Pig herpesvirose: Aujeszky's disease

Aujeszky's disease, due to Suid herpesvirus 1, is a disease of wild and domestic pigs, which can occasionally infect other mammal species, such as cattle and domestic carnivores. Eradicated or in the process of being eradicated in domestic pig herds in most countries of the European Union and in North America, the disease remains endemic in wild boar populations, with a prevalence varying according to population densities. In domestic pigs, symptoms vary depending on the age of the animals, ranging from severe nervous disorders in piglets to respiratory and reproductive disorders in adults. In other species, the disease causes a fatal meningo-encephalitis. Control programmes usually combine vaccination with marker vaccines and screening with companion diagnostic kits. In countries free from Aujeszky's disease, serological surveillance is supplemented by active surveillance.La maladie d'Aujeszky, due à Suid herpesvirus 1, est une maladie des suidés sauvages et domestiques, qui peut atteindre occasionnellement d'autres espèces de mammifères comme les bovins et les carnivores domestiques. Éradiquée ou en cours d'éradication dans les élevages de porcs domestiques dans la plupart des pays de l'Union européenne et en Amérique du Nord, la maladie demeure endémique dans les populations de suidés sauvages, avec une prévalence qui diffère selon leur densité. Les symptômes varient selon l'âge des porcs, allant des troubles nerveux sévères chez les jeunes aux troubles respiratoires et troubles de la reproduction chez les adultes. Chez les autres espèces, la maladie se traduit par une méningo-encéphalite mortelle. Les plans de lutte associent généralement vaccination par des vaccins marqueurs et dépistage par des kits sérologiques compagnons. Dans les pays où la maladie est éradiquée, la surveillance sérologique active est complétée par la surveillance évènementielle

Plasmacytoid dendritic cells initiate a complex chemokine and cytokine network and are a viable drug target in chronic HCV patients

Plasmacytoid dendritic cells (pDCs) are the professional type I interferon (IFN)-producing cells, and upon activation they traffic to lymph organs, where they bridge innate and adaptive immunity. Using multianalyte profiling (MAP), we have mapped the key chemokines and cytokines produced in response to pDC activation, taking into consideration the role of autocrine IFN, as well as paracrine effects on other innate cells (e.g., monocytes and conventional DCs). Interestingly, we identify four distinct cytokine/chemokine loops initiated by Toll-like receptor engagement. Finally, we applied this analytic approach to the study of pDC activity in chronic hepatitis C patients. Based on the activation state of pDCs in fresh blood, the lack of agonistic activity of infectious virions, the production of a broad array of cytokines/chemokines once stimulated, and the direct effects of pDCs on other PBMCs, we conclude that the pDCs from hepatitis C virus (HCV)-infected individuals are fully functional and are, indeed, a viable drug target. In sum, this study provides insight into the use of MAP technology for characterizing cytokine networks, and highlights how a rare cell type integrates the activation of other inflammatory cells. Furthermore, this work will help evaluate the therapeutic application of pDC agonists in diseases such as chronic HCV infection

Management of a wild reservoir : Swine fever in European wild boars (sus scrofa)

Classical swine fever (CSF) is a disease affecting wild and domestic Suidae. Wild boars (Sus scrofa) are considered as a reservoir for the disease, as CSF may persist for years in certain wild populations. The presence of this infection is a threat for the pig industry in the European Union where most of the member States are free of CSF.We describe the possible outcomes of an outbreak of CSF in wild animals, as well as the factors likely to influence the virus transmission and persistence. We also detail the management measures that were tested to date to prevent geographical spreading from the infected zones, and to eradicate CSF within the infected areas. The complexity of health measures dealing with an outbreak within natural populations is explained, with further details on the vaccination approach implemented in France since 2004.La peste porcine classique (PPC) est une maladie virale des Suidés domestiques et sauvages. Le sanglier (Sus scrofa) est considéré comme un réservoir de PPC car la maladie peut persister plusieurs années dans certaines populations sauvages. Or la présence de cette infection représente une menace pour la filière porcine de l'union européenne dont la plupart des États membres sont indemnes. Nous présentons ici les évolutions possibles d'un foyer sauvage de PPC en déclinant les facteurs probables de la transmission et de la persistance du virus. Nous abordons ensuite les différents moyens de gestion qui ont été mis en place jusqu'à aujourd'hui pour empêcher l'extension des zones infectées, et permettre l'éradication des foyers au sein des zones infectées. L'accent est mis sur la complexité de la gestion sanitaire d'un foyer en population naturelle. Un développement plus particulier est consacré à la gestion vaccinale qui est mise en oeuvre en France depuis 2004

New Insights on the Management of Wildlife Diseases Using Multi-State Recapture Models: The Case of Classical Swine Fever in Wild Boar

