Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice

Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice

Johannes Haybaeck1#¤a, Mathias Heikenwalder1#¤b, Britta Klevenz2#, Petra Schwarz1, Ilan Margalith1, Claire Bridel1, Kirsten Mertz1,3, Elizabeta Zirdum2, Benjamin Petsch2, Thomas J. Fuchs4, Lothar Stitz2*, Adriano Aguzzi1*

1 Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland, 2 Institute of Immunology, Friedrich-Loeffler-Institut, Tübingen, Germany, 3 Department of Pathology, Clinical Pathology, University Hospital Zurich, Zurich, Switzerland, 4 Department of Computer Science, Machine Learning Laboratory, ETH Zurich, Zurich, Switzerland

Abstract Top Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrPC, efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrPC selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrPSc and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories.

Author Summary Top Prions, which are the cause of fatal neurodegenerative disorders termed transmissible spongiform encephalopathies (TSEs), can be experimentally or naturally transmitted via prion-contaminated food, blood, milk, saliva, feces and urine. Here we demonstrate that prions can be transmitted through aerosols in mice. This also occurs in the absence of immune cells as demonstrated by experiments with mice lacking B-, T-, follicular dendritic cells (FDCs), lymphotoxin signaling or with complement-deficient mice. Therefore, a functionally intact immune system is not strictly needed for aerogenic prion infection. These results suggest that current biosafety guidelines applied in diagnostic and scientific laboratories ought to include prion aerosols as a potential vector for prion infection.

Citation: Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, et al. (2011) Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice. PLoS Pathog 7(1): e1001257. doi:10.1371/journal.ppat.1001257

Editor: David Westaway, University of Alberta, Canada

Received: March 22, 2010; Accepted: December 13, 2010; Published: January 13, 2011

Copyright: © 2011 Haybaeck et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported in part by EU grants ANTEPRION and PRIORITY (LS), and the TSE-Forschungsprogramm des Landes Baden-Wuerttemberg, Germany (LS). This work was also supported by grants from the UK Department of Environment, Food and Rural Affairs (AA), the EU grants LUPAS and PRIORITY (AA), the Novartis Research Foundation (AA), and an Advanced Grant of the European Research Council to AA. MH was supported by the Foundation for Research at the Medical Faculty, the Prof. Dr. Max-Cloetta foundation and the Bonizzi-Theler Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: adriano.aguzzi@usz.ch (AA); lothar.stitz@fli.bund.de (LS)

# These authors contributed equally to this work.

¤a Current address: Institute of Pathology, Medical University Graz, Graz, Austria

¤b Current address: Institute of Virology, Technical University München/Helmholtz Zentrum München, Munich, Germany

snip...

In summary, our results establish aerosols as a surprisingly efficient modality of prion transmission. This novel pathway of prion transmission is not only conceptually relevant for the field of prion research, but also highlights a hitherto unappreciated risk factor for laboratory personnel and personnel of the meat processing industry. In the light of these findings, it may be appropriate to revise current prion-related biosafety guidelines and health standards in diagnostic and scientific laboratories being potentially confronted with prion infected materials. While we did not investigate whether production of prion aerosols in nature suffices to cause horizontal prion transmission, the finding of prions in biological fluids such as saliva, urine and blood suggests that it may be worth testing this possibility in future studies.

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001257



Greetings,

This science is really old news, science that should have been taken seriously long ago. The ramifications from this could be monumental for all grazing livestock for human and animal consumption. The environmental poisoning of the land with prions from so many different strains, and so many different species here in the USA, and with these animals grazing and feeding off these prion toxic lands, and then rendered up for consumption for both man and animal, it's just a toxic mess. The fact the testing and surveillance for the TSE prion in the USA bovine was so flawed with corruption and fraud, there is no telling just how much of the pasture grazing land is contaminated. NOT to forget the meat-bone-meal for flowers, plants, etc., that most all of us have used, and still are in use, and the inhalation of these prions there from via this very mode of transmission. We were discussing this a decade ago. I mean, how long do we have to keep discussing all these potential routes and modes of transmission of the prion diseases that are killing people, before the industries involved take this seriously $


Then you have water tables contaminated with prion disease ;

