CWD, TSE, PRION, MATERNAL mother to offspring, testes, epididymis, seminal fluid, and blood
Prion 2018 Conference
WA1 An overview— Chronic Wasting Disease mother to offspring transmission studies conducted at Colorado State University
Nalls AV1‡, McNulty EE1‡, Hoover C1, Hoover EA1, Wild M2, Powers J2, Selariu A1, Mathiason CK1
1Colorado State University, Fort Collins, CO USA, 2 National Park Services, Fort Collins, CO USA.
Chronic wasting disease (CWD) demonstrates remarkable transmission efficiency among captive and free-ranging cervid populations. Intrigued by this facile transmission, we designed a series of studies to determine the potential for CWD transmission from mother to offspring. Viable offspring born to early or late-stage CWD-infected Reeves‘ muntjac dams demonstrated lymphoid biopsy positivity as early as 40 days post birth and developed clinical disease in 2-5 years. Prion infectivity was validated in the milk and colostrum collected from these dams via oral infection studies in naïve fawns, providing a potential mechanism for maternal transmission. High nonviability (~60%) was noted in full-term offspring born to this cohort of CWD-infected muntjac dams. Tissues harvested from the nonviable offspring contained prion seeding activity, suggesting that CWD had been trafficked from mother-to- offspring during gestation. Gestational timing of CWD transfer was assessed by analysis of in utero harvested tissues from a second cohort of preclinical and clinical CWD-infected muntjac dams, and it was found that transmission can occur as early as the first trimester of pregnancy. The next series of studies were initiated to determine if this was a phenomenon of experimental infection, or whether it also occurs in naturally-infected cervids. In collaboration with the National Park Service we evaluated in utero derived tissues from healthy free-ranging elk dams whose habitat is a known CWD endemic region. Prion seeding activity was detected in fetal tissues harvested from several preclinical CWD positive naturally-infected dams in this population. To begin to unravel the biological relevance of these findings we initiated mouse bioassay to assess the infectivity of the pregnancy microenvironment of muntjac dams. Uterus, placenta, ovary and amniotic fluid contained prion infectivity. Ongoing mouse bioassay will further define infectivity in fetal and reproductive tissues harvested from free-ranging naturally-exposed elk dams. This work has led to a better understanding of the transmission dynamics of CWD, demonstrating that: (i) fetuses of preclinical infected cervid dams are exposed to CWD long before exposure to maternal saliva or contaminated environments, (ii) CWD mother-to- offspring transmission occurs in free-ranging naturally-exposed cervid populations, and (iii) the Reeves‘ muntjac deer can be used to further explore mechanisms of in utero prion trafficking and the potential for multigenerational CWD transmission.
P74 High Prevalence of CWD prions in male reproductive samples
Carlos Kramm (1,2), Ruben Gomez-Gutierrez (1,3), Tracy Nichols (4), Claudio Soto (1) and Rodrigo Morales (1) (1) Mitchell Center for Alzheimer´s disease and Related Brain Disorders, Dept. of Neurology, University of Texas Houston Medical School, Houston, TX 77030, USA (2) Universidad de los Andes, Facultad de Medicina, Av. San Carlos de Apoquindo 2200, Las Condes, Santiago, Chile (3) Universidad de Málaga, Málaga, Spain (4) National Wildlife Research Center, United States Department of Agriculture, Fort Collins, CO 80521, USA.
Chronic wasting disease (CWD) is a highly infectious and fatal illness affecting captive and free-ranging cervids. Mother-to-offspring prion transmission has been described in some animal prion diseases, including CWD. However, few studies have been performed to analyze the prevalence of CWD prions in reproductive male tissues and fluids. Here, we optimized the Protein Misfolding Cyclic Amplification (PMCA) assay for the efficient detection of CWD prions in these samples. This study was done in collaboration with United States Department of Agriculture (USDA) scientists who provided blindly field-collected testes, epididymis and seminal fluid samples from 21 white-tailed deer that were analyzed for prion infection by post-mortem histological studies in brain stem and lymphoid tissues. The results showed positive CWD prion detection in testes, epididymis and seminal fluid samples. A high prevalence of CWD-PrPSc was found in samples collected at the late-presymptomatic stage of the disease. Our results showed a correlation between the presence of CWD-PrPSc in male reproductive organs and blood. These findings demonstrate a high efficiency of CWD prion detection by PMCA in testes, epididymis and seminal fluid, and offer a possibility for a routine screening of semen samples to be commercially distributed for artificial insemination. Our results may uncover new opportunities to understand the mechanisms of CWD spreading and decrease putative inter-individual transmission associated to insemination using CWD contaminated specimens.
SUNDAY, AUGUST 02, 2015
TEXAS CWD, Have you been ThunderStruck, deer semen, straw bred bucks, super ovulation, and the potential TSE Prion connection, what if?
Prion 2017 Conference
P176 Infectious CWD prions at the fetal-maternal interface
Ms. Amy Nalls1, Ms. Erin McNulty1, Ms. Laura Pulscher1, Dr. Clare Hoover1, Dr. Edward Hoover1, Dr. Candace Mathiason1
1Colorado State University, Fort Collins, United States
Aims: Ample evidence exists for the trafficking of infectious agents across the placenta, often with grave outcomes to the developing fetus (i.e. zika, brucella, cytomegalovirus). While less studied, pregnancy-related transmissible spongiform encephalopathies (TSEs) have been implicated in several species, including humans.
