RESUMEN
BACKGROUND: The disease-associated form of prion protein (PrP(res)) has been noted in lymphoreticular tissues in patients with variant Creutzfeldt-Jakob disease (vCJD). Thus, the disease could be transmitted iatrogenically by surgery or use of blood products. We aimed to assess transmissibility of the bovine spongiform encephalopathy (BSE) agent to primates by the intravenous route and study its tissue distribution compared with infection by the oral route. METHODS: Cynomolgus macaques were infected either intravenously or orally with brain homogenates from first-passage animals with BSE. They were clinically monitored for occurrence of neurological signs and killed humanely at the terminal stage of the disease. Brain, lymphoreticular tissues, digestive tract, and peripheral nerves were obtained and analysed by sandwich ELISA and immunohistochemistry for quantitative and qualitative assessment of their PrP(res) content. FINDINGS: Incubation periods after intravenous transmission of BSE were much shorter than after oral infection. We noted that PrP(res) was present in lymphoreticular tissues such as spleen and tonsils and in the entire gut from the duodenum to the rectum. In the gut, PrP(res) was present in Peyer's patches and in the enteric nervous system and nerve fibres of intestinal mucosa. Furthermore, PrP(res) was found in locomotor peripheral nerves and the autonomic nervous system. Amount of PrP(res) ranged from 0.02% to more than 10% of that recorded in brain. Distribution of PrP(res) was similar in animals infected by the intravenous or oral route. INTERPRETATION: Our findings suggest that the possible risk of vCJD linked to endoscopic procedures might be currently underestimated. Human iatrogenic vCJD cases infected intravenously raise the same public-health concerns as primary cases and need the same precautionary measures with respect to blood and tissue donations and surgical procedures.
Asunto(s)
Encefalopatía Espongiforme Bovina/metabolismo , Priones/administración & dosificación , Priones/metabolismo , Administración Oral , Animales , Sistema Nervioso Autónomo/metabolismo , Encéfalo/metabolismo , Química Encefálica , Trasplante de Tejido Encefálico/métodos , Bovinos , Humanos , Inmunohistoquímica , Inyecciones Intravenosas , Mucosa Intestinal/química , Mucosa Intestinal/metabolismo , Tejido Linfoide/química , Tejido Linfoide/metabolismo , Macaca fascicularis , Tejido Nervioso/química , Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/administración & dosificación , Proteínas del Tejido Nervioso/aislamiento & purificación , Proteínas del Tejido Nervioso/metabolismo , Nervios Periféricos/química , Nervios Periféricos/metabolismo , Proteínas PrPSc/aislamiento & purificación , Proteínas PrPSc/metabolismo , Priones/aislamiento & purificación , Distribución TisularRESUMEN
Transmissible spongiform encephalopathies (TSEs) represent a group of neurodegenerative diseases characterised by a very long incubation period in regard to the life expectancy of the host species. The lesions are restricted to the central nervous system, although the pathogenesis of infection implies a primary replication step of TSE agents in the lymphoid organs followed by a neuroinvasive phase. The outcome is always fatal and today there is neither cure nor prophylaxis for these diseases. For years, the causative agents of TSEs have posed a conundrum in terms of current knowledge of microorganisms, and there are still open questions about their exact nature. They are usually called TSE agents or prions because they are thoughtto be primarily composed of a modified host protein, the prion protein (PrP). A pathological form of the prion protein, called PrPSc (for scrapie) or PrPRes, an operational definition referring to resistance to proteolytic digestion, accumulates in target organs. The aim of this introductory chapter is to presentthe general features of TSEs and a modern understanding of TSE agents and their mode of replication. Notwithstanding the plethora of unsolved questions on these diseases and their aetiology, knowledge of their pathogenesis and recent advances in understanding of the molecular basis of PrP accumulation, together with detection systems, provide the tools to conduct sound TSE risk management.