Wednesday, October 14, 2009

Detection of protease-resistant cervid prion protein in water from a CWD-endemic area

http://chronic-wasting-disease.blogspot.com/2009/10/detection-of-protease-resistant-cervid.html


Friday, January 7, 2011

MEAT AND BONE MEAL AND MINERAL FEED ADDITIVES MAY INCREASE THE RISK OF ORAL PRION DISEASE TRANSMISSION

Journal of Toxicology and Environmental Health, Part A, 74:161–166, 2011 Copyright © Taylor & Francis Group, LLC ISSN: 1528-7394 print / 1087-2620 online DOI: 10.1080/15287394.2011.529066

http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/meat-and-bone-meal-and-mineral-feed.html



April 6, 2010 12:45 PM

Terry S. Singeltary Sr. said...

Greetings,

I have been following the novel polyradiculoneuropathy that was identified at a pork abattoir with great interest.

MY concern are with not only the pig brains, but cattle brains and risk fact to Transmissible Spongiform Encephalopathy.

my concern ;

nasal aerosol CJD, never say never.

PLEASE note, certain orthopedic surgery and bone grinding is a risk factor for potential nasal aerosol transmission of TSE. There may be no documented case of this mode of transmission to date, however, this does not mean it has not, or cannot take place, and a keen watch should be mandated. There is recent science with other TSE that indeed this mode of transmission is real. AS well, precaution should be used when working with TSE and aerosol of the TSE agent at hand i.e. bone grinding for example.

PrPTSE has also been detected in olfactory epithelium in sporadic CJD patients at post mortem (11), and in the olfactory tract in vCJD


http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@ab/documents/digitalasset/dh_114045.pdf


http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@ab/documents/digitalasset/dh_111792.pdf


P10. Aerosol, Nasal, and Oral Transmission of Chronic Wasting Disease

Nathaniel D. Denkers1, Glenn C. Telling2 and Edward A. Hoover1

1Department of Microbiology, Immunology, and Pathology Colorado State University, Fort Collins, Colorado 80523. E-mail: nddenk@lamar.colostate.edu 2Department of Microbiology, Immunology and Molecular Genetics, and Department of Neurology, University of Kentucky, Lexington, Kentucky 40536

Purpose: While the exact mechanisms of chronic wasting disease (CWD) prion transmission, entry, and trafficking remain incompletely elucidated, transmission by exposure of the oral and/or nasal mucous membranes seems certain. Little is known regarding the potential risk posed by aerosolized prions. In addition, as part of foraging, cervids likely experience minor lesions in the oral mucous membranes. We explored whether CWD may be transmissible by aerosol or nasal mucosal exposure and whether or not micro-abrasions to the lingual mucosa may enhance susceptibility to oral CWD infection in mice transgenetically expressing cervid PrP.

Methods: FVB mice transgenically expressing the normal cervid PrPC protein [Tg(cerPrP) mice] were exposed to CWD prions by either nose-only exposure to an aerosol (0.5 ml of a 5% w/v brain homogenate), by drop-wise instillation into the nostrils (10µl of a 10% w/v brain homogenate), or inoculated orally (same inoculum) with or without micro-abrasions on the lingual mucosa. Cohorts were sacrificed at 1, 2, 12, 52, 78, and 104 weeks post inoculation (pi) or when signs of neurologic disease were observed. Mice were assessed for PrPCWD by western blotting and immunohistochemistry, with particular scrutiny directed to the nasal mucosa, vomeronasal organ, tongue, lymphoid tissue, and brain.

Results: Six of 7 aerosol-exposed and 2 of 9 IN-inoculated Tg(cerPrP) mice developed clinical signs of neurologic dysfunction mandating euthanasia between 411 and 755 dpi. Between 296 and 515 dpi, 9 of 9 CWD-inoculated mice with lingual lesions developed clinical signs of neurologic dysfunction mandating euthanasia. Conversely, all mice without oral lesions remain asymptomatic at >575 dpi. All of the symptomatic mice were positive for PrPCWD by western blot and immunohistochemistry. No evidence of PrPCWD could be detected in any Tg(cerPrP) mice sacrificed and examined at any of the pre-terminal time points.