Our previous work demonstrated that prions can be transferred from mother-to-offspring resulting in the development of clinical TSE disease in offspring born to CWD-infected muntjac dams (Nalls 2013). We also revealed PMCA-prion seeding activity in maternal and fetal tissues harvested in utero from muntjac dams at various stages of pregnancy and CWD infection. What remained unknown was whether the prions detected at the fetal-maternal interface were infectious. In addition, we were interested to determine if the ultrasensitive RT-QuIC methodology may enhance our ability to detect prion seeding activity within the pregnancy microenvironment.
We undertook this study to assess CWD infectivity and RT-QuIC PrPc seeding activity in in utero harvested— (1) female reproductive tissues and fluids associated with the pregnancy microenvironment; the ovary, uterus and birthing fluids, and (2) the semipermeable interface between cervid mother and fetus throughout pregnancy; the placentome.
Methods: RT-QuIC: A total of 12 replicates/sample of ovary (n=6), uterus (n=6), placentome (n=5-6 placentomes each from n=2 pregnancies) and birthing fluids (n=4) were analyzed. Bioassay: Transgenic mice expressing the cervid prion protein, Tg(CerPrP-E226)5037+/- (n=9/cohort), were IC-inoculated with 30μl 10% homogenate of uterus (n=2), placentome (n=2) or 5-fold concentrated birthing fluids (n=3).
Results: RT-QuIC: PrPC seeding activity was consistently detected in 5/6 ovary, 6/6 uterus, 9/11 placentomes, 2/2 amniotic and 0/2 allantoic fluids. Bioassay: Clinical TSE disease (ataxia, weight loss and stiff tail) was observed in mice inoculated with uterus, placentome and amniotic fluid, but not allantoic fluid between 180-343 day pi while negative control cohorts remained healthy. Bioassay mice were confirmed TSE positive: brain (uterus 7/8, placentome 8/8, amniotic fluid 1/9, allantoic fluid 0/9) and spleen (uterus 7/8, placentome 7/8, amniotic fluid 2/9, allantoic fluid 0/0) by western blot and RT-QuIC.
Conclusions: Here, using a native CWD susceptible host, we have— for the first time— demonstrated infectious prions in the cervid pregnancy microenvironment and placental structure at the fetal-maternal interface. These findings reveal a source of infectious prions that the developing fetus is exposed to long before the birthing process, maternal grooming, or encounter with contaminated environments. Thus suggesting that CWD mother-to-offspring transmission may contribute to the facile transmission of CWD and be underappreciated for all TSEs.
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P172 Multigenerational transmission of CWD prions from mother to offspring
Erin Mcnulty1, MS Amy Nalls1, Dr Clare Hoover1, Dr Jenny Powers2, Dr Edward Hoover1, Dr Candace Mathiason1 1Colorado State University, Fort Collins, United States, 2National Park Services, Fort Collins, United States
Aims: Chronic wasting disease (CWD) continues to demonstrate geographic expansion, now found in captive and/or free-range cervid populations in North America, South Korea and Norway. While horizontal transmission is credited for much of the spread of CWD, few studies have monitored the transmission of this disease from mother-to-offspring.
CWD-infected muntjac dams are able to become pregnant, carry, deliver and rear offspring during the long asymptomatic phase of prion infection. We have demonstrated that CWD prions can be transmitted from mother to first-generation offspring leading to prion infection and subsequent development of TSE disease, and that transmission occurs during gestation (Nalls 2013). We have also observed fecundity in first-generation offspring. In fact, one first-generation female muntjac gave birth to two nonviable second-generation offspring. Tissues harvested from these nonviable second-generation offspring harbor protein misfolding cyclic amplification (PMCA) competent prions.
Recently we revealed PrPC seeding activity and infectious prions within the reproductive milieu (uterus, ovaries, placentomes, amniotic fluid) of CWD-infected Reeve’s muntjac dams by PMCA, real time quaking-induced conversion (RT-QuIC) and bioassay. The presence of CWD prions in the pregnancy microenvironment begs the question: Is it possible CWD is transmitted from one generation to the next via intrauterine or germline exposure to infectious prions?
Methods: To begin to address this question we assessed tissues harvested from full-term second-generation nonviable muntjac offspring for infectivity by mouse bioassay. Transgenic mice expressing the cervid prion protein, Tg(CerPrP-E226)5037+/- (n=6/cohort), were IP-inoculated with PMCA-amplified lung, mammary gland, kidney or uterus from nonviable 2nd generation muntjac offspring (n=2) born to a first generation dam (n=1), or PMCA-amplified age and tissue-matched negative control second-generation offspring (n=2). Mice from all cohorts were examined for prions by western blot and RTQuIC.
Results: All mice (n=20) inoculated with PMCA-amplified tissue from “gestational CWD-exposed” second-generation offspring developed signs consistent with TSE disease, including severe ataxia and weight loss between 209-373 days pi, and were confirmed CWD positive by western blot and RT-QuIC. Negative control mice (n=9) receiving PMCA-amplified negative age and tissue-matched homogenates remained healthy and TSE-free for the same duration. Studies have been initiated to further assess the relationship between prions in ovaries and CWD transmission.