Asunto(s)
Enfermedades por Prión/etiología , Priones/fisiología , Animales , Humanos , Enfermedades por Prión/patología , Priones/químicaRESUMEN
Cell-binding and internalization studies on neuronal and non-neuronal cells have demonstrated that the 37-kDa/67-kDa laminin receptor (LRP/LR) acts as the receptor for the cellular prion protein (PrP). Here we identify direct and heparan sulfate proteoglycan (HSPG)-dependent interaction sites mediating the binding of the cellular PrP to its receptor, which we demonstrated in vitro on recombinant proteins. Mapping analyses in the yeast two-hybrid system and cell-binding assays identified PrPLRPbd1 [amino acids (aa) 144-179] as a direct and PrPLRPbd2 (aa 53-93) as an indirect HSPG-dependent laminin receptor precursor (LRP)-binding site on PrP. The yeast two-hybrid system localized the direct PrP-binding domain on LRP between aa 161 and 179. Expression of an LRP mutant lacking the direct PrP-binding domain in wild-type and mutant HSPG-deficient Chinese hamster ovary cells by the Semliki Forest virus system demonstrates a second HSPG-dependent PrP-binding site on LRP. Considering the absence of LRP homodimerization and the direct and indirect LRP-PrP interaction sites, we propose a comprehensive model for the LRP-PrP-HSPG complex.
Asunto(s)
Proteoglicanos de Heparán Sulfato/metabolismo , Priones/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Laminina/metabolismo , Técnicas del Sistema de Dos Híbridos , Animales , Sitios de Unión/fisiología , Células CHO , Línea Celular , Cromatografía en Gel , Cricetinae , Galactósidos/metabolismo , Glutatión Transferasa/genética , Proteoglicanos de Heparán Sulfato/genética , Humanos , Ratones , Oligopéptidos , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Péptidos/genética , Priones/genética , Unión Proteica/fisiología , Precursores de Proteínas/genética , Estructura Terciaria de Proteína/fisiología , Receptores de Laminina/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Virus de los Bosques Semliki/genéticaRESUMEN
Recently, we identified the 37-kDa laminin receptor precursor (LRP) as an interactor for the prion protein (PrP). Here, we show the presence of the 37-kDa LRP and its mature 67-kDa form termed high-affinity laminin receptor (LR) in plasma membrane fractions of N2a cells, whereas only the 37-kDa LRP was detected in baby hamster kidney (BHK) cells. PrP co-localizes with LRP/LR on the surface of N2a cells and Semliki Forest virus (SFV) RNA transfected BHK cells. Cell-binding assays reveal the LRP/LR-dependent binding of cellular PrP by neuronal and non-neuronal cells. Hyperexpression of LRP on the surface of BHK cells results in the binding of exogenous PrP. Cell binding is similar in PrP(+/+) and PrP(0/0) primary neurons, demonstrating that PrP does not act as a co-receptor of LRP/LR. LRP/LR-dependent internalization of PrP is blocked at 4 degrees C. Secretion of an LRP mutant lacking the transmembrane domain (aa 86-101) from BHK cells abolishes PrP binding and internalization. Our results show that LRP/LR acts as the receptor for cellular PrP on the surface of mammalian cells.
Asunto(s)
Priones/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Laminina/metabolismo , Animales , Línea Celular , Membrana Celular/metabolismo , Cricetinae , Citometría de Flujo , Humanos , Riñón/citología , Riñón/metabolismo , Ratones , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Neuroblastoma/metabolismo , Neuronas/citología , Neuronas/metabolismo , Oligopéptidos , Péptidos/genética , Enfermedades por Prión/etiología , Priones/genética , Unión Proteica/fisiología , Precursores de Proteínas/genética , Estructura Terciaria de Proteína/fisiología , Receptores de Laminina/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Virus de los Bosques Semliki/genética , TransfecciónRESUMEN
There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy (BSE) has contaminated human beings, causing variant Creutzfeldt-Jakob disease (vCJD). This disease has raised concerns about the possibility of an iatrogenic secondary transmission to humans, because the biological properties of the primate-adapted BSE agent are unknown. We show that (i) BSE can be transmitted from primate to primate by intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD to humans could be readily recognized pathologically, whether it occurs by the central or peripheral route. Strain typing in mice demonstrates that the BSE agent adapts to macaques in the same way as it does to humans and confirms that the BSE agent is responsible for vCJD not only in the United Kingdom but also in France. The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/transmisión , Encefalopatía Espongiforme Bovina/transmisión , Priones/análisis , Adaptación Biológica , Animales , Bovinos , Síndrome de Creutzfeldt-Jakob/fisiopatología , Modelos Animales de Enfermedad , Encefalopatía Espongiforme Bovina/fisiopatología , Femenino , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Fenotipo , Enfermedades de los Primates/transmisión , Primates , Scrapie/fisiopatologíaRESUMEN
