Type I interferon protects neurons from prions in<i>in vivo</i>models

Ishibashi, Daisuke; Homma, Takujiro; Nakagaki, Takehiro; Fuse, Takayuki; Sano, Kazunori; Satoh, Katsuya; Mori, Tsuyoshi; Atarashi, Ryuichiro; Nishida, Naoshi

doi:10.1093/brain/awz016

Cited by 24 publications

(22 citation statements)

References 53 publications

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“…Conversely, data from another series of studies have proposed that type I IFN may play a protective role [ 239 , 240 ]. In contrast to data above [ 235 ], prion disease developed earlier in Ifnar1 −/− mice infected with 22L scrapie prions, whereas treatment with a type I IFN antagonist (RO8191) extended survival times [ 240 ]. The reasons behind these discrepancies are not immediately apparent, but further studies may help to identify specific type I IFN regulators that influence the rate of development of CNS prion disease in certain individuals.…”

Section: Cns Prion Diseasementioning

confidence: 99%

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

Mabbott

Bradford

Pal

et al. 2020

IJMS

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Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.

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Section: Cns Prion Diseasementioning

confidence: 99%

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

Mabbott

Bradford

Pal

et al. 2020

IJMS

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“…These proteins are upstream of I-IFN, which results in a cascade of signals inducing immune response [29]. Moreover, ex vivo experiments in scrapie infected mice have shown that inducing I-IFN via TLR signalling reduces PrP Sc concentration in the model host during the early stages of infection [31]. With these two treatments, prion formation can be slown with pharmacological chaperones and the prion population can be significantly diminished with interferons.…”

Section: Possible Treatments For Prion Diseasesmentioning

confidence: 99%

“…Two types of treatments are incorporated in this biological model. The first one consists of a dose of pharmacological chaperones which prevent prion formation based on in vivo experiments by Gunther et al [32]; the second treatment consists of a dose of interferons that decreases the amount of prions in the brain [31]. Our model is based on two previous mathematical models.…”

Section: Possible Treatments For Prion Diseasesmentioning

confidence: 99%

“…In this model, the interferon treatment is represented by the interferoninduced mortality of PrP Sc chains, µ I . In order to define the functional form linking µ I with an interferon daily dosage I, we analyzed recent experimental data measuring prion degradation after inoculation with interferons [31]. The study reports the ratio between prion concentrations in treated and untreated mice, 48h after the inoculation with increasing interferon dosages.…”

Section: Linking Interferon Dosage To Prion Mortalitymentioning

confidence: 99%

“…The values of the concentrations of interferon's were taken from experimental data [31]. In the experiments,the concentration is measured in kU/ml and 48h after interferon doses the rate is considered dividing the total amount of prion over the control amount (which does not include the interferon treatment).…”

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Dynamics of Prion Proliferation Under Combined Treatment of Pharmacological Chaperones and Interferons via a Mathematical Model

Garzón

Castillo

Navas-Zuloaga

et al. 2020

Preprint

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AbstractPrion diseases are lethal neurodegenerative disorders such as mad cow disease in bovines, chronic wasting disease in cervids, and Creutzfeldt-Jakob disease in humans. They are caused when the prion protein PrPC misfolds into PrPSc, which is capable of inducing further misfolding in healthy PrPC proteins. Recent in vivo experiments show that pharmacological chaperones can temporarily prevent this conversion by binding to PrPC molecules, and thus constitute a possible treatment. A second strategic approach uses interferons to decrease the concentration of PrPSc. In order to study the quantitative effects of these treatments on prion proliferation, we develop a model using a non-linear system of ordinary differential equations. By evaluating their efficacy and potency, we find that interferons act at lower doses and achieve greater prion decay rates. However, there are benefits in combining them with pharmacological chaperones in a two-fold therapy. This research is crucial to guide future prion experiments and inform potential treatment protocols.

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Administration of FK506 from Late Stage of Disease Prolongs Survival of Human Prion-Inoculated Mice

et al. 2020

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Human prion diseases are etiologically categorized into three forms: sporadic, genetic, and infectious. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common type of human prion disease that manifests as subacute progressive dementia. No effective therapy for sCJD is currently available. Potential therapeutic compounds are frequently tested in rodents infected with mouse-adapted prions that differ from human prions. However, therapeutic effect varies depending on the prion strain, which is one of the reasons why candidate compounds have shown little effect in sCJD patients. We previously reported that intraperitoneal administration of FK506 was able to prolong the survival of mice infected with a mouse-adapted prion by suppressing the accumulation of abnormal prion protein (PrP) and inhibiting the activation of microglia. In this study, we tested oral administration of FK506 in knock-in mice expressing chimeric human prion protein (KiChM) that were infected with sCJD to determine if this compound is also effective against a clinically relevant human prion, i.e., one that has not been adapted to mice. Treatment with FK506, started either just before or just after disease onset, suppressed typical sCJD pathology (gliosis) and slightly but significantly prolonged the survival of sCJD-inoculated mice. It would be worthwhile to conduct a clinical trial using FK506, which has been safety-approved and is widely used as a mild immunosuppressant.

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Type I interferon protects neurons from prions inin vivomodels

Cited by 24 publications

References 53 publications

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

Dynamics of Prion Proliferation Under Combined Treatment of Pharmacological Chaperones and Interferons via a Mathematical Model

Administration of FK506 from Late Stage of Disease Prolongs Survival of Human Prion-Inoculated Mice

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