Conclusions: Our data indicates that: (1) multigenerational transmission of infectious CWD prions from mother-to-offspring may be possible and (2) early and persistent exposure of the developing embryo to infectious CWD prions in the uterine microenvironment may help explain the facile transmission of CWD in the native host.
Mother to Offspring Transmission of Transmissible Spongiform Encephalopathy TSE prion disease
Mother to Offspring Transmission of Chronic Wasting Disease in Reeves’ Muntjac Deer
Amy V. Nalls1, Erin McNulty1, Jenny Powers2, Davis M. Seelig3, Clare Hoover1, Nicholas J. Haley1, Jeanette Hayes-Klug1, Kelly Anderson1, Paula Stewart4, Wilfred Goldmann4, Edward A. Hoover1, Candace K. Mathiason1*
1 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America, 2 Biological Resource Management Division, National Park Service, Fort Collins, Colorado, United States of America, 3 Department of Veterinary Clinical Sciences, University of Minnesota, Saint Paul, Minnesota, United States of America, 4 The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, Scotland, United Kingdom
Abstract
The horizontal transmission of prion diseases has been well characterized in bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) of deer and elk and scrapie of sheep, and has been regarded as the primary mode of transmission. Few studies have monitored the possibility of vertical transmission occurring within an infected mother during pregnancy. To study the potential for and pathway of vertical transmission of CWD in the native cervid species, we used a small cervid model–the polyestrous breeding, indoor maintainable, Reeves’ muntjac deer–and determined that the susceptibility and pathogenesis of CWD in these deer reproduce that in native mule and white-tailed deer. Moreover, we demonstrate here that CWD prions are transmitted from doe to fawn. Maternal CWD infection also appears to result in lower percentage of live birth offspring. In addition, evolving evidence from protein misfolding cyclic amplification (PMCA) assays on fetal tissues suggest that covert prion infection occurs in utero. Overall, our findings demonstrate that transmission of prions from mother to offspring can occur, and may be underestimated for all prion diseases.
Introduction Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurodegenerative diseases that affect a variety of species, including humans (Kuru; variant Creutzfeldt-Jakob disease [vCJD]), cattle (bovine spongiform encephalopathy [BSE]), sheep (scrapie), mink (transmissible mink encephalopathy [TME]), domestic and nondomestic cats (feline spongiform encephalopathy [FSE]) and cervids (chronic wasting disease [CWD]).
The transmission of prions, while remaining poorly understood, has obvious public health significance and requires sustained re-appraisal of present concepts for both TSE spread and intervention strategies. It is clear that TSEs are spread by horizontal means of transmission via oral ingestion (Kuru, BSE, vCJD, TME, FSE, CWD) and environmental (scrapie, CWD) contact with infectious prions, as well as by medical means including blood transfusion (vCJD, CWD, scrapie), or iatrogenic exposure (vCJD, sCJD). While less studied, supporting evidence has emerged for an additional path of transmission– that from mother to offspring.
A variant form of the human prion disease CJD, known as variant CJD (vCJD), was attributed to the ingestion of BSE-infected meat products [1], [2]. It is known that vCJD can be transmitted from human to human via blood transfusion from both symptomatic and asymptomatic donors [3]–[6] and that a prolonged asymptomatic incubation period occurs in 129 Met/Val individuals [7]. It is estimated that up to 1 in 4,000 individuals in the UK are asymptomatic carriers of vCJD [8]–[10].
To date, 125 children have been born to women who later developed CJD [11]. This is concerning because PrPCJD has been detected in the fetal and pregnancy related tissues of a woman infected with CJD [12]. Although decades may pass before the onset of clinical effects associated with such transmission due to a long subclinical carrier state, the probability that these individuals harbor infectious prions remains high.
Animal TSEs suggest similar disease patterns. Scrapie prions have been detected in maternal and fetal sheep tissues [13]–[22], and there is a higher incidence of clinical disease during the lambing season [14], [23]–[27]. It is known that BSE incidence is higher in calves born to BSE-infected cattle [28], [29] and that BSE has been transmitted to the offspring of BSE-infected female mice expressing bovid PrP [30]. A cheetah cub, born to a FSE-infected cheetah, was housed in a TSE-free environment and fed a TSE-free diet, yet succumbed to FSE at 7 years of age [31], suggesting maternal exposure.
Importantly, infectious prions are present in the brain, bodily fluids and excreta of animals showing no clinical signs of TSE [32]–[37]. For example, the blood, saliva and urine from deer subclinically infected with CWD contain infectious prions [32], [38], [39]. Race and coworkers [40] found a long-term subclinical carrier state in mice infected with hamster scrapie. Atypical BSE (BASE) can be transmitted from non-clinical cattle to primates [41] and cattle exposed to large oral doses of BSE can remain free of clinical signs but are found to harbor infectious prions upon bioassay into bovid PrP transgenic mice [42]. Taken together, these findings suggest that carriers without clinical signs exist and may transmit infection to their offspring via milk, transplacental trafficking or blood.