Conclusions: CWD can be transmitted by aerosol and nasal exposure--potentially implicating exposure via the respiratory mucosa in CWD. Micro-abrasions to the lingual surface substantially facilitated CWD transmission, suggesting a co-factor that may be significant in foraging cervids or other species. These findings could have implications for the mucosal transmission of other prion diseases.

http://www.neuroprion.org/resources/pdf_docs/conferences/prion2009/brochure-tse_workshop.pdf


P.4.26

Aerosol and intranasal transmission of CWD

http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf


J Gen Virol (2010), DOI 10.1099/vir.0.017335-0 © 2010 Society for General Microbiology

Aerosol and Nasal Transmission of Chronic Wasting Disease in Cervidized Mice

Nathaniel D Denkers1, Davis M Seelig1, Glenn C. Telling2 and Edward A Hoover, Jr1,3

1 Colorado State University; 2 University of Kentucky Medical Center

These results demonstrate that CWD can be transmitted by aerosol (as well as nasal) exposure and suggest that exposure via the respiratory system merits consideration for prion disease transmission and biosafety.

Received 30 October 2009; accepted 15 February 2010.

http://vir.sgmjournals.org/cgi/content/abstract/vir.0.017335-0v1


http://jvi.asm.org/cgi/content/abstract/83/13/6435


http://jvi.asm.org/cgi/content/abstract/83/8/3657


http://vet.sagepub.com/content/46/1/59.abstract


see ;


April 6, 2010 12:45 PM

http://neuropathologyblog.blogspot.com/2010/03/interferon-gamma-in-pig-pin.html



Aerosol and nasal transmission of chronic wasting disease in cervidized mice

Nathaniel D. Denkers1, Davis M. Seelig1, Glenn C. Telling2 and Edward A. Hoover1 1 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1619, USA 2 Department of Microbiology, Immunology and Molecular Genetics, Sanders Brown Center of Aging and Department of Neurology, University of Kentucky, Lexington, KY, USA Correspondence Edward A. Hoover edward.hoover@colostate.edu

Little is known regarding the potential risk posed by aerosolized prions. Chronic wasting disease (CWD) is transmitted horizontally, almost surely by mucosal exposure, and CWD prions are present in saliva and urine of infected animals. However, whether CWD may be transmissible by the aerosol or nasal route is not known. To address this question, FVB mice transgenetically expressing the normal cervid PrPC protein [Tg(cerPrP) mice] were exposed to CWD prions by either nose-only aerosol exposure or by drop-wise instillation into the nostrils. Mice were monitored for signs of disease for up to 755 days post-inoculation (p.i.) and by examination of tissues for lesions and PrPCWD after necropsy. In particular, nasal mucosa, vomeronasal organ, lungs, lymphoid tissue and the brain were assessed for PrPCWD by Western blotting and immunohistochemistry. Six of seven aerosol-exposed Tg(cerPrP) mice developed clinical signs of neurological dysfunction mandating euthanasia between 411 and 749 days p.i. In all these mice, CWD infection was confirmed by detection of spongiform lesions and PrPCWD in the brain. Two of nine intranasally inoculated Tg(cerPrP) mice also developed transmissible spongiform encephalopathy associated with PrPCWD between 417 and 755 days p.i. No evidence of PrPCWD was detected in CWD-inoculated Tg(cerPrP) mice examined at pre-terminal time points. These results demonstrate that CWD can be transmitted by aerosol (as well as nasal) exposure and suggest that exposure via the respiratory system merits consideration for prion disease transmission and biosafety.

http://vir.sgmjournals.org/cgi/content/abstract/91/6/1651


http://chronic-wasting-disease.blogspot.com/2010/11/cwd-update-98-november-10-2010.html



nasal aerosol CJD

PLEASE note, certain orthopedic surgery and bone grinding is a risk factor for potential nasal aerosol transmission of TSE. There may be no documented case of this mode of transmission to date, however, this does not mean it has not, or cannot take place, and a keen watch should be mandated. There is recent science with other TSE that indeed this mode of transmission is real. AS well, precaution should be used when working with TSE and aerosol of the TSE agent at hand i.e. bone grinding for example.

ALSO, there has been a documented case of husband and wife CJD, and a man and his cat, both with CJD. a cat with Creutzfeldt Jakob Disease instead of Feline Spongiform Encephalopathy raises many questions, as with the man and his wife with CJD. ...

Kindest Regards, Terry S. Singeltary Sr.