The involvement of spleen macrophages in the early stages of scrapie pathogenesis was studied by applying the 'macrophage-suicide technique' to scrapie-infected mice. This method comprises critically the intravenous administration to mice of dichloromethylene disphosphonate encapsulated into liposomes. Depletion of spleen macrophages before scrapie infection induced an increased amount of scrapie inoculum in the spleen, consequently leading to accelerated scrapie agent replication in the early phase of pathogenesis, as followed by PrPres accumulation, a specific hallmark of scrapie. The same effect was observed when spleen macrophages were depleted just before the beginning of scrapie agent replication. These findings suggest that macrophages may partly control scrapie infection in peripheral tissues by sequestration of the scrapie inoculum and may thus impair early scrapie agent replication in the spleen. In addition to macrophages, most follicular dendritic cells and B lymphocytes, which are thought to support scrapie agent replication, were also transiently depleted by dichloromethylene disphosphonate administration. This suggests that a compensatory mechanism is sufficient to ensure the persistence of infection in these early stages of pathogenesis.
Asunto(s)
Macrófagos/inmunología , Scrapie/inmunología , Bazo/inmunología , Analgésicos no Narcóticos/farmacología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Ácido Clodrónico/farmacología , Macrófagos/efectos de los fármacos , Ratones , Priones/metabolismo , Scrapie/virología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Prions are thought to consist of infectious proteins that cause, in the absence of detectable nucleic acid, a group of fatal neurodegenerative diseases, called transmissible spongiform encephalopathies (TSE). Among these diseases are bovine spongiform encephalopathy (BSE), scrapie of sheep and Creutzfeldt-Jakob disease (CJD) in humans. They occur as sporadic, infectious or genetic disorders and have in common the accumulation of an abnormal, pathogenic isoform of the cellular prion protein PrPc which is converted in a post-translational process into PrPSc concomitant with conformational changes of the protein. During this process PrPc acquires a high beta-sheet content and becomes partially resistant to proteases. The mechanism of this conversion as well as the physiological function of the cellular prion protein PrPc are poorly understood, but studies employing PrP knock-out mice demonstrated that PrPc is required for the development of prion diseases. The involvement of co-factors such as chaperones, receptors or an unknown protein, designated "protein X" in the conversion process are discussed. In a yeast two-hybrid screen we have identified the 37 kDa laminin receptor precursor (LRP) as an interactor of the cellular prion protein and this interaction could be confirmed by co-infection and co-transfection studies in mammalian and insect cells. LRP evolved from the ribosomal protein p40 essential for protein synthesis lacking any laminin binding activity to a cell surface receptor binding laminin, elastin and carbohydrates. The gene encoding 37 kDa LRP/p40 has been identified in a variety of species including the sea urchin Urechis caupo, Chlorohydra viridissima, the archaebacterium Haloarcula marismortui, the yeast Saccharomyces cerevisiae as well as in mammals where it is highly conserved. LRP works as a receptor for alphaviruses and is associated with the metastatic potential of solid tumors where it was first identified. The 37 kDa LRP forms its mature 67 kDa isoform with high laminin binding capacity by an unknown mechanism involving acylation. The multifunctionality of LRP as a ribosomal protein and a cell surface receptor for infectious agents such as viruses and prions might be extended by additional properties.