Chronic wasting disease, known for its efficient transmission among cervids, is now recognized in 22 states, two Canadian provinces and South Korea (http://www.nwhc.usgs.gov/disease_information/chronic_wasting_disease/index.jsp). Studies proved that CWD can be horizontally transmitted among cervids either by direct contact with infected animals [43], their secreta [32], [33], [38], [44] or indirectly through the environment they inhabit [39], [45]. As observed in other animal TSEs, even cervids in the subclinical phase of disease harbor transmissible infectious prions [32], [39], [46]–[49]. Although there is a growing body of evidence that identifies the sources of infectious prions, less defined are the mechanisms by which prions are shed by infected hosts and taken up by their naïve counterparts. One such mechanism may include that from mother to offspring, either in utero (vertical transmission), or shortly after birth in colostrum or milk (maternal transmission).
To address the possibility of CWD mother to offspring transmission we utilized Reeves’ muntjac deer (Muntiacus reevesi) [50]. This small Asian deer reaches sexual maturity at 6 months of age, is polyestrous, and can be bred and housed conveniently in indoor controlled laboratory conditions, thus providing a suitable in vivo model for cervid vertical/maternal transmission studies [51].
We undertook this study to determine: 1) whether Reeves’ muntjac deer are susceptible to CWD, 2) whether CWD is transmitted from mother to offspring, and 3) whether offspring born to CWD-infected mothers develop clinical TSE disease.
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Implications Associated with Transmission of CWD to Offspring
The facile transmission of CWD seen in herds of free ranging and captive cervids has led to questions regarding the modes of transmission. While direct contact with infected cervids, as well as indirect contact with infectious bodily fluids and contaminated environments are suspected to account for much of this transmission, a third path of transmission, the one from mother to offspring, may be underappreciated. PrPCWD placental accumulation and CWD in utero acquirement would help explain the surprisingly high rates of CWD among cervids. Moreover, CWD positive nonviable offspring carcasses 1) would contribute to environmental prion contamination [77] and 2) would be available for consumption by scavenger species, thus increasing the potential for cross-species transmission [53,78,79]. Viable offspring may spread disease by 1) direct cervid-to-cervid contact, 2) multigenerational mother to offspring transmission, as well as 3) shedding infectious prions in bodily secretions (urine, feces, saliva, blood) during their entire lifespan.
Here, in an experimental model of CWD, we have demonstrated the transmission of infectious prions from clinical and subclinical mothers to full-term viable, nonviable and in utero harvested offspring, revealing that the transmission of TSEs from mother to offspring can occur and may be underestimated for all prion diseases.
Citation: Nalls AV, McNulty E, Powers J, Seelig DM, Hoover C, et al. (2013) Mother to Offspring Transmission of Chronic Wasting Disease in Reeves’ Muntjac Deer. PLoS ONE 8(8): e71844. doi:10.1371/journal.pone.0071844
Editor: Ilia V. Baskakov, University of Maryland School of Medicine, United States of America Received May 1, 2013; Accepted July 3, 2013; Published August 14, 2013
Copyright: 2013 Nalls 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 by NIH grants N01-AI-25491 and R01-AI-093634. 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: Candace.Mathiason@colostate.edu
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Prion2013 Chronic Wasting Disease CWD risk factors, humans, domestic cats, blood, and mother to offspring transmission
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Oral.08: Mother to offspring transmission of chronic wasting disease in Reeve's Muntjac deer Amy Nalls,1 Erin McNulty,1 Jenny Powers,2 Davis Seelig,1 Clare Hoover,1 Nicholas Haley,1 Jeanette Hayes-Klug,1 Kelly Anderson,1 Paula Stewart,3 Wilfred Goldmann,3 Edward A. Hoover1 and Candace K. Mathiason1 1Colorado State University; Fort Collins, CO USA; 2National Park Service; Fort Collins, CO USA; 3The Roslin Institute and Royal School of Veterinary Studies; Edinburgh, UK To investigate the role mother to offspring transmission plays in chronic wasting disease (CWD), we have developed a cervid model employing the Reeve's muntjac deer (Muntiacus reevesi). Eight muntjac doe were orally inoculated with CWD and tested PrPCWD lymphoid positive by 4 mo post infection. Fourteen fawns were born to these eight CWD-infected doe-3 were born viable, 6 were born non-viable and 5 were harvested as fetuses from early or end-stage CWD-infected doe. All three viable fawns have demonstrated CWD IHC lymphoid biopsy positivity between 43 d post birth and 11 mo post birth. Two of these three CWD positive viable offspring have developed clinical signs consistent with TSE disease (28-33 mo post birth). Moreover, CWD prions have been detected by sPMCA in 11 of 16 tissues harvested from 6 full-term non-viable fawns and in 7 of 11 fetal tissues harvested in utero from the second and third trimester fetuses. Additional tissues and pregnancy related fluids from doe and offspring are being analyzed for CWD prions. In summary, using the muntjac deer model we have demonstrated CWD clinical disease in offspring born to CWD-infected doe, and in utero transmission of CWD from mother to offspring. These studies provide basis to further investigate the mechanisms of maternal transfer of prions.
