Carmarthen, United Kingdom
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Kiran D.,Colorado State University | Podell B.K.,Colorado State University | Chambers M.,Animal and Plant Health Agency APHA | Chambers M.,University of Surrey | Basaraba R.J.,Colorado State University
Seminars in Immunopathology | Year: 2016

Infection by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb) is a major cause of morbidity and mortality worldwide. Slow progress has been made in lessening the impact of tuberculosis (TB) on human health, especially in parts of the world where Mtb is endemic. Due to the complexity of TB disease, there is still an urgent need to improve diagnosis, prevention, and treatment strategies to control global spread of disease. Active research targeting avenues to prevent infection or transmission through vaccination, to diagnose asymptomatic carriers of Mtb, and to improve antimicrobial drug treatment responses is ongoing. However, this research is hampered by a relatively poor understanding of the pathogenesis of early infection and the factors that contribute to host susceptibility, protection, and the development of active disease. There is increasing interest in the development of adjunctive therapy that will aid the host in responding to Mtb infection appropriately thereby improving the effectiveness of current and future drug treatments. In this review, we summarize what is known about the host response to Mtb infection in humans and animal models and highlight potential therapeutic targets involved in TB granuloma formation and resolution. Strategies designed to shift the balance of TB granuloma formation toward protective rather than destructive processes are discussed based on our current knowledge. These therapeutic strategies are based on the assumption that granuloma formation, although thought to prevent the spread of the tubercle bacillus within and between individuals contributes to manifestations of active TB disease in human patients when left unchecked. This effect of granuloma formation favors the spread of infection and impairs antimicrobial drug treatment. By gaining a better understanding of the mechanisms by which Mtb infection contributes to irreversible tissue damage, down regulates protective immune responses, and delays tissue healing, new treatment strategies can be rationally designed. Granuloma-targeted therapy is advantageous because it allows for the repurpose of existing drugs used to treat other communicable and non-communicable diseases as adjunctive therapies combined with existing and future anti-TB drugs. Thus, the development of adjunctive, granuloma-targeted therapy, like other host-directed therapies, may benefit from the availability of approved drugs to aid in treatment and prevention of TB. In this review, we have attempted to summarize the results of published studies in the context of new innovative approaches to host-directed therapy that need to be more thoroughly explored in pre-clinical animal studies and in human clinical trials. © 2015, The Author(s).


PubMed | Animal and Plant Health Agency APHA, Aix - Marseille University, Institute Salud Carlos III and Friedrich Loeffler Institute FLI
Type: Journal Article | Journal: Genome announcements | Year: 2017

All lyssaviruses (family Rhabdoviridae) cause the disease rabies, an acute progressive encephalitis for which, once symptoms occur, there is no effective cure. Using next-generation sequencing, the full-genome sequence for a novel lyssavirus, Lleida bat lyssavirus (LLEBV), from the original brain of a common bent-winged bat has been confirmed.


JONES R.A.,Aberystwyth University | BROPHY P.M.,Aberystwyth University | MITCHELL E.S.,Animal and Plant Health Agency APHA | WILLIAMS H.W.,Aberystwyth University
Parasitology | Year: 2016

Reports of Calicophoron daubneyi infecting livestock in Europe have increased substantially over the past decade; however, there has not been an estimate of its farm level prevalence and associated risk factors in the UK. Here, the prevalence of C. daubneyi across 100 participating Welsh farms was recorded, with climate, environmental and management factors attained for each farm and used to create logistic regression models explaining its prevalence. Sixty-one per cent of farms studied were positive for C. daubneyi, with herd-level prevalence for cattle (59%) significantly higher compared with flock-level prevalence for sheep (42%, P = 0·029). Co-infection between C. daubneyi and Fasciola hepatica was observed on 46% of farms; however, a significant negative correlation was recorded in the intensity of infection between each parasite within cattle herds (rho = −0·358, P = 0·007). Final models showed sunshine hours, herd size, treatment regularity against F. hepatica, the presence of streams and bog habitats, and Ollerenshaw index values as significant positive predictors for C. daubneyi (P < 0·05). The results raise intriguing questions regarding C. daubneyi epidemiology, potential competition with F. hepatica and the role of climate change in C. daubneyi establishment and its future within the UK. Copyright © Cambridge University Press 2016 This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.