PrPTSE has also been detected in olfactory epithelium in sporadic CJD patients at post mortem (11), and in the olfactory tract in vCJD

http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@ab/documents/digitalasset/dh_114045.pdf


http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@ab/documents/digitalasset/dh_111792.pdf

http://www.michigan-sportsman.com/forum/showthread.php?p=3390684



The development of transgenic (Tg) mice expressing cervid PrP, and thus susceptible to CWD, has enhanced detection of CWD and the estimation of prion titers (Browning et al. 2004; Tamgüney et al. 2006). Shedding of prions in the feces, even in presymptomatic deer, has been identified as a likely source of infection for these grazing animals (Williams and Miller 2002; Tamgüney et al. 2009b). CWD has been transmitted to cattle after intracerebral inoculation, although the infection rate was low (4 of 13 animals [Hamir et al. 2001]). This finding raised concerns that CWD prions might be transmitted to cattle grazing in contaminated pastures.

snip...please see full text here ;


http://cshperspectives.cshlp.org/content/3/1/a006833.full.html#ref-24


***

Thursday, December 23, 2010

Alimentary prion infections: Touch-down in the intestine, Alzheimer, Parkinson disease and TSE mad cow diseases $ The Center for Consumer Freedom


http://betaamyloidcjd.blogspot.com/2010/12/alimentary-prion-infections-touch-down.html


http://betaamyloidcjd.blogspot.com/




Tuesday, August 12, 2008

Biosafety in Microbiological and Biomedical Laboratories Fifth Edition 2007 (occupational exposure to prion diseases)


http://creutzfeldt-jakob-disease.blogspot.com/2008/08/biosafety-in-microbiological-and.html



snip...

In BASE, in addition to PrP-amyloid plaques in the olfactory bulb, the highest levels of PrPSc were recovered from the thalamus and olfactory regions.2 Also, in both captive and free-ranging mule deer with chronic wasting disease, the olfactory cortex has been found to be among the most severely affected areas of the brain.8 Such patterns may be solely a reflection of selective vulnerability of certain neuroanatomic loci and, in end-stage disease, a reflection of phenotype, but equally, they arouse speculation as to possible olfactory portals of infection or excretion of agent. In human transmissible spongiform encephalopathies (TSEs), PrPSc immunolabeling has been reported in the olfactory tract of a variant Creutzfeldt-Jakob disease patient, and in sporadic Creutzfeldt-Jakob disease (sCJD), selective deposition of PrPSc in olfactory glomeruli, olfactory tracts, and olfactory cortex is recorded.6 In the latter study, PrPSc was also reported in the cilia of olfactory receptor neurons and basal cells of the olfactory epithelium but not in the respiratory epithelium. Detection of PrPSc in an olfactory mucosa biopsy, performed 45 days after disease onset in a sCJD patient, led to the suggestion that the involvement of olfactory epithelium might be an early event in sCJD.6

snip...

The present study demonstrates that, in clinical cases, involvement of the olfactory lobe is a consistent phenotypic feature of classic BSE but, in contrast to BASE,3 it is not preferentially affected compared with the cerebral cortex or brainstem. In studies of the pathogenesis of classical BSE after oral exposure, infectivity has not been demonstrated in nasal mucosa,11 but it has been shown, albeit at low titer, in this tissue in clinical cases of scrapie of sheep and goats.5 The detection of PrPSc in olfactory bulb in this study and indeed in other TSEs in terminal disease suggests that olfactory pathways cannot be excluded as a secondary or ancillary route of infection.

http://www.vetpathology.org/cgi/content/abstract/46/1/59


http://www.vetpathology.org/cgi/reprint/46/1/59



see full text ;


http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html



Friday, December 11, 2009

CWD, FECES, ORAL LESIONS, Aerosol and intranasal transmission

http://chronic-wasting-disease.blogspot.com/2009/12/cwd-feces-oral-lesions-aerosol-and.html


http://chronic-wasting-disease.blogspot.com/


http://creutzfeldt-jakob-disease.blogspot.com/2010/06/cjd-annex-h-update-after-death.html


http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf


Wednesday, December 29, 2010

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY PRION END OF YEAR REPORT DECEMBER 29, 2010

http://transmissiblespongiformencephalopathy.blogspot.com/2010/12/transmissible-spongiform-encephalopathy.html



TSS