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Sunday, August 25, 2013
Prion2013 Chronic Wasting Disease CWD risk factors, humans, domestic cats, blood, and mother to offspring transmission
>>> Here, in an experimental model of CWD, we have demonstrated the transmission of infectious prions from clinical and subclinical mothers to full-term viable, nonviable and in utero harvested offspring, revealing that the transmission of TSEs from mother to offspring can occur and may be underestimated for all prion diseases. <<<
EFSA Journal 2013;11(2):3080
Suggested citation: EFSA Panel on Biological Hazards (BIOHAZ); Scientific Opinion on the risk of transmission of classical
scrapie via in vivo derived embryo transfer in ovine animals. EFSA Journal 2013;11(2):3080. [15 pp.]
doi:10.2903/j.efsa.2013.3080. Available online: www.efsa.europa.eu/efsajournal
© European Food Safety Authority, 2013
SCIENTIFIC OPINION
Scientific Opinion on the risk of transmission of classical scrapie via in vivo derived embryo transfer in ovine animals1
EFSA Panel on Biological Hazards2, 3
European Food Safety Authority (EFSA), Parma, Italy
ABSTRACT
The risk of transmission of classical scrapie via the transfer of in vivo derived embryo in ovines was assessed, taking into account the scientific information made available since the last EFSA opinion on this topic (2010) (see http://www.efsa.europa.eu/en/efsajournal/pub/1429.htm). The potential impact of PrP genotype of the embryo and/or of the ram and donor ewe on this risk was also assessed. The new data made available over the last three years further reinforce the view that classical scrapie could be vertically transmitted in sheep. Since the possibility of such vertical transmission was already considered in the previous opinion, its conclusions and recommendations relating to the risk of classical scrapie transmission via embryo transfer remain valid. In ovines, the susceptibility to classical scrapie infection in sheep is strongly influenced by certain polymorphisms of the PrP gene. Under natural exposure conditions, animals that are heterozygous or homozygous A136R154R171 display respectively a low or negligible risk of being infected. The genetic control of the susceptibility to classical scrapie is also likely to impact on the risk of transmitting the disease via embryo transfer. Irrespective of the embryo’s genotype, embryos derived from rams and dams carrying at least one ARR allele would significantly decrease this risk (compared to an embryo from parents of unknown genotypes). The use of homozygous ARR embryos would provide the highest level of safety regarding the risk of transmitting classical scrapie through embryo transfer (in vivo derived embryos). The use of heterozygous ARR embryos would ensure a higher level of safety compared to Q171/Q171 embryos. Finally, it was concluded that, providing the OIE recommendations and procedures relating to embryo transfer are adhered to, the risk of transmitting classical scrapie due to the transfer of homozygous or heterozygous ovine ARR embryos can be considered negligible.
© European Food Safety Authority, 2013
KEY WORDS
Classical scrapie, ovine, sheep, embryo transfer, transmission risk
1 On request from the European Commission, Question No EFSA-Q-2012-00647, adopted on 24 January 2013.
2 Panel members: Olivier Andreoletti, Dorte Lau Baggesen, Declan Bolton, Patrick Butaye, Paul Cook, Robert Davies, Pablo S. Fernandez Escamez, John Griffin, Tine Hald, Arie Havelaar, Kostas Koutsoumanis, Roland Lindqvist, James McLauchlin, Truls Nesbakken, Miguel Prieto Maradona, Antonia Ricci, Giuseppe Ru, Moez Sanaa, Marion Simmons, John Sofos and John Threlfall. One member of the Panel did not participate in the discussion on the subject referred to above because of potential conflicts of interest identified in accordance with the EFSA policy on declarations of interests. Correspondence: biohaz@efsa.europa.eu
3 Acknowledgement: The Panel wishes to thank the members of the Working Group on the risk of transmission of classical scrapie via in vivo embryo transfer in ovine animals: Olivier Andreoletti, Nora Hunter and Ciriaco Ligios for the preparatory work on this scientific opinion and the hearing experts: Michel Thibier and Pascale Chavatte-Palmer, and EFSA staff: Pablo Romero Barrios for the support provided to this scientific opinion.
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CONCLUSIONS AND RECOMMENDATIONS
CONCLUSIONS
Since the 2010 opinion only two relevant studies have been published. None of them suggest a need to revise the previous conclusion adopted by the BIOHAZ Panel in January 2010 i.e ‘Based on the data currently available the risk of TSE transmission associated with embryos collected from Classical scrapie incubating ewes and she-goats ranges from negligible to low. However, data are insufficient to conclude that such a risk is negligible.’ In sheep the susceptibility to classical scrapie infection is strongly influenced by the polymorphisms of the PrP gene. Under natural exposure conditions, animals that are heterozygous or homozygous ARR show respectively a low or negligible risk of being infected by classical scrapie. This genetic control of the susceptibility to classical scrapie infection directly influences the risk of transmitting the disease via embryo transfer:
Since the 2010 opinion only two relevant studies have been published. None of them suggest a need to revise the previous conclusion adopted by the BIOHAZ Panel in January 2010 i.e ‘Based on the data currently available the risk of TSE transmission associated with embryos collected from Classical scrapie incubating ewes and she-goats ranges from negligible to low. However, data are insufficient to conclude that such a risk is negligible.’ In sheep the susceptibility to classical scrapie infection is strongly influenced by the polymorphisms of the PrP gene. Under natural exposure conditions, animals that are heterozygous or homozygous ARR show respectively a low or negligible risk of being infected by classical scrapie. This genetic control of the susceptibility to classical scrapie infection directly influences the risk of transmitting the disease via embryo transfer:
– Irrespective of the embryo’s genotype, the use of embryos derived from rams and dams carrying at least one ARR allele would significantly decrease the risk of transmitting classical scrapie via embryo transfer (by comparison to an embryo from parents of unknown genotypes).
