffected animal into the central nervous system of healthy sheep,which developed experimental scrapie within 2 years. The samemethodology was used by Gajdusek and co-workers for the experimental transmission of Kuru and Creutzfeldt-Jakob diseasein the mid 1960s.Natural andexperimental TSEs have a long asymptomatic incubation period which can last in humansfor 40 years, although the clinical courseof the disease is usually short (6 weeks to 6 months in humans).Their clinical presentationis that of a neurological degeneration. Thesediseasesare characterisedby the accumulation of the host encodedprotein, the prion protein, or PrP The PrP is now well known, and in infected individuals accumulates under a pathological isoform (either PrP-resor PrP-SC)which resistsproteinaseK and proteinases,and is generally not metabolisedby the host cells. It then accumulates. This accumulation of a hydrophobic highly aggregableprotein is lethal for the neuronesin which it occurs. The differences between the normal isoform and the pathological isoform of the prion protein are not at the level of the amino acid sequence.The sequencesare the sameand differences can be evidencedonly at the level of the conformation. This is today the unique example in microbiology of a pathogenicity which is acquiredonly by a modification of the conformation of the protein: the normal isoform is mainly constituted of alpha helices, although there are strong indications that the pathological isoform has an excessof P-sheetstructures.Today, most of the scientific data support the fact that this protein under its
abnormal isoform is the infectious agent itself; in this “protein only hypothesis”, infectivity propagation occurs by transmission of abnormal conformation through direct contacts betweennormal and abnormal forms of PrP. This underlines the role of protein conformation in biological information, and the presence of different prion strainsthat can bederived in the same PrP genotype suggeststhat PrP can adopt several conformations that are stable and also be transmitted between speciesevent by oral route. The most frequent, although rare, TSE in humansis Creutzfeldt-Jakob disease(CJD), a severe dementia which can be recognised in three epidemiological forms. The first, which is the most frequent, is the sporadic fotm, which occurs in patients around the age 65 (90% of CJD casesare sporadic); somecasesof iatrogenie CJD have been reported in the literature and 510% are genetic dise&es.All three forms, including the genetic one, are transmissibleto animals. Transmissionof TSE can also occur betweenspecies: prions are capable of crossingthe speciesbarrier. For example, the CJD agentis capableof infecting monkey, guineapig, hamster,mouse,rat, sheep,goat, mink, ferret, and cat. The molecular determinant of the species barrier is the homology of the sequenceof the two PrP genesof the recipient and of the donor. Moreover, it has beendemonstratedthat mutationsoccurring in the open readingframe of the PrP geneareassociatedwith familial TSE in humans,andthat polymorphismsin this gene are associatedeither with susceptibility to TSE agent infection or with variations in incubation times. A doublecausality, “infectious” and genetic, of these diseasescan be derived from the various ideascurrently accepted. Indeed, transmissibility has been proven in natural situationssuch asthe outbreak of CreutzfeldtJakob diseasesamongchildren treated with extractive growth hormone,and the recent surgeof a new disease
2
D. Domont
decimating British cattle, the bovine spongiform subacute encephalopathy, or “‘mad cow disease”. This double causality has a number of consequences, one of them of paramount importance: although it is difficult to assessthe risk at the individual level, their transmissibility requires a strict compliance to security regulations in the preparation of biological products for therapeutic use. This is reinforced by the fact that prions resist all procedures that usually inactivate microorganisms. On the other hand, the appearance of the bovine spongiform encephalopathy in the United Kingdom demonstrates that, in particular conditions, TSE may be epidemic and induce consequences on both economic and animal health levels. The main problem in TSE is the subclinical phase during which amplification can occur through many passages in the same host species. We know that there were TSE “epidemics” in the past in sheep, humans and cattle which were related to intra-
specific recycling of prions via food and use of drugs of biological origin. The description of a new variant of Creutzfeldt-Jakob disease in the United Kingdom and in France since 1996 has raised the question of a potential pathogenicity of the BSE agent for humans; this hypothesises is unfortunately supported by all the scientific data that have been accumulated since 1996, and one has to consider now that BSE is transmissible to man. Nevertheless, it is today too early to estimate the future number of new variant cases that may appear within and outside of the U.K. The intrication of transmissible agent and host genetic in TSE is remarkable, and does not have any equivalent in the field of infectious diseases. For this reason, and because TSEs are degenerative diseases wherein molecular mechanisms might be close to those of Alzheimer’s disease and normal ageing, “prions” (or TSA) are the most exciting research domain in modem biology.