Asunto(s)
Priones/fisiología , Precursores de Proteínas/fisiología , Receptores de Laminina/fisiología , Proteínas Ribosómicas/fisiología , Animales , Bovinos , Evolución Molecular , Humanos , Ratones , Ratones Noqueados , Peso Molecular , Conformación Proteica , Precursores de Proteínas/genética , Receptores de Laminina/genética , Proteínas Ribosómicas/genéticaRESUMEN
The scrapie isoform of the prion protein (PrPres) induces neurodegeneration and gliosis in the central nervous system. These features may be reproduced in vitro on exposure of neuronal and glial cultures to PrPres and the peptide HuPr P106-126. In the present study, we investigated the role of microglial cells and astrocytes in the pathological process by studying their molecular response to PrP 106-126 exposure. PrP 106-126 elicited a specific overproduction of pro-inflammatory cytokines IL1beta and IL6 in microglial cells (but not increased expression of TNFalpha, IL10, and TGFbeta1) and over-expression of GFAP in astrocytes. These effects were strictly dependent on the ability of the peptide to form amyloid fibrils. These data strongly suggest that microglial cells contribute to prion-related neurodegenerative processes by producing proinflammatory cytokines in the brain areas of amyloid PrP deposition.
Asunto(s)
Citocinas/biosíntesis , Microglía/metabolismo , Fragmentos de Péptidos/farmacología , Priones/farmacología , Animales , Células Cultivadas , Electroforesis en Gel de Poliacrilamida , Humanos , Inflamación/metabolismo , Interleucina-1/biosíntesis , Interleucina-6/biosíntesis , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Degeneración Nerviosa/patología , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
We examined the localization of the normal cellular isoform of prion protein (PrPc) in mammalian skeletal muscle. Using two anti-PrP antibodies, the neuromuscular junction (NMJ) was preferentially stained after immunohistofluorescence. The mouse, hamster, and human NMJ displayed a fluorescent signal specific for PrPc. Postembedding immunoelectron microscopy analysis performed in the mouse muscle showed that the PrPc-specific colloidal gold immunolabelling was concentrated over the sarcoplasmic cytoplasm. The membrane of the postsynaptic domain was devoid of gold particles, while a weak signal was occasionally observed close to the presynaptic vesicles of the terminal axons. These results indicate that the PrP gene is expressed in mammalian muscle at the NMJ. The subsynaptic sarcoplasm of the NMJ appears to be the privileged site where PrPc presumably associated with endosome membrane may play a role in either physiological activity or maintenance of the morphological integrity of the synapse.
Asunto(s)
Unión Neuromuscular/metabolismo , Unión Neuromuscular/ultraestructura , Priones/metabolismo , Animales , Western Blotting , Cricetinae , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Inmunohistoquímica , Mesocricetus , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Microscopía Electrónica , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Fracciones Subcelulares/metabolismo , Fracciones Subcelulares/ultraestructuraRESUMEN
In transmissible spongiform encephalopathies (TSE), such as scrapie in animals and Creutzfeldt-Jakob disease in humans, the central event is the conversion of a host-encoded amyloidogenic protein (PrPc) into an abnormal isoform (PrPsc) that accumulates as amyloid in TSE brain. PrPc is a membrane sialoglycoprotein synthesized in the central nervous system and elsewhere. We have examined the ultrastructural localization of PrPc in numerous hamster and some human extracerebral tissues, by means of a post-embedding electron-microscopic method combined with immunogold labeling. In stomach, intestine, lung, and kidney from hamsters, and in stomach, kidney, and spleen from humans, immunogold labeling specific for PrPc is observed on various cellular substructures related to secretory pathways: Golgi apparatus, secretory globules, and plasma membrane. In mucous epithelial cells of stomach and intestine, PrPc appears to be concentrated in secretory globules, suggesting a role for PrPc in the secretory function of the digestive tract. The secretory aspect of PrPc may be a key to understanding the physiopathological mechanisms underlying TSE.
Asunto(s)
Proteínas PrPC/metabolismo , Animales , Química Encefálica , Cricetinae , Humanos , Mesocricetus , Microscopía Inmunoelectrónica/métodos , Especificidad de Órganos , Fracciones Subcelulares/química , Fracciones Subcelulares/metabolismo , Fracciones Subcelulares/ultraestructura , Adhesión del TejidoRESUMEN
Prions are thought to consist of infectious proteins that cause transmissible spongiform encephalopathies. According to overwhelming evidence, the pathogenic prion protein PrPSc converts its host encoded isoform PrPC into insoluble aggregates of PrPSc, concomitant with pathological modifications (for review, see refs. 1-3). Although the physiological role of PrPC is poorly understood, studies with PrP knockout mice demonstrated that PrPC is required for the development of prion diseases. Using the yeast two-hybrid technology in Saccharomyces cerevisiae, we identified the 37-kDa laminin receptor precursor (LRP) as interacting with the cellular prion protein PrPC. Mapping analysis of the LRP-PrP interaction site in S. cerevisiae revealed that PrP and laminin share the same binding domain (amino acids 161 to 180) on LRP. The LRP-PrP interaction was confirmed in vivo in insect (Sf9) and mammalian cells (COS-7). The LRP level was increased in scrapie-infected murine N2a cells and in brain and spleen of scrapie-infected mice. In contrast, the LRP concentration was not significantly altered in these organs from mice infected with the bovine spongiform encephalopathic agent (BSE), which have a lower PrPSc accumulation. LRP levels, however, were dramatically increased in brain and pancreas, slightly increased in the spleen and not altered in the liver of crapie-infected hamsters. These data show that enhanced LRP concentrations are correlated with PrPSc accumulation in organs from mice and hamsters. The laminin receptor precursor, which is highly conserved among mammals and is located on the cell surface, may act as a receptor or co-receptor for the prion protein on mammalian cells.
Asunto(s)
Proteínas PrPSc/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Laminina/metabolismo , Actinas/metabolismo , Animales , Sitios de Unión , Células COS , Línea Celular , Cricetinae , Células Eucariotas , Humanos , Ratones , Ratones Endogámicos C57BL , Precursores de Proteínas/química , Precursores de Proteínas/genética , Conejos , Receptores de Laminina/química , Receptores de Laminina/genética , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Saccharomyces cerevisiae/metabolismo , Spodoptera/citologíaRESUMEN
Amphotericin B (AmB) is one of the few drugs able to prolong survival times in experimental scrapie and delays the accumulation of PrPres, a specific marker of this disease in the brain in vivo. Previous reports showed that the AmB effect is observed only if the drug is administered around the time of infection. In the present study, intracerebrally infected mice were treated with AmB or one of its derivatives, MS-8209, between 80 and 140 days postinoculation. We observed an increased incubation time and a delay in PrPres accumulation and glial fibrillary acidic protein gene expression. Treatment starting at 80 days postinoculation was as efficient as long-term treatment starting the day of inoculation. Our results indicate that polyene antibiotics may interfere, throughout the course of the experimental disease, with the propagation of the scrapie agent.
Asunto(s)
Anfotericina B/análogos & derivados , Polienos/farmacología , Scrapie/tratamiento farmacológico , Secuencia de Aminoácidos , Anfotericina B/farmacología , Animales , Antibacterianos/farmacología , Esquema de Medicación , Femenino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Proteínas PrPSc , Conejos , Scrapie/fisiopatología , Factores de TiempoRESUMEN
The agent responsible for transmissible spongiform encephalopathies (TSEs) is thought to be a malfolded, protease-resistant version (PrPres) of the normal cellular prion protein (PrP). The interspecies transmission of bovine spongiform encephalopathy (BSE) to mice was studied. Although all of the mice injected with homogenate from BSE-infected cattle brain exhibited neurological symptoms and neuronal death, more than 55 percent had no detectable PrPres. During serial passage, PrPres appeared after the agent became adapted to the new host. Thus, PrPres may be involved in species adaptation, but a further unidentified agent may actually transmit BSE.
