PMCA generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice
- Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy
- Centro de Investigación en Sanidad Animal (CISA-INIA), Spain
- ASST Santi Paolo e Carlo Università Degli Studi di Milano, Italy
- Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Italy
Abstract
Background: Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA).
Methods In this work, we have challenged PMCA generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology.
Results: All inoculated mice developed mild spongiform changes, astroglial activation and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate.
Conclusions: Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious.
Funding: This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer's Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (Speedy) to FM; by the Spanish Ministerio de Economía y Competitividad [grant AGL2016-78054-R (AEI/FEDER, UE)] to J.M.T. and J.C.E.; A.M.-M. was supported by a fellowship from the INIA (FPI-SGIT-2015-02).
Data availability
All data generated or analyzed during this study are included in the manuscript.
Article and author information
Author details
Juan Carlos Espinosa
Funding
Ministero della Salute (GR-2013-02355724)
- Fabio Moda
Ministero della Salute (Ricerca Corrente)
- Fabio Moda
MJFF, ALZ, Alzheimer's Research UK and the Weston Brain Institute (BAND2015)
- Fabio Moda
Euronanomed III (Speedy)
- Fabio Moda
Spanish Ministerio de Economia y Competitividad (AGL2016-78054-R (AEI/FEDER,UE))
- Juan Maria Torres
INIA (Fellowship FPI-SGIT-2015-02)
- Alba Marín Moreno
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: We conducted animal experiments in accordance with the Code for Methods and Welfare Considerations in Behavioural Research with Animals (Directive 2010/63/EU) and made every effort to minimize suffering. Experiments developed in Centro de Investigación en Sanidad Animal-Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (Madrid, Spain) were evaluated by the Committee on the Ethics of Animal Experiments of the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria and approved by the General Directorate of the Madrid Community Government (permit no. PROEX 263-15)
Human subjects: Written informed consent for participation in research and all procedures for sample collection and experimental studies were in accordance with the 1964 Declaration of Helsinki and its later amendments and were approved by the Ethical Committee of "Fondazione IRCCS Istituto Neurologico Carlo Besta" (Milan, Italy).
Copyright
© 2021, Bistaffa et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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PMCA generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice
eLife 10:e65311.
https://doi.org/10.7554/eLife.65311
Further reading
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Background:
Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.
Methods:
We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.
Results:
42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.
Conclusions:
The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.
Funding:
Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.