– The use of homozygous ARR embryos would provide the highest possible level of safety with regard to the risk of transmitting classical scrapie through embryo transfer (in vivo derived embryos).
– The use of heterozygous ARR embryos would ensure a higher level of safety by comparison with Q171/Q17110 embryos.
– The risk of transmitting classical scrapie by implantation of a Q171/Q171 embryo collected from a dam with an unknown classical scrapie status cannot be considered negligible. Providing that the OIE recommendations and procedures relating to embryo transfer are adhered to, the risk of transmitting classical scrapie by the implantation of homozygous or heterozygous ovine ARR embryos can be considered negligible.
RECOMMENDATIONS The recommendations relating to the risk of transmitting classical scrapie via embryo transfer that were formulated in the 2010 opinion remain valid. In particular, the presence of infectivity in ovine embryos collected from scrapie infected dams bearing susceptible genotypes needs to be assessed before a definitive assessment of the risk of transmitting classical scrapie via the use of embryos bearing a susceptible genotype can be made.
10 By convention Q171 refers to ARQ, VRQ, and AHQ alleles.
>>>Finally, it was concluded that, providing the OIE recommendations and procedures relating to embryo transfer are adhered to, the risk of transmitting classical scrapie due to the transfer of homozygous or heterozygous ovine ARR embryos can be considered negligible.<<<
‘’LOL’’ ! ...tss
Tuesday, April 30, 2013
Transmission of classical scrapie via goat milk
Veterinary Record2013;172:455 doi:10.1136/vr.f2613
Friday, May 10, 2013
Evidence of effective scrapie transmission via colostrum and milk in sheep
Thursday, April 26, 2012
Maternal Transmission of the BSE and Birth Cohorts
December 14, 2011
Detection of PrPres in Genetically Susceptible Fetuses from Sheep with Natural Scrapie
María Carmen Garza1, Natalia Fernández-Borges2, Rosa Bolea1, Juan José Badiola1, Joaquín Castilla2,3, Eva Monleón1,4*
1 Centro de Investigación en Encefalopatías Espongiformes Transmisibles y Enfermedades Emergentes, Universidad de Zaragoza, Zaragoza, Spain, 2 CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Spain, 3 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain, 4 Producció Animal, Universitat de Lleida, LLeida, Spain
Scrapie is a transmissible spongiform encephalopathy with a wide PrPres dissemination in many non-neural tissues and with high levels of transmissibility within susceptible populations. Mechanisms of transmission are incompletely understood. It is generally assumed that it is horizontally transmitted by direct contact between animals or indirectly through the environment, where scrapie can remain infectious for years. In contrast, in utero vertical transmission has never been demonstrated and has rarely been studied. Recently, the use of the protein misfolding cyclic amplification technique (PMCA) has allowed prion detection in various tissues and excretions in which PrPres levels have been undetectable by traditional assays. The main goal of this study was to detect PrPres in fetal tissues and the amniotic fluid from natural scrapie infected ewes using the PMCA technique. Six fetuses from three infected pregnant ewes in an advanced clinical stage of the disease were included in the study. From each fetus, amniotic fluid, brain, spleen, ileo-cecal valve and retropharyngeal lymph node samples were collected and analyzed using Western blotting and PMCA. Although all samples were negative using Western blotting, PrPres was detected after in vitro amplification. Our results represent the first time the biochemical detection of prions in fetal tissues, suggesting that the in utero transmission of scrapie in natural infected sheep might be possible.
PLoS ONE 6(12): e27525. doi:10.1371/journal.pone.0027525
Editor: Jason Bartz, Creighton University, United States of America
Received: July 20, 2011; Accepted: October 18, 2011; Published: December 14, 2011
Copyright: © 2011 Garza 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 supported by a national grant from Spain (AGL2009-11553-C02-01), a Basque government grant (PI2010-18) and the Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs 2011/2013), from the Innovation Technology Department of the Bizkaia County. Dr. Garza was supported by a FPU doctoral grant from the Spanish Ministry of Education (AP2007-03842). 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: emonleon@unizar.es
Saturday, February 11, 2012
PrPSc Detection and Infectivity in Semen from Scrapie-Infected Sheep
Envt.18: Mother to Offspring Transmission of Chronic Wasting Disease
Candace K. Mathiason,† Amy Nalls, Kelly Anderson, Jeanette Hayes-Klug, Jenny G. Powers, Nicholas J. Haley and Edward A. Hoover
Colorado State University; Fort Collins, CO USA†Presenting author; Email: ckm@lamar.colostate.edu
We have developed a new cervid model in small Asian muntjac deer (Muntiacus reevesi) to study potential modes of vertical transmission of chronic wasting disease (CWD) from mother to offspring. Eight of eight (8/8) muntjac doe orally infected with CWD tested PrPCWD lymphoid positive by four months post infection. Ten fawns were born to these CWD-infected doe— four of the fawns were viable, five were non-viable and one was a first trimester fetus harvested from a CWD-infected doe euthanized at end-stage disease. The viable fawns have been monitored for CWD infection by immunohistochemistry and sPMCA performed on serial tonsil and rectal lymphoid tissue biopsies. PrPCWD has been detected in one fawn by IHC as early as 40 days of age. Moreover, sPMCA performed on rectal lymphoid tissue has yielded positive results on another fawn at ten days of age. In addition, sPMCA assays have demonstrated amplifiable prions in fetal placental or spleen tissue of three non-viable fawns and mammary tissue of the dams.