The understanding of host-parasite systems in wildlife is of increasing interest in relation to the risk of emerging diseases in livestock and humans. In this respect, many efforts have been dedicated to controlling classical swine fever (CSF) in the European Wild Boar. But CSF eradication has not always been achieved even though vaccination has been implemented at a large-scale. Piglets have been assumed to be the main cause of CSF persistence in the wild since they appeared to be more often infected and less often immune than older animals. However, this assumption emerged from laboratory trials or cross-sectional surveys based on the hunting bags.In the present paper we conducted a capture-mark-recapture study in free-ranging wild boar piglets that experienced both CSF infection and vaccination under natural conditions. We used multi-state capture recapture models to estimate the immunization and infection rates, and their variations according to the periods with or without vaccination. According to the model prediction, 80% of the infected piglets did not survive more than two weeks, while the other 20% quickly recovered. The probability of becoming immune did not increase significantly during the summer vaccination sessions, and the proportion of immune piglets was not higher after the autumn vaccination.Given the high lethality of CSF in piglets highlighted in our study, we consider unlikely that piglets could maintain the chain of CSF virus transmission. Our study also revealed the low efficacy of vaccination in piglets in summer and autumn, possibly due to the low palatability of baits to that age class, but also to the competition between baits and alternative food sources. Based on this new information, we discuss the prospects for the improvement of CSF control and the interest of the capture-recapture approach for improving the understanding of wildlife diseases

The Human Papillomavirus E6 Oncogene Represses a Cell Adhesion Pathway and Disrupts Focal Adhesion through Degradation of TAp63β upon Transformation

Cervical carcinomas result from cellular transformation by the human papillomavirus (HPV) E6 and E7 oncogenes which are constitutively expressed in cancer cells. The E6 oncogene degrades p53 thereby modulating a large set of p53 target genes as shown previously in the cervical carcinoma cell line HeLa. Here we show that the TAp63β isoform of the p63 transcription factor is also a target of E6. The p63 gene plays an essential role in skin homeostasis and is expressed as at least six isoforms. One of these isoforms, ΔNp63α, has been found overexpressed in squamous cell carcinomas and is shown here to be constitutively expressed in Caski cells associated with HPV16. We therefore explored the role of p63 in these cells by performing microarray analyses after repression of endogenous E6/E7 expression. Upon repression of the oncogenes, a large set of p53 target genes was found activated together with many p63 target genes related to cell adhesion. However, through siRNA silencing and ectopic expression of various p63 isoforms we demonstrated that TAp63β is involved in activation of this cell adhesion pathway instead of the constitutively expressed ΔNp63α and β. Furthermore, we showed in cotransfection experiments, combined with E6AP siRNA silencing, that E6 induces an accelerated degradation of TAp63β although not through the E6AP ubiquitin ligase used for degradation of p53. Repression of E6 transcription also induces stabilization of endogenous TAp63β in cervical carcinoma cells that lead to an increased concentration of focal adhesions at the cell surface. Consequently, TAp63β is the only p63 isoform suppressed by E6 in cervical carcinoma as demonstrated previously for p53. Down-modulation of focal adhesions through disruption of TAp63β therefore appears as a novel E6-dependent pathway in transformation. These findings identify a major physiological role for TAp63β in anchorage independent growth that might represent a new critical pathway in human carcinogenesis

Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses

SummarySystems approaches for the study of immune signaling pathways have been traditionally based on purified cells or cultured lines. However, in vivo responses involve the coordinated action of multiple cell types, which interact to establish an inflammatory microenvironment. We employed standardized whole-blood stimulation systems to test the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immunomodulatory molecules. Moreover, we provide an interactive R-Shiny application with healthy donor reference values for induced inflammatory genes

A compendium of single extracellular vesicle flow cytometry

Flow cytometry (FCM) offers a multiparametric technology capable of characterizing single extracellular vesicles (EVs). However, most flow cytometers are designed to detect cells, which are larger than EVs. Whereas cells exceed the background noise, signals originating from EVs partly overlap with the background noise, thereby making EVs more difficult to detect than cells. This technical mismatch together with complexity of EV-containing fluids causes limitations and challenges with conducting, interpreting and reproducing EV FCM experiments. To address and overcome these challenges, researchers from the International Society for Extracellular Vesicles (ISEV), International Society for Advancement of Cytometry (ISAC), and the International Society on Thrombosis and Haemostasis (ISTH) joined forces and initiated the EV FCM working group. To improve the interpretation, reporting, and reproducibility of future EV FCM data, the EV FCM working group published an ISEV position manuscript outlining a framework of minimum information that should be reported about an FCM experiment on single EVs (MIFlowCyt-EV). However, the framework contains limited background information. Therefore, the goal of this compendium is to provide the background information necessary to design and conduct reproducible EV FCM experiments. This compendium contains background information on EVs, the interaction between light and EVs, FCM hardware, experimental design and preanalytical procedures, sample preparation, assay controls, instrument data acquisition and calibration, EV characterization, and data reporting. Although this compendium focuses on EVs, many concepts and explanations could also be applied to FCM detection of other particles within the EV size range, such as bacteria, lipoprotein particles, milk fat globules, and viruses

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers