Prions of Ruminants Show Distinct Splenotropisms in an Ovine Transgenic Mouse Model

Background: Transmissible agents involved in prion diseases differ in their capacities to target different regions of the central nervous system and lymphoid tissues, which are also host-dependent. Methodology/Principal Findings: Protease-resistant prion protein (PrP res) was analysed by Western blot in the spleen of transgenic mice (TgOvPrP4) that express the ovine prion protein under the control of the neuron-specific enolase promoter, after infection by intra-cerebral route with a variety of transmissible spongiform encephalopathies (TSEs) from cattle and small ruminants. Splenic PrP res was consistently detected in classical BSE and in most natural scrapie sources, the electrophoretic pattern showing similar features to that of cerebral PrP res. However splenic PrP res was not detected in L-type BSE and TME-in-cattle, or in the CH1641 experimental scrapie isolate, indicating that some TSE strains showed reduced splenotropism in the ovine transgenic mice. In contrast with CH1641, PrP res was also consistently detected in the spleen of mice infected with six natural ‘‘CH1641-like’ ’ scrapie isolates, but then showed clearly different molecular features from those identified in the brains (unglycosylated PrP res at,18 kDa with removal of the 12B2 epitope) of ovine transgenic mice or of sheep. These features included different cleavage of the main PrP res cleavage product (unglycosylated PrP res at,19 kDa with preservation of the 12B2 epitope) and absence of the additional C-terminally cleaved PrP res product (unglycosylated form at,14 kDa) that was detected in the brain. Conclusion/Significance: Studies in a transgenic mouse model expressing the sheep prion protein revealed differen

Unsupervised clustering of wildlife necropsy data for syndromic surveillance

<p>Abstract</p> <p>Background</p> <p>The importance of wildlife disease surveillance is increasing, because wild animals are playing a growing role as sources of emerging infectious disease events in humans. Syndromic surveillance methods have been developed as a complement to traditional health data analyses, to allow the early detection of unusual health events. Early detection of these events in wildlife could help to protect the health of domestic animals or humans. This paper aims to define syndromes that could be used for the syndromic surveillance of wildlife health data. Wildlife disease monitoring in France, from 1986 onward, has allowed numerous diagnostic data to be collected from wild animals found dead. The authors wanted to identify distinct pathological profiles from these historical data by a global analysis of the registered necropsy descriptions, and discuss how these profiles can be used to define syndromes. In view of the multiplicity and heterogeneity of the available information, the authors suggest constructing syndromic classes by a multivariate statistical analysis and classification procedure grouping cases that share similar pathological characteristics.</p> <p>Results</p> <p>A three-step procedure was applied: first, a multiple correspondence analysis was performed on necropsy data to reduce them to their principal components. Then hierarchical ascendant clustering was used to partition the data. Finally the k-means algorithm was applied to strengthen the partitioning. Nine clusters were identified: three were species- and disease-specific, three were suggestive of specific pathological conditions but not species-specific, two covered a broader pathological condition and one was miscellaneous. The clusters reflected the most distinct and most frequent disease entities on which the surveillance network focused. They could be used to define distinct syndromes characterised by specific post-mortem findings.</p> <p>Conclusions</p> <p>The chosen statistical clustering method was found to be a useful tool to retrospectively group cases from our database into distinct and meaningful pathological entities. Syndrome definition from post-mortem findings is potentially useful for early outbreak detection because it uses the earliest available information on disease in wildlife. Furthermore, the proposed typology allows each case to be attributed to a syndrome, thus enabling the exhaustive surveillance of health events through time series analyses.</p

Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model

L-type BSE is a more likely candidate for the origin of TME than typical BSE

Evaluation using latent class models of the diagnostic performances of three ELISA tests commercialized for the serological diagnosis of <i>Coxiella burnetii</i> infection in domestic ruminants

International audienceELISA methods are the diagnostic tools recommended for the serological diagnosis of Coxiella burnetii infection in ruminants but their respective diagnostic performances are difficult to assess because of the absence of a gold standard. This study focused on three commercial ELISA tests with the following objectives (1) assess their sensitivity and specificity in sheep, goats and cattle, (2) assess the between-and within-herd seroprevalence distribution in these species, accounting for diagnostic errors, and (3) estimate optimal sample sizes considering sensitivity and specificity at herd level. We comparatively tested 1413 cattle, 1474 goat and 1432 sheep serum samples collected in France. We analyzed the cross-classified test results with a hierarchical zero-inflated beta-binomial latent class model considering each herd as a population and conditional dependence as a fixed effect. Potential biases and coverage probabilities of the model were assessed by simulation. Conditional dependence for truly seropositive animals was high in all species for two of the three ELISA methods. Specificity estimates were high, ranging from 94.8% [92.1; 97.8] to 99.2% [98.5; 99.7], whereas sensitivity estimates were generally low, ranging from 39.3 [30.7; 47.0] to 90.5% [83.3; 93.8]. Betweenand within-herd seroprevalence estimates varied greatly among geographic areas and herds. Overall, goats showed higher within-herd seroprevalence levels than sheep and cattle. The optimal sample size maximizing both herd sensitivity and herd specificity varied from 3 to at least 20 animals depending on the test and ruminant species. This study provides better interpretation of three widely used commercial ELISA tests and will make it possible to optimize their implementation in future studies. The methodology developed may likewise be applied to other human or animal diseases

A C-Terminal Protease-Resistant Prion Fragment Distinguishes Ovine “CH1641-Like” Scrapie from Bovine Classical and L-Type BSE in Ovine Transgenic Mice

The protease-resistant prion protein (PrPres) of a few natural scrapie isolates identified in sheep, reminiscent of the experimental isolate CH1641 derived from a British natural scrapie case, showed partial molecular similarities to ovine bovine spongiform encephalopathy (BSE). Recent discovery of an atypical form of BSE in cattle, L-type BSE or BASE, suggests that also this form of BSE might have been transmitted to sheep. We studied by Western blot the molecular features of PrPres in four “CH1641-like” natural scrapie isolates after transmission in an ovine transgenic model (TgOvPrP4), to see if “CH1641-like” isolates might be linked to L-type BSE. We found less diglycosylated PrPres than in classical BSE, but similar glycoform proportions and apparent molecular masses of the usual PrPres form (PrPres #1) to L-type BSE. However, the “CH1641-like” isolates differed from both L-type and classical BSE by an abundant, C-terminally cleaved PrPres product (PrPres #2) specifically recognised by a C-terminal antibody (SAF84). Differential immunoprecipitation of PrPres #1 and PrPres #2 resulted in enrichment in PrPres #2, and demonstrated the presence of mono- and diglycosylated PrPres products. PrPres #2 could not be obtained from several experimental scrapie sources (SSBP1, 79A, Chandler, C506M3) in TgOvPrP4 mice, but was identified in the 87V scrapie strain and, in lower and variable proportions, in 5 of 5 natural scrapie isolates with different molecular features to CH1641. PrPres #2 identification provides an additional method for the molecular discrimination of prion strains, and demonstrates differences between “CH1641-like” ovine scrapie and bovine L-type BSE transmitted in an ovine transgenic mouse model

Transmissibility of Atypical Scrapie in Ovine Transgenic Mice: Major Effects of Host Prion Protein Expression and Donor Prion Genotype

Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ∼0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ∼6× the normal PrPc level died after a survival periods of 400 days, those with ∼1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein

Characterisation of the temperature effects on cattle mortality in France

En dépit d’une capacité d’adaptation remarquable, les bovins subissent un stress thermique qui résulte d’un déséquilibre d'homéostasie dès lors que les températures s’éloignent des conditions environnementales optimales. Plusieurs études expérimentales ont montré que ce stress thermique impactait la production de lait et de viande, la reproduction et le bien-être des bovins. La relation entre la température et la mortalité chez les bovins quant à elle a été peu décrite et reste à être précisée. Notre objectif principal était de caractériser les effets de la température sur la mortalité bovine et notamment l’impact des vagues de froid et canicules. Dans un premier temps, nous avons développé une méthode de partitionnement du territoire qui permet de définir des zones d’étude optimales pour l’estimation de nos relations d’intérêt. Nous nous sommes ensuite attachés à évaluer la relation entre l’exposition journalière de la température ambiante et la mortalité le même jour et les jours suivants pour les bovins laitiers et allaitants, au sein de différentes classes d’âge, à partir de modèles de régression adaptés. Au-delà de l’effet direct de la température journalière, nous avons également quantifié l’effet de l’exposition prolongée à des températures extrêmes sur la mortalité bovine, mettant ainsi en évidence un excès de risque associé à la fois à la durée et à l’intensité de l’exposition. Nos travaux fournissent une meilleure connaissance des risques de mortalité associés à la température, ont permis de quantifier ces risques au sein de multiples zones géographiques en France métropolitaine, et contribuent ainsi à améliorer le bien-être des bovins et à limiter les pertes économiques de la filière.Despite a remarkable ability to adapt to a large range of temperatures, cattle may experience thermal stress resulting from an imbalance in the homeostasis of the animals when temperatures exceed optimal environmental conditions. Several experimental studies showed that the thermal stress had an impact on milk and meat production, on reproduction and cattle welfare. However, the relationship between temperature and cattle mortality is poorly described and remains to be specified. Our main objective was to characterize the temperature effects and their impacts on cattle mortality. We first proposed an original approach for a spatial partitioning of the territory, defining optimal study areas for the assessment of the relationship of interest. We then to modeled the relationship between the daily exposure to ambient temperature and mortality during the same and the following days for beef and dairy cattle, and for the different age categories. Beyond this relationship, we also studied the effect of exposure to extreme meteorological events on cattle mortality, such as the prolonged exposure to extreme temperatures. We showed a risk excess associated with both the length and the intensity of the exposure. Our studies give a better knowledge of the risks of death associated with temperatures and contribute to improve to the cattle wellfare and to limit economic losses

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