Additional pregnancy related fluids and tissues from the doe as well as tissue from the nonviable fawns are currently being probed for the presence of CWD. In summary, we have employed the muntjac deer model, to demonstrate for the first time the transmission of CWD from mother to offspring. These studies provide the foundation to investigate the mechanisms and pathways of maternal prion transfer.
===========================
***PPo3-18: A Possible Case of Maternal Transmission of the BSE Agent within Captive Cheetah Affected with Feline Spongiform Encephalopathy
Anna Bencsik, Sabine Debeer, Thierry Petit and Thierry Baron
Afssa; Unité ATNC; Lyon, France; Zoo de la Palmyre; Les Mathes, France
Key words: BSE, FSE, vertical transmission
Introduction. Feline spongiform encephalopathy (FSE) is considered to be related to bovine spongiform encephalopathy (BSE). It has been reported in domestic cats as well as in captive wild cats including cheetahs, first in the United Kingdom (UK) and then in other European countries. In France, several cases were described in cheetahs either imported from UK or born in France. Here we report details of two other FSE cases in captive cheetah. These cases are of particular interest since the 2nd case of FSE in a cheetah born in France, appears most likely due to maternal transmission.1
Results. Complete PrPd study showed the close likeness between the two cheetah cases. The TgOvPrP4 mouse brains infected with cattle BSE and cheetah FSE revealed similar vacuolar lesion profiles, PrPd brain mapping with occurrence of typical florid plaques.
Materials and Methods. Using immunohistochemistry (IHC), pathological form of PrP(PrPd) was analyzed in the brains and peripheral organs of these two cheetahs. Transmission studies to the TgOvPrP4 mouse line were also performed, for comparison with the transmission of cattle BSE. Lesion profiles of the infected transgenic mice were analyzed as well as type and brain distribution of PrPd.
Conclusion. Collectively, these data indicate that both FSE cases harbor the same strain of agent as the cattle BSE agent. Because this is most probably a case of maternal transmission of the disease, this new observation may have some impact on our knowledge of vertical transmission of BSE agent-linked TSEs such as in human variant Creutzfeldt Jakob disease.
References
1. Bencsik et al. PLoS One 2009; 4:6929.
=========================
PPo3-40: Mother to Offspring Transmission of Chronic Wasting Disease
Candace K. Mathiason, Amy V. Nalls, Kelly Anderson, Jeanette Hayes-Klug, Nicholas Haley and Edward A. Hoover
Colorado State University, Department of Microbiology, Immunology and Pathology, Fort Collins, CO USA
Key words: Chronic wasting disease, vertical transmission, muntjac deer
We have developed a new cervid model in small Asian muntjac deer (Muntiacus reevesi) to study potential modes of vertical transmission of chronic wasting disease (CWD) from mother to offspring. Eight of eight (8/8) muntjac doe orally infected with CWD tested PrPCWD lymphoid positive by 4 months post infection. Six fawns were born to these CWD-infected doe. Six fawns were born to 6 CWD-infected doe; 4 of the fawns were non-viable. The viable fawns have been monitored for CWD infection by immunohistochemistry and sPMCA performed on serial tonsil and rectal lymphoid tissue biopsies. PrPCWD has been detected in one fawn as early as 40 days of age. Moreover, sPMCA performed on rectal lymphoid tissue has yield positive results on another fawn at 10 days of age. In addition, sPMCA assays have also demonstrated amplifiable prions in maternal placental (caruncule) and mammary tissue of the dam.
Additional pregnancy related fluids and tissues from the doe as well as tissue from the nonviable fawns are currently being probed for the presence of CWD. In summary, we have employed the muntjac deer model, to demonstrate for the first time the transmission of CWD from mother to offspring. These studies provide the foundation to investigate the mechanisms and pathways of maternal prion transfer.
PRION 2011
International Prion Congress: From agent to diseaseSeptember 8–11, 2010Salzburg, Austria
PRION 2010
Wednesday, December 30, 2009
Is there evidence of vertical transmission of variant CJD ?
J Neurol Neurosurg Psychiatry doi:10.1136/jnnp.2009.172148
Monday, November 22, 2010
SHEEP WITH MASTITIS TRANSMIT INFECTIOUS PRIONS THROUGH THE MILK
Monday, November 22, 2010
SHEEP WITH MASTITIS TRANSMIT INFECTIOUS PRIONS THROUGH THE MILK
J. Virol. doi:10.1128/JVI.02022-10 Copyright (c) 2010, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.
Saturday, December 3, 2011
Isolation of Prion with BSE Properties from Farmed Goat
Volume 17, Number 12—December 2011
communicated by: Terry S Singeltary Sr [ These research confirms experimentally previous observations by others (such as, Lacroux C et al: Prions in Milk from Ewes Incubating Natural Scrapie. PLoS Pathog 4(12): e1000238.doi:10.1371/journal.ppat.1000238;
SNIP...
