Prions in Milk from Ewes Incubating Natural Scrapie
Caroline Lacroux1, Stéphanie Simon2, Sylvie L. Benestad3, Séverine Maillet2, Jacinthe Mathey1, Séverine Lugan1, Fabien Corbière1, Hervé Cassard1, Pierrette Costes1, Dominique Bergonier1, Jean-Louis Weisbecker4, Torffin Moldal3, Hugh Simmons5, Frederic Lantier6, Cécile Feraudet-Tarisse1,2, Nathalie Morel2, François Schelcher1, Jacques Grassi2, Olivier Andréoletti1*
1 UMR INRA ENVT 1225, Interactions Hôte Agent Pathogène, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France, 2 CEA, Service de Pharmacologie et d'Immunoanalyse, IBiTec-S, DSV, CEA/Saclay, Gif sur Yvette, France, 3 National Veterinary Institute, Sentrum, Oslo, Norway, 4 INRA Domaine de Langlade, Pompertuzat, France, 5 VLA Weybridge, New Haw, Addlestone, Surrey, United Kingdom, 6 INRA IASP, Centre INRA de Tours, Nouzilly, France
Abstract Since prion infectivity had never been reported in milk, dairy products originating from transmissible spongiform encephalopathy (TSE)-affected ruminant flocks currently enter unrestricted into the animal and human food chain. However, a recently published study brought the first evidence of the presence of prions in mammary secretions from scrapie-affected ewes. Here we report the detection of consistent levels of infectivity in colostrum and milk from sheep incubating natural scrapie, several months prior to clinical onset. Additionally, abnormal PrP was detected, by immunohistochemistry and PET blot, in lacteal ducts and mammary acini. This PrPSc accumulation was detected only in ewes harbouring mammary ectopic lymphoid follicles that developed consequent to Maedi lentivirus infection. However, bioassay revealed that prion infectivity was present in milk and colostrum, not only from ewes with such lympho-proliferative chronic mastitis, but also from those displaying lesion-free mammary glands. In milk and colostrum, infectivity could be recovered in the cellular, cream, and casein-whey fractions. In our samples, using a Tg 338 mouse model, the highest per ml infectious titre measured was found to be equivalent to that contained in 6 µg of a posterior brain stem from a terminally scrapie-affected ewe. These findings indicate that both colostrum and milk from small ruminants incubating TSE could contribute to the animal TSE transmission process, either directly or through the presence of milk-derived material in animal feedstuffs. It also raises some concern with regard to the risk to humans of TSE exposure associated with milk products from ovine and other TSE-susceptible dairy species.
Author Summary A decade ago, a new variant form of Creutzfeldt-Jakob disease was identified. The emergence of this prion disease in humans was the consequence of the zoonotic transmission of bovine spongiform encephalopathy through dietary exposure. Since then, the control of human exposure to prions has become a priority, and a policy based on the exclusion of known infectious materials from the food chain has been implemented. Because all investigations carried out failed to reveal evidence of infectivity in milk from affected ruminants, this product has continuously been considered as safe. In this study, we demonstrate the presence of prions in colostrum and milk from sheep incubating natural scrapie and displaying apparently healthy mammary glands. This finding indicates that milk from small ruminants could contribute to the transmission of prion disease between animals. It also raises some concern with regard to the risk to humans associated with milk products from ovine and other dairy species.
Citation: Lacroux C, Simon S, Benestad SL, Maillet S, Mathey J, et al. (2008) Prions in Milk from Ewes Incubating Natural Scrapie. PLoS Pathog 4(12): e1000238. doi:10.1371/journal.ppat.1000238
Editor: Umberto Agrimi, Istituto Superiore di Sanità, Italy
Received: July 1, 2008; Accepted: November 12, 2008; Published: December 12, 2008
Copyright: © 2008 Lacroux 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 study was financially supported by GIS infections à prion (French Research Ministry), EU FAIR (QLK-CT 2001-390), and DEFRA (SE2004, contract: CSA 6914).
Competing interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
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Human and animal exposure risk related to TSEs from milk
Sun Nov 9, 2008 08:46 22.214.171.124
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Human and animal exposure risk related to Transmissible Spongiform Encephalopathies (TSEs) from milk and milk products derived from small ruminants Scientific opinion of the Panel on Biological Hazards Question number: EFSA-Q-2008-310
Adopted date: 22 October 2008 Summary (0.1Mb)
Following a request from the European Commission (EC), the Panel on Biological Hazards (BIOHAZ) was asked to deliver a scientific opinion on the Human and animal exposure risk related to Transmissible Spongiform Encephalopathies (TSEs) from milk and milk products derived from small ruminants.
In a recent scientific article from Konold et al., published on 8 April 2008 in BMC Veterinary Research, on "Evidence of scrapie transmission via milk" it is concluded that: ".there is a risk of the transmission of scrapie from ewe to lamb via milk or colostrum. Infection of lambs via milk may result in shedding of the infectious agent into the environment.".
The BIOHAZ Panel was invited to provide an opinion on the conclusions from the article of Konold et al. (2008), and if considered necessary, based on any additional available scientific data, to update the current risk assessments on the human and animal exposure related to Transmissible Spongiform Encephalopathies (TSEs) from milk and milk products derived from small ruminants.
When approaching the mandate the BIOHAZ Panel did not consider the zoonotic potential of small ruminant TSE agents. This aspect is considered in detail in previous EFSA documents,. The TSE agents considered in the assessment were Classical scrapie, Atypical scrapie and BSE. Moreover, the assessment was performed employing mainly data from TSE in sheep, which were considered valid also for TSE in goats due to the lack of more specific data in that species.
The Panel considered valid the conclusion of the article of Konold et al. (2008). Expanding the article of Konold et al. (2008), another study from Lacroux et al. (2008) independently demonstrated that Classical scrapie can be transmitted from susceptible ewe to transgenic mice via colostrum and milk. It was emphasized that both studies were designed to achieve the highest possibility of transmission success and that this could differ from the field situation. The Panel noted that in both studies, milk from asymptomatic donor ewes transmitted disease, indicating that clinically healthy, Classical scrapie-incubating sheep may shed the causal agents of these TSEs in milk. Moreover, the level of prion infectivity in small ruminant milk could become higher during the course of mastitis but the somatic cell count was considered as an unreliable indicator for presence or absence of TSE infectivity in small ruminant milk.
The Panel concluded that the use of milk and milk products from a flock with Classical scrapie may carry a TSE exposure risk for humans and animals. Furthermore, the use of milk and milk products from the general small ruminant population may carry a TSE exposure risk for humans and animals due to the presence of undetected affected flocks in that population. However, because of the difference in scrapie prevalence between affected flocks and the general small ruminant population, the risk of exposure for humans and animals associated with milk and milk products from the general small ruminant population will be lower than the risk from detected scrapie affected flocks.
The Panel also concluded that the exposure to a Classical scrapie agent via milk of an infected animal can be estimated to be 4 to 5 logs10 lower than the infectivity found in the same weight of brainstem from a terminally affected animal, and 2 to 3 logs10 lower the than infectivity found in the same weight of lymphoid tissues from an animal incubating scrapie or from a clinically affected animal.
The BIOHAZ Panel further noted that no information is available concerning the presence of infectivity or PrPSc in colostrum or milk from small ruminants affected by Atypical scrapie or BSE. However, the Panel emphasized that due to the early and progressive peripheral tissue dissemination of the BSE agent in experimentally infected susceptible sheep, the occurrence of infectivity in colostrum and milk of BSE infected susceptible small ruminants would be likely. On the other hand, the apparent restricted dissemination of the agent of Atypical scrapie in affected individuals could limit its transmissibility through milk.
As there is large variation between MS in prevalence of scrapie and production of small ruminant milk, the human and animal exposure associated with small ruminant dairy products varies greatly between MS.
The Panel further concluded that breeding of sheep for relative resistance to Classical scrapie according to the previous EFSA opinion can be expected to reduce human and animal exposure associated with small ruminant dairy products.