Asunto(s)
Química Encefálica , Encefalopatía Espongiforme Bovina/transmisión , Proteínas del Tejido Nervioso/análisis , Priones/análisis , Animales , Apoptosis , Astrocitos/patología , Encéfalo/patología , Bovinos , Encefalopatía Espongiforme Bovina/metabolismo , Encefalopatía Espongiforme Bovina/patología , Endopeptidasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Fenotipo , Células de Purkinje/patología , Pase Seriado , Factores de Tiempo , Vacuolas/patologíaAsunto(s)
Síndrome de Creutzfeldt-Jakob , Adulto , Encéfalo/metabolismo , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patología , Duramadre/trasplante , Electroforesis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosforribosil Pirofosfato/genética , Fosforribosil Pirofosfato/metabolismo , Proteínas PrPSc/metabolismoRESUMEN
The development of transmissible spongiform encephalopathies in experimental models depends on two major factors: the intracerebral accumulation of an abnormal, protease-resistant isoform of PrP (PrPres), which is a host protein mainly expressed in neurons; and the existence of different strains of agent. In order to make a distinction between pathogenic mechanisms depending upon the accumulation of host-derived PrPres and the strain-specific effects, we quantified and compared the sequence of molecular [PrPres and glial fibrillary acidic protein (GFAP) accumulation] and pathological events in the brains of syngeneic mice throughout the course of infection with two different strains of agent. The bovine spongiform encephalopathy (BSE) agent exhibits properties different from any known scrapie source and has been studied in comparison with a classical scrapie strain. Convergent kinetic data in both models confirmed the cause-effect relationship between PrPres and pathological changes and showed that PrPres accumulation is directly responsible for astrocyte activation in vivo. Moreover, we observed a threshold level of PrPres for this effect on astroglial cells. However, despite similar infectivity titres, the BSE model produced less PrPres than scrapie, and the relative importance of gliosis was higher. The comparison of the molecular and pathological features after intracerebral or intraperitoneal inoculation also revealed differences between the models. Therefore, the mechanisms leading to the targeting and the fine regulation of the molecular events seem to be independent of the host PrP and to depend upon the agent. The possible involvement of a regulatory molecule accounting for these specificities has to be considered.
Asunto(s)
Encefalopatía Espongiforme Bovina/etiología , Proteínas PrPSc/patogenicidad , Scrapie/etiología , Animales , Astrocitos/metabolismo , Bovinos , Modelos Animales de Enfermedad , Encefalopatía Espongiforme Bovina/patología , Encefalopatía Espongiforme Bovina/fisiopatología , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones , Ratones Endogámicos C57BL , Scrapie/patología , Scrapie/fisiopatología , Ovinos , Factores de TiempoRESUMEN
Mice were infected intracerebrally with the bovine spongiform encephalopathy (BSE) or the scrapie agent and treated during 8 weeks postinfection to test the protective effect of a new amphotericin B (AmB) derivative, MS-8209, in experimental transmissible spongiform encephalopathies. The results show that (i) the treatment prolonged the incubation period of both BSE-infected and scrapie-infected mice, (ii) MS-8209 and AmB were much more efficient in delaying the onset of scrapie than that of BSE, and (iii) a delay in Prp-res (proteinase K-resistant prion protein) and GFAP (glial fibrillary acidic protein) accumulation was observed in the brains of scrapie-infected mice, but was not significant in BSE-infected mice. The analysis of the molecular and clinical results strongly suggests a common mechanism of action of this category of drugs on the different transmissible spongiform encephalopathy strains. This could be due to an interaction with the PrP transconformation process leading to the formation of PrP-res.
Asunto(s)
Anfotericina B/análogos & derivados , Antivirales/uso terapéutico , Encefalopatía Espongiforme Bovina/tratamiento farmacológico , Scrapie/tratamiento farmacológico , Anfotericina B/uso terapéutico , Animales , Antibacterianos , Bovinos , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Ratones Endogámicos C57BL , Polienos , Proteínas PrPSc/metabolismoAsunto(s)
Síndrome de Creutzfeldt-Jakob/transmisión , Encefalopatía Espongiforme Bovina/transmisión , Animales , Encéfalo/patología , Bovinos , Síndrome de Creutzfeldt-Jakob/patología , Encefalopatía Espongiforme Bovina/patología , Humanos , Macaca , Proteínas PrPSc/metabolismo , Priones/genética , Especificidad de la EspecieRESUMEN
Using the severe combined immunodeficiency (SCID) mouse model, we investigated the requirement of the immune system for the development of scrapie after peripheral inoculation. A total of 33% of SCID mice, all but one immunologically reconstituted SCID mice (93%), and all CB17 control mice developed the disease. PrPres was detectable in the brains of all diseased animals and in the spleens of reconstituted SCID and CB17 control mice but not of the diseased non-immunologically reconstituted SCID mice. The immune system appears to be a primary target in the pathogenesis of scrapie, but direct spread to the central nervous system from the peritoneum via visceral nerve fibers can probably also occur.