-------- Original Message --------
Subject: POSITION STATEMENT MATERNAL TRANSMISSION OF vCJD SEAC
Date: Fri, 04 Feb 2005 09:54:58 –0600
From: "Terry S. Singeltary Sr."
To: Bovine Spongiform Encephalopathy
1
POSITION STATEMENT MATERNAL TRANSMISSION OF vCJD
Issue
1. The Chief Medical Officer for England asked SEAC to consider current evidence and comment on the potential transmission of vCJD from mother to child via human breast milk. In utero transmission was also considered. The committee also commented on the scientific basis of a risk reduction measure for possible transmission of vCJD via banked breast milk.
Background
2. No diagnostic test is currently available for the detection of abnormal PrP in milk. Research is under way to develop tests to screen for the possible presence of abnormal prion protein (PrP) in milk samples from cattle experimentally infected with BSE1. These modified tests may also be applicable to human milk. However, it is not yet clear when/if a reliable test will be available.
3. A small number of breast milk banks in the UK supply highly vulnerable premature babies for whom no milk may be available from the mother. A model developed by the Department of Health to assess the effect of pooling breast milk from multiple donors on the possible risks of transmission of vCJD via breast milk banks was considered.
4. There is some, albeit limited, published epidemiological and experimental research on maternal transmission of prion diseases. There are also unpublished surveillance data of children born to vCJD cases from the National CJD Surveillance Unit and UK surveillance of neurological illness in children which might inform on potential risks of maternal transmission.
1 A joint FSA/SEAC milk working group is monitoring and providing advice on this research carried out at the Veterinary Laboratories Agency.
2 Breast milk banks
5. There is no evidence that vCJD infectivity has ever been transmitted through breast milk. However, a theoretical risk exists. Modelling studies clearly show that the practice of pooling breast milk increases the number of donors to which a recipient is exposed and thereby increases the potential risk of an infant receiving milk contaminated with vCJD infectivity. The theoretical risk of infection can be minimised by not pooling the milk, by the use of individual hand operated breast milk pumps for single donors, and by the use of single-use sterilised bottles for collection. In addition, available evidence suggests that infection/inflammation of the breast results in increased lymphocytes in milk and therefore increased risk of infectivity. This risk would be minimised if milk from donors showing signs of infection is not used.
6. The committee suggested that, if practicable, milk could be stored for an appropriate period of time to allow the health status of donors to be monitored, before it is released. However, information was not available to the committee on whether long-term storage of human milk is detrimental to its nutritional quality.
Maternal transmission
7. There is evidence from animal studies for low level maternal transmission of prions in cattle and sheep. This transmission may occur in utero, via milk and/or perinatally. However, the possibility that this putative maternal transmission might have been due to another mode of transmission, for example through a contaminated environment or feed, cannot be ruled out.
8. In contrast, in humans there is no evidence for maternal transmission in cases of familial prion disease, other than the transfer of a mutant form of the PrP gene, and there is no evidence of maternal transmission of Kuru. However, compared with other human prion diseases vCJD may pose a greater risk because of the greater involvement of the lymphoreticular system in vCJD pathogenesis. Although, breast tissue (and placenta) from a single vCJD case tested negative for PrPvCJD, transfer of infectivity to breast milk may depend on the physiological status of the mammary gland. Similar tests or infectivity bioassays have not been conducted on breast tissue from lactating patients with vCJD. 3
9. A published study suggesting transmission of sCJD in colostrum2 was considered unreliable because tissues not normally associated with high levels of infectivity (blood and placenta) showed equivalent infectivity to that of the brain in this study.
10. Analysis of prospective surveillance data of UK children born to mothers with, or that had subsequently developed clinical vCJD, provide no evidence for maternal transmission of vCJD. However, the number of cases is very small and the incubation period of vCJD, if transmitted from mother to child, is unknown and so the children may yet be too young to have developed symptoms.
11. The phenotype of BSE infection in humans expressing PrP genotypes other than M/M at codon 129 is not known. Given recently published studies in mice expressing the human PrP gene3, which suggest that the human PrP genotype may affect disease phenotype, the committee considered it very important that undiagnosed neurological diseases be carefully monitored. In this respect, amongst others, it is recommended that the careful monitoring of neurological illnesses through the PIND surveillance of children4 continue.
Conclusions
12. In summary, there is currently no epidemiological evidence for maternal transmission of vCJD, including transmission via breast milk. However, there is a hypothetical risk. Although available evidence is limited and mostly indirect rather than direct, this risk, if any, appears to be low. As a risk cannot be excluded, a watching brief should be maintained.
SEAC
January 2005
2 Tamai Y et al. Demonstration of the transmissible agent in tissue from a pregnant woman with CJD. New Eng J Med 1992 327, 649.
3 Wadsworth et al. Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science. 2004 306, 1793-1796.
4 Devereux G et al. Variations in neurodegenerative disease across the UK: findings from the national study of Progressive Intellectual and Neurological Deterioration (PIND). Arch Dis Child. 2004 89, 8-12.
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