Value chain analysis provides a rational and systematic framework for describing and evaluating the roles and relationships of people and organisations that exist in complex and dynamic systems and networks. This includes understanding the flows of materials and commodities and value-adding activities between the different parts of value chains. Value chain analysis also has people as a primary focus, thereby enabling an understanding of their roles, motivations and behaviours in context with cultural, socio-economic and other drivers.This study explores the hypothesis, proposed here for the first time, that the utility of value chain analysis can be further extended to enable evaluation of health surveillance systems. The main characteristics of a poultry food system value chain were evaluated first to provide a conceptual framework for the description of a surveillance system value chain. The scanning surveillance system for the detection and early warning of diseases and health threats in poultry in Great Britain was then used as an example, to which a value chain analysis was applied.The key surveillance value chain commodity was identified as livestock health data and intelligence, which describes and contextualises the health status of the given 'at risk' population. Furthermore, some fundamental asymmetries in the surveillance system value chain have been identified relating to poultry demographics (as the denominator livestock population) and the people, organisations, resource flows, power and institutional environment.In addition, other insights have been gained enabling the identification of factors that help to understand the behaviours of people, which in turn may influence their decision-making, and may also result in changes to the activities and risk profile and management in the surveillance system value chain, specifically: (i) information-sharing and collaboration; (ii) social capital and trust; (iii) prioritisation and deployment of resources; (iv) the basis for people to engage and participate; (v) cooperation between the public and private sectors, including sharing of responsibility and costs.This study has shown that value chain analysis provides a robust, systems-based approach that can be used as a systematic framework to evaluate a livestock health surveillance system and the context in which disease and associated surveillance information is placed in the surveillance system value chain by the people, businesses and organisations involved. In addition, this information can be used for decision-support, to manage risk, generate value and ensure that people in the system bear the costs of surveillance and disease management appropriately. © 2014.


Hutchinson J.P.,Animal and Plant Health Agency APHA | Smith R.P.,Weybridge
Veterinary Record | Year: 2015

Ovine serum samples submitted to Animal and Plant Health Agency (APHA) (formerly the Animal Health and Veterinary Laboratories Agency) - Weybridge regional laboratories in England and Wales for diagnostic and monitoring purposes between 2005 and 2012 were investigated for possible spatial and temporal variations in seropositivity to Toxoplasma gondii infection. Of the 4354 samples tested by latex agglutination, 2361 (54.2 per cent) were seropositive. No correlation between seropositivity and climatic conditions was identified by mixed-effects modelling using meteorological data summaries. The proportion of seropositive samples collected during November was found to be significantly lower than those collected during other months and samples from the North West England and North Wales Regions had significantly lower odds of being positive. Spatial cluster analysis identified a significantly higher proportion of seropositive animals in East Anglia and the South, East and Midlands of England. Spatio-temporal cluster analysis detected a single significant cluster of seropositive animals dating from January 2006 to January 2011, which covered a large proportion of the farm locations. As well as confirming high overall levels of infection within the national flock, these findings also indicate possible temporal and regional variations in exposure of sheep to T. gondii.


Garcia-Pelayo M.C.,Animal and Plant Health Agency APHA | Bachy V.S.,Animal and Plant Health Agency APHA | Bachy V.S.,Current Address Orbio Laboratoire | Kaveh D.A.,Animal and Plant Health Agency APHA | Hogarth P.J.,Animal and Plant Health Agency APHA
Tuberculosis | Year: 2015

Summary It is generally assumed that the inbred mouse strains BALB/c (H-2d) and C57BL/6 (H-2b) respond to mycobacterial infection with distinct polarisation of T helper responses, with C57BL/6 predisposed to Th1 and BALB/c to Th2. We investigated this in a BCG-immunisation, Mycobacterium bovis challenge model. Following immunisation, lung and spleen cell cytokine responses to in vitro re-stimulation with a cocktail of seven secreted, immunogenic, recombinant mycobacterial proteins were determined. In both lung and spleen, BALB/c cells produced at least 2-fold more IFN-γ, and up to 7-fold more IL-2 and IL-17 than C57BL/6 cells, whereas IL-10 production was reciprocally increased in C57BL/6 mice. These data suggest that, contrary to reports in the literature, specific mycobacterial antigens are able to induce strong Th1 and Th17 responses in BALB/c mice following BCG vaccination, whilst in C57BL/6 mice, the Th1 response is partly counterbalanced by IL-10. After subsequent M. bovis low dose challenge, protection, as measured in the lungs and dissemination to the spleen, was equivalent in BALB/c and C57BL/6 mice, indicating that BCG-induced immunity was equivalent in both strains. Thus, the differential immune responses do not appear to have a role in protection, but further, as yet unidentified, specific immune responses play a significant role. © 2014 Elsevier Ltd. All rights reserved.


Smith R.P.,Animal and Plant Health Agency APHA | Pollitt W.J.,APHA South East | Paiba G.A.,Animals in Science Regulation Unit
Epidemiology and Infection | Year: 2016

A longitudinal study in England and Wales of two dairy, five beef-fattener and three beef-suckler herds was carried out to identify risk factors for young cattle excreting verocytotoxin-producing Escherichia coli O157 (VTEC O157). A total of 1383 cattle, selected into cohorts at 0-24 months were sampled between March 2000 and February 2001. Mixed-effects logistic regression was employed to identify significant associations between VTEC O157 isolation from rectal faecal samples and explanatory factors (P < 0·001 unless shown). The results revealed a positive association with feeding root crops and a negative association with animals fed silage, milk (P = 0·001) or grain (P = 0·027). Cattle in suckler herds (P = 0·001) and those changing group between sampling visits were identified as negatively associated with VTEC O157 presence. The recovery of VTEC O157 varied throughout the year. However, the winter period from December to February was a risk factor in the multivariable analysis. Cattle in pens were 4·7 times more likely to shed VTEC O157 than those group-housed or at pasture. VTEC O157 detected in pooled environmental faecal pats and biofilm of the water supply within a group's enclosure were positively associated