The Panel recommended to perform research in order to characterise the exposure risk via milk especially in Atypical scrapie and BSE in small ruminants, to investigate on the stability of prion infectivity in milk during further processing, and to obtain more data to confirm and expand the preliminary information available on the quantitation of infectivity levels in small ruminant milk fractions. ___________________________________ Opinion of the Scientific Panel on Biological Hazards on certain aspects related to the risk of Transmissible Spongiform Encephalopathies (TSEs) in ovine and caprine animals. The EFSA Journal (2007) 466, 1-10  Scientific and technical clarification in the interpretation and consideration of some facets of the conclusions of its Opinion of 8 March 2007 on certain aspects related to the risk of Transmissible Spongiform Encephalopathies (TSEs) in ovine and caprine animals. The EFSA Journal (2008) 626, 1-11  Opinion of the Scientific Panel on Biological Hazards on "the breeding programme for TSE resistance in sheep", The EFSA Journal (2006), 382, 1-46
Publication date: 6 November 2008
Prion Protein in Milk
Nicola Franscini1, Ahmed El Gedaily1, Ulrich Matthey1, Susanne Franitza1, Man-Sun Sy2, Alexander Bürkle3, Martin Groschup4, Ueli Braun5, Ralph Zahn1*
1 Alicon AG, Schlieren, Switzerland, 2 Institute of Pathology, Biomedical Research Building, Case Western University School of Medicine, Cleveland, Ohio, United States of America, 3 Lehrstuhl Molekulare Toxikologie, University of Konstanz, Konstanz, Germany, 4 Friedrich-Loeffler-Institut, Bundesforschungsinstitut für Tiergesundheit, Greifswald, Gemany, 5 Departement für Nutztiere, University of Zurich, Zurich, Switzerland
Abstract Background Prions are known to cause transmissible spongiform encephalopathies (TSE) after accumulation in the central nervous system. There is increasing evidence that prions are also present in body fluids and that prion infection by blood transmission is possible. The low concentration of the proteinaceous agent in body fluids and its long incubation time complicate epidemiologic analysis and estimation of spreading and thus the risk of human infection. This situation is particularly unsatisfactory for food and pharmaceutical industries, given the lack of sensitive tools for monitoring the infectious agent.
Methodology/Principal Findings We have developed an adsorption matrix, Alicon PrioTrap®, which binds with high affinity and specificity to prion proteins. Thus we were able to identify prion protein (PrPC)-the precursor of prions (PrPSc)-in milk from humans, cows, sheep, and goats. The absolute amount of PrPC differs between the species (from µg/l range in sheep to ng/l range in human milk). PrPC is also found in homogenised and pasteurised off-the-shelf milk, and even ultrahigh temperature treatment only partially diminishes endogenous PrPC concentration.
Conclusions/Significance In view of a recent study showing evidence of prion replication occurring in the mammary gland of scrapie infected sheep suffering from mastitis, the appearance of PrPC in milk implies the possibility that milk of TSE-infected animals serves as source for PrPSc.
Citation: Franscini N, Gedaily AE, Matthey U, Franitza S, Sy M-S, et al. (2006) Prion Protein in Milk. PLoS ONE 1(1): e71. doi:10.1371/journal.pone.0000071
Academic Editor: Matthew Baylis, University of Liverpool, United Kingdom
Received: October 19, 2006; Accepted: November 6, 2006; Published: December 20, 2006
Copyright: © 2006 Franscini 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: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
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Saturday, April 12, 2008 Evidence of scrapie transmission via milk
HAVE ANOTHER GLASS OF CWD PRIONS COURTESY Dane County Wisconsin Mike DiMaggio, solid waste manager
Friday, October 24, 2008
CBER 2007 Annual Report Assessing the Potential Risk of variant Creutzfeldt-Jakob Disease from Blood Products
Friday, November 07, 2008 Human and animal exposure risk related to Transmissible Spongiform Encephalopathies (TSEs) from milk and milk products derived from small ruminants
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
A The Present Position with respect to Scrapie A] The Problem
Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it ia fatal. It is enzootic in the United Kingdom but not in all countries.
The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep.
It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible.
Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"
Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.
Epidemiology of Scrapie in the United States 1977
CHAPTER 3 Animal Disease Eradication Programs and Control and Certification Programs
In FY 2007, two field cases, one validation study case, and two RSSS cases were consistent with a variant of the disease known as Nor98 scrapie.1 These five cases originated from flocks in California, Minnesota, Colorado, Wyoming, and Indiana, respectively.
NOR-98 Scrapie FY 2008 to date 1
NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007