Creutzfeldt-Jakob Disease In Humans Research Articles

A Comparison of RML Prion Inactivation Efficiency by Heterogeneous and Homogeneous Photocatalysis.

Prions are proteinaceous pathogens responsible for a variety of devastating diseases in mammals, including scrapie in sheep and goats, chronic wasting disease in cervids, and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by their exceptional persistence to common inactivation procedures. This applies to all possible sources of prion contamination as prions may be present in the tissues and biological fluids of infected individuals. Hence, efficient prion inactivation procedures are still being sought to minimize the risk of intra- or inter-species transmission. In the past, photocatalytic treatment has been proven to be capable of efficiently oxidizing and inactivating prions. In the present study, the efficacy of homogeneous photo-Fenton-based photocatalysis as well as heterogeneous photocatalysis with TiO2 in reducing RML mouse scrapie infectivity was evaluated. Prion inactivation was assessed by means of a bioassay, and the results were confirmed by in vitro experiments. While the prion infectivity of the RML mouse scrapie was reduced after treatment with the photo-Fenton reagent, the heterogeneous photocatalytic treatment of the same prion strain completely eliminated prion infectivity.

Assessment of the zoonotic potential of atypical scrapie prions in humanized mice reveals rare phenotypic convergence but not identity with sporadic CJD prions.

Atypical/Nor98 scrapie (AS) is an idiopathic infectious prion disease affecting sheep and goats. Recent findings suggest that zoonotic prions from bovine spongiform encephalopathy (C-BSE) may co-propagate with atypical/Nor98 prions in AS sheep brains. Investigating the risk AS poses to humans is crucial. To assess the risk of sheep/goat-to-human transmission of AS, we serially inoculated brain tissue from field and laboratory isolates into transgenic mice overexpressing human prion protein (Met129 allele). We studied clinical outcomes as well as presence of prions in brains and spleens. No transmission occurred on the primary passage, with no clinical disease or pathological prion protein in brains and spleens. On subsequent passages, one isolate gradually adapted, manifesting as prions with a phenotype resembling those causing MM1-type sporadic Creutzfeldt-Jakob disease in humans. However, further characterization using in vivo and in vitro techniques confirmed both prion agents as different strains, revealing a case of phenotypic convergence. Importantly, no C-BSE prions emerged in these mice, especially in the spleen, which is more permissive than the brain for C-BSE cross-species transmission. The results obtained suggest a low the zoonotic for AS. Rare adaptation may allow the emergence of prions phenotypically resembling those spontaneously forming in humans.

Efficacy of Wex-cide 128 disinfectant against multiple prion strains.

Prion diseases are transmissible, fatal neurologic diseases that include Creutzfeldt-Jakob Disease (CJD) in humans, chronic wasting disease (CWD) in cervids, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. Prions are extremely difficult to inactivate and established methods to reduce prion infectivity are often dangerous, caustic, expensive, or impractical. Identifying viable and safe methods for treating prion contaminated materials is important for hospitals, research facilities, biologists, hunters, and meat-processors. For three decades, some prion researchers have used a phenolic product called Environ LpH (eLpH) to inactivate prions. ELpH has been discontinued, but a similar product, Wex-cide 128, containing the similar phenolic chemicals as eLpH is now available. In the current study, we directly compared the anti-prion efficacy of eLpH and Wex-cide 128 against prions from four different species (hamster 263K, cervid CWD, mouse 22L and human CJD). Decontamination was performed on either prion infected brain homogenates or prion contaminated steel wires and mouse bioassay was used to quantify the remaining prion infectivity. Our data show that both eLpH and Wex-cide 128 removed 4.0-5.5 logs of prion infectivity from 22L, CWD and 263K prion homogenates, but only about 1.25-1.50 logs of prion infectivity from human sporadic CJD. Wex-cide 128 is a viable substitute for inactivation of most prions from most species, but the resistance of CJD to phenolic inactivation is a concern and emphasizes the fact that inactivation methods should be confirmed for each target prion strain.

Innate Immune Tolerance in Microglia Does Not Impact on Central Nervous System Prion Disease.

Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep, are infectious and chronic neurodegenerative diseases to which there are no cures. Infection with prions in the central nervous system (CNS) ultimately causes extensive neurodegeneration, and this is accompanied by prominent microglial and astrocytic activation in affected regions. The microglia are the CNS macrophages and help maintain neuronal homeostasis, clear dead or dying cells and provide defense against pathogens. The microglia also provide neuroprotection during CNS prion disease, but their pro-inflammatory activation may exacerbate the development of the neuropathology. Innate immune tolerance induced by consecutive systemic bacterial lipopolysaccharide (LPS) treatment can induce long-term epigenetic changes in the microglia in the brain that several months later can dampen their responsiveness to subsequent LPS treatment and impede the development of neuritic damage in a transgenic mouse model of Alzheimer’s disease-like pathology. We therefore reasoned that innate immune tolerance in microglia might similarly impede the subsequent development of CNS prion disease. To test this hypothesis groups of mice were first infected with prions by intracerebral injection, and 35 days later given four consecutive systemic injections with LPS to induce innate immune tolerance. Our data show that consecutive systemic LPS treatment did not affect the subsequent development of CNS prion disease. Our data suggests innate immune tolerance in microglia does not influence the subsequent onset of prion disease-induced neuropathology in mice, despite previously published evidence of this effect in an Alzheimer’s disease mouse model.

Prions: Some Details and Diseases

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of rare progressive neurodegenerative disorders that affect both humans and animals. They are distinguished by long incubation periods, characteristic spongiform changes associated with neuronal loss, and a failure to induce inflammatory response. Prion diseases in animals, Scrapie in sheep, chronic wasting disease (CWD) in deer, bovine spongiform encephalopathy (commonly known as "mad cow disease") in cattle, and Creutzfeldt-Jakob disease in humans are all examples of infectious diseases. The prion protein (PrP) was identified in a patient in 2015, and it was previously believed to be the cause of all known mammalian prion diseases. However, The protein alpha-synuclein, which is thought to be responsible for MSA, was suggested to be the cause of the disease in 2015.

PRION PROTEIN GENE SEQUENCES ANALYSIS IN TWELVE SHEEP BREEDS OF PAKISTAN

Prions are considered the only agents of transmissible spongiform encephalopathies (TSEs) and are harmful pathogens of mammals. These infectious agents of host are made up through aggregation of conformational isomers (PrPSc) and encode glycoprotein (PrPC) of 33-35 kDa. TSEs are the fatal group of diseases which are neurodegenerative and include chronic wasting disease in deer and elk, Creutzfeldt-Jakob disease (CJD) and transmissible mink encephalopathy (TME) in humans and scrapie in goats and sheep. The accumulation of abnormal form of the normal protein (PrP) is common in all diseases related TSE. This abnormal form of PrP called PrPSc is resistant to proteolysis as well as infectious. Present study was conducted in order to do sequence analysis of prion protein gene in twelve breeds of the sheep. We studied this gene to elucidate 12 of Pakistani sheep breeds and to compare gene order with other mammalian species. PCR amplification of 771 bp fragment was done on selected samples from all twelve breeds followed by sequencing. Sequence analysis was done and some sites were found to be heterozygous. These findings on prion protein gene in sheep will provide assistance for further studies on pathogenesis, cross-species transmission, breeding programs, resistance and susceptibility to scrapie.

Distribution of microRNA profiles in pre-clinical and clinical forms of murine and human prion disease

Prion diseases are distinguished by long pre-clinical incubation periods during which prions actively propagate in the brain and cause neurodegeneration. In the pre-clinical stage, we hypothesize that upon prion infection, transcriptional changes occur that can lead to early neurodegeneration. A longitudinal analysis of miRNAs in pre-clinical and clinical forms of murine prion disease demonstrated dynamic expression changes during disease progression in the affected thalamus region and serum. Serum samples at each timepoint were collected whereby extracellular vesicles (EVs) were isolated and used to identify blood-based biomarkers reflective of pathology in the brain. Differentially expressed EV miRNAs were validated in human clinical samples from patients with human sporadic Creutzfeldt-Jakob disease (sCJD), with the molecular subtype at codon 129 either methionine-methionine (MM, n = 14) or valine-valine (VV, n = 12) compared to controls (n = 20). EV miRNA biomarkers associated with prion infection predicted sCJD with an AUC of 0.800 (85% sensitivity and 66.7% specificity) in a second independent validation cohort (n = 26) of sCJD and control patients with MM or VV subtype. This study discovered clinically relevant miRNAs that benefit diagnostic development to detect prion-related diseases and therapeutic development to inhibit prion infectivity.

Post-Translational Protein Deimination Signatures in Plasma and Plasma EVs of Reindeer (Rangifer tarandus).

Simple SummaryReindeer are an important wild and domesticated species of the Arctic, Northern Europe, Siberia and North America. As reindeer have developed various strategies to adapt to extreme environments, this makes them an interesting species for studies into diversity of immune and metabolic functions in the animal kingdom. Importantly, while reindeer carry natural infections caused by viruses (including coronaviruses), bacteria and parasites, they can also act as carriers for transmitting such diseases to other animals and humans, so called zoonosis. Reindeer are also affected by chronic wasting disease, a neuronal disease caused by prions, similar to scrapie in sheep, mad cows disease in cattle and Creutzfeldt-Jakob disease in humans. The current study assessed a specific protein modification called deimination/citrullination, which can change how proteins function and allow them to take on different roles in health and disease processes. Profiling of deiminated proteins in reindeer showed that many important pathways for immune defenses, prion diseases and metabolism are enriched in deiminated proteins, both in plasma, as well as in plasma extracellular vesicles. This study provides a platform for the development of novel biomarkers to assess wild life health status and factors relating to zoonotic disease.The reindeer (caribou) Rangifer tarandus is a Cervidae in the order Artiodactyla. Reindeer are sedentary and migratory populations with circumpolar distribution in the Arctic, Northern Europe, Siberia and North America. Reindeer are an important wild and domesticated species, and have developed various adaptive strategies to extreme environments. Importantly, deer have also been identified to be putative zoonotic carriers, including for parasites, prions and coronavirus. Therefore, novel insights into immune-related markers are of considerable interest. Peptidylarginine deiminases (PADs) are a phylogenetically conserved enzyme family which causes post-translational protein deimination by converting arginine into citrulline in target proteins. This affects protein function in health and disease. Extracellular vesicles (EVs) participate in cellular communication, in physiological and pathological processes, via transfer of cargo material, and their release is partly regulated by PADs. This study assessed deiminated protein and EV profile signatures in plasma from sixteen healthy wild female reindeer, collected in Iceland during screening for parasites and chronic wasting disease. Reindeer plasma EV profiles showed a poly-dispersed distribution from 30 to 400 nm and were positive for phylogenetically conserved EV-specific markers. Deiminated proteins were isolated from whole plasma and plasma EVs, identified by proteomic analysis and protein interaction networks assessed by KEGG and GO analysis. This revealed a large number of deimination-enriched pathways for immunity and metabolism, with some differences between whole plasma and EVs. While shared KEGG pathways for whole plasma and plasma EVs included complement and coagulation pathways, KEGG pathways specific for EVs were for protein digestion and absorption, platelet activation, amoebiasis, the AGE–RAGE signaling pathway in diabetic complications, ECM receptor interaction, the relaxin signaling pathway and the estrogen signaling pathway. KEGG pathways specific for whole plasma were pertussis, ferroptosis, SLE, thyroid hormone synthesis, phagosome, Staphylococcus aureus infection, vitamin digestion and absorption, and prion disease. Further differences were also found between molecular function and biological processes GO pathways when comparing functional STRING networks for deiminated proteins in EVs, compared with deiminated proteins in whole plasma. This study highlights deiminated proteins and EVs as candidate biomarkers for reindeer health and may provide information on regulation of immune pathways in physiological and pathological processes, including neurodegenerative (prion) disease and zoonosis.

Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt–Jakob disease

Creutzfeldt–Jakob Disease (CJD) is a fatal, currently incurable, neurodegenerative disease. The search for candidate treatments would be greatly facilitated by the availability of human cell-based models of prion disease. Recently, an induced pluripotent stem cell derived human cerebral organoid model was shown to take up and propagate human CJD prions. This model offers new opportunities to screen drug candidates for the treatment of human prion diseases in an entirely human genetic background. Here we provide the first evidence that human cerebral organoids can be a viable model for CJD drug screening by using an established anti-prion compound, pentosan polysulfate (PPS). PPS delayed prion propagation in a prophylactic-like treatment paradigm and also alleviated propagation when applied following establishment of infection in a therapeutic-like treatment paradigm. This study demonstrates the utility of cerebral organoids as the first human 3D cell culture system for screening therapeutic drug candidates for human prion diseases.

N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases.

The normal cellular isoform of prion protein, designated PrPC, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrPSc, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrPC is a membrane glycoprotein consisting of the non-structural N-terminal domain and the globular C-terminal domain. During conversion of PrPC to PrPSc, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrPSc. Reverse genetic studies using reconstituted PrPC-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrPC and the conversion of PrPC to PrPSc. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrPC, the conversion of PrPC to PrPSc, and the neurotoxicity of PrPSc by focusing on the roles of the N-terminal regions in these topics.

Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice.

The cellular prion protein, PrPC, is a glycosylphosphatidylinositol anchored-membrane glycoprotein expressed most abundantly in neuronal and to a lesser extent in non-neuronal cells. Its conformational conversion into the amyloidogenic isoform in neurons is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. However, the normal functions of PrPC remain largely unknown, particularly in non-neuronal cells. Here we show that stimulation of PrPC with anti-PrP monoclonal antibodies (mAbs) protected mice from lethal infection with influenza A viruses (IAVs), with abundant accumulation of anti-inflammatory M2 macrophages with activated Src family kinases (SFKs) in infected lungs. A SFK inhibitor dasatinib inhibited M2 macrophage accumulation in IAV-infected lungs after treatment with anti-PrP mAbs and abolished the anti-PrP mAb-induced protective activity against lethal influenza infection in mice. We also show that stimulation of PrPC with anti-PrP mAbs induced M2 polarization in peritoneal macrophages through SFK activation in vitro and in vivo. These results indicate that PrPC could activate SFK in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype after stimulation with anti-PrP mAbs, thereby eliciting protective activity against lethal infection with IAVs in mice after treatment with anti-PrP mAbs. These results also highlight PrPC as a novel therapeutic target for IAV infection.

Molecular dynamics studies of dog prion protein wild-type and its D159N mutant

Prion diseases (e.g. ‘mad cow’ disease in cattle, chronic wasting disease in deer and elk, Creutzfeldt-Jakob disease in humans) have been a major public health concern affecting humans and almost all animals. However, dogs are strongly resistant to prion diseases. Recently, through transgenic techniques, it was reported that the single (surface) residue D159 is sufficient to confer protection against protein conformational change and pathogenesis, thus provides conformational stability for dog prion protein. This made a big breakthrough in dog prion protein research field. For dog prion protein, another advancement is the produce of its NMR structure in 2005. However, all these breakthroughs are still short of enough structural informatics of dog prion protein. This paper studies dog prion protein wild-type and D159N mutant through molecular dynamics (MD) techniques. Our MD results reveal sufficient structural informatics on the residue at position 159 to understand the mechanism underlying the resistance to prion diseases of dogs. The structural informatics of this paper should be very useful for the medicinal treatment of prion diseases. Communicated by Ramaswamy H. Sarma

Transmission characteristics of heterozygous cases of Creutzfeldt-Jakob disease with variable abnormal prion protein allotypes

In the human prion disease Creutzfeldt-Jakob disease (CJD), different CJD neuropathological subtypes are defined by the presence in normal prion protein (PrPC) of a methionine or valine at residue 129, by the molecular mass of the infectious prion protein PrPSc, by the pattern of PrPSc deposition, and by the distribution of spongiform change in the brain. Heterozygous cases of CJD potentially add another layer of complexity to defining CJD subtypes since PrPSc can have either a methionine (PrPSc-M129) or valine (PrPSc-V129) at residue 129. We have recently demonstrated that the relative amount of PrPSc-M129 versus PrPSc-V129, i.e. the PrPSc allotype ratio, varies between heterozygous CJD cases. In order to determine if differences in PrPSc allotype correlated with different disease phenotypes, we have inoculated 10 cases of heterozygous CJD (7 sporadic and 3 iatrogenic) into two transgenic mouse lines overexpressing PrPC with a methionine at codon 129. In one case, brain-region specific differences in PrPSc allotype appeared to correlate with differences in prion disease transmission and phenotype. In the other 9 cases inoculated, the presence of PrPSc-V129 was associated with plaque formation but differences in PrPSc allotype did not consistently correlate with disease incubation time or neuropathology. Thus, while the PrPSc allotype ratio may contribute to diverse prion phenotypes within a single brain, it does not appear to be a primary determinative factor of disease phenotype.

Prevalence in Britain of abnormal prion protein in human appendices before and after exposure to the cattle BSE epizootic

Widespread dietary exposure of the population of Britain to bovine spongiform encephalopathy (BSE) prions in the 1980s and 1990s led to the emergence of variant Creutzfeldt-Jakob Disease (vCJD) in humans. Two previous appendectomy sample surveys (Appendix-1 and -2) estimated the prevalence of abnormal prion protein (PrP) in the British population exposed to BSE to be 237 per million and 493 per million, respectively. The Appendix-3 survey was recommended to measure the prevalence of abnormal PrP in population groups thought to have been unexposed to BSE. Immunohistochemistry for abnormal PrP was performed on 29,516 samples from appendices removed between 1962 and 1979 from persons born between 1891 through 1965, and from those born after 1996 that had been operated on from 2000 through 2014. Seven appendices were positive for abnormal PrP, of which two were from the pre-BSE-exposure era and five from the post BSE-exposure period. None of the seven positive samples were from appendices removed before 1977, or in patients born after 2000 and none came from individuals diagnosed with vCJD. There was no statistical difference in the prevalence of abnormal PrP across birth and exposure cohorts. Two interpretations are possible. Either there is a low background prevalence of abnormal PrP in human lymphoid tissues that may not progress to vCJD. Alternatively, all positive specimens are attributable to BSE exposure, a finding that would necessitate human exposure having begun in the late 1970s and continuing through the late 1990s.

An Analysis of Media Reports on Key Issues of Mad Cow Disease in South Korea

Since 2008, South Korea has seen controversy over the risk of mad cow disease (bovine spongiform encephalopathy [BSE]) and its potential to lead to variant Creutzfeldt-Jakob disease (vCJD) in humans. National news organizations have covered the topic differently according to their ideological positions. This study sought to quantify these differences focusing on the five key BSE-related issues covered by the media as follows: 1) possibility of confusion between vCJD and degenerative brain disease, 2) vCJD incidence in humans, 3) risk of vCJD infection from eating beef from cattle aged 30 months or older, 4) scope of specified risk, and 5) vulnerability of South Koreans to BSE infection. Based on the analysis of media reports on each issue, we found that the progressive media tended to emphasize the risks of BSE more than the conservative media who promoted views opposing those of the progressive media. National public broadcasting companies tended to take a neutral position. Despite the scientific findings on each issue mentioned above, the South Korean press has failed to provide them to the public unbiasedly. We identified the need to reduce politicization and promote scientific approach in media coverage of the issues of mad cow disease in South Korea.

Introduction to Current Progress in Advanced Research on Prions.

Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurological diseases that include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, camel spongiform encephalopathy (CSE) in camels and chronic wasting disease (CWD) in cervids. A key event in prion diseases is the conversion of the cellular, host-encoded prion protein (PrPC) to its abnormal isoform (PrPSc) predominantly in the central nervous system of the infected host (Aguzzi et al., 2004). These diseases are transmissible under some circumstances, but unlike other transmissible disorders, prion diseases can also be caused by mutations in the host gene. The mechanism of prion spread among sheep and goats that develop natural scrapie is unknown. CWD, transmissible mink encephalopathy (TME), BSE, feline spongiform encephalopathy (FSE), and exotic ungulate encephalopathy (EUE) are all thought to occur after the consumption of prion-infected material. Most cases of human prion disease occur from unknown reasons, and greater than 20 mutations in the prion protein (PrP) gene may lead to inherited prion disease. In other instances, prion diseases are contracted by exposure to prion infectivity. These considerations raise the question of how a mere protein aggregate can bypass mucosal barriers, circumvent innate and adoptive immunity, and traverse the blood-brain barrier to give rise to brain disease. Here, we will briefly introduce a few topics in current prion studies.

Protective Role of the Host Innate Immune System in Prion Pathogenesis

Prion diseases, including human Creutzfeldt-Jakob disease, are infectious, intractable central neurodegenerative diseases, which are also zoonoses that commonly infect not only higher organisms but also a wide variety of animals. Pathogenic prions induce abnormal prion protein (PrP), which is produced by structural conversion of normal PrP, a beta-sheet-rich structure with high aggregation propensity. Thus, it is believed that the host is immunotolerant against prions because there is no difference in the primary structure of normal and abnormal PrP, and prions do not induce a marked immune response. Recently, using mutated Toll-like receptor (TLR) 4-transgenic mice, a bioassay after prion inoculation has intriguingly found that the TLR4-signaling pathway may have a protective role against prion infection. Meanwhile, we reported that a transcription factor, interferon regulatory factor-3 (IRF-3), located downstream of TLR4 signaling, showed resistance to prions. IRF-3-inducing type I interferon (I-IFN) is a critical factor for the host defense against pathogen invasion. These findings indicate that the TLR-signaling pathway of the innate immune system might regulate prion invasion. However, the details have not been fully determined. In this symposium, we will introduce new findings including the relationship between I-IFN and prions.

Physiological role of Prion Protein in Copper homeostasis and angiogenic mechanisms of endothelial cells

Abstract The Prion Protein (PrP) is mostly known for its role in prion diseases, where its misfolding and aggregation can cause fatal neurodegenerative conditions such as the bovine spongiform encephalopathy and human Creutzfeldt–Jakob disease. Physiologically, PrP is involved in several processes including adhesion, proliferation, differentiation and angiogenesis, but the molecular mechanisms behind its role remain unclear. PrP, due to its well-described structure, is known to be able to regulate copper homeostasis; however, copper dyshomeostasis can lead to developmental defects. We investigated PrP-dependent regulation of copper homeostasis in human endothelial cells (HUVEC) using an RNA-interference protocol. PrP knockdown did not influence cell viability in silenced HUVEC (PrPKD) compared to control cells, but significantly increased PrPKD HUVEC cells sensitivity to cytotoxic copper concentrations. A reduction of PrPKD cells reductase activity and copper ions transport capacity was observed. Furthermore, PrPKD-derived spheroids exhibited altered morphogenesis and their derived cells showed a decreased vitality 24 and 48 hours after seeding. PrPKD spheroid-derived cells also showed disrupted tubulogenesis in terms of decreased coverage area, tubule length and total nodes number on matrigel, preserving unaltered VEGF receptors expression levels. Our results highlight PrP physiological role in cellular copper homeostasis and in the angiogenesis of endothelial cells.

Richard Lacey: microbiologist who came under fire for claiming a link between mad cow disease and variant CJD in humans

Photo credit: UPPA/PHOTOSHOT Richard Lacey was the dissident University of Leeds medical microbiologist who was ridiculed in 1990 for suggesting a possible link between the cattle disease bovine spongiform encephalopathy...

Type I interferon protects neurons from prions in in vivo models.

Infectious prions comprising abnormal prion protein, which is produced by structural conversion of normal prion protein, are responsible for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease in humans. Prions are infectious agents that do not possess a genome and the pathogenic protein was not thought to evoke any immune response. Although we previously reported that interferon regulatory factor 3 (IRF3) was likely to be involved in the pathogenesis of prion diseases, suggesting the protective role of host innate immune responses mediated by IRF3 signalling, this remained to be clarified. Here, we investigated the reciprocal interactions of type I interferon evoked by IRF3 activation and prion infection and found that infecting prions cause the suppression of endogenous interferon expression. Conversely, treatment with recombinant interferons in an ex vivo model was able to inhibit prion infection. In addition, cells and mice deficient in type I interferon receptor (subunit interferon alpha/beta receptor 1), exhibited higher susceptibility to 22L-prion infection. Moreover, in in vivo and ex vivo prion-infected models, treatment with RO8191, a selective type I interferon receptor agonist, inhibited prion invasion and prolonged the survival period of infected mice. Taken together, these data indicated that the interferon signalling interferes with prion propagation and some interferon-stimulated genes might play protective roles in the brain. These findings may allow for the development of new strategies to combat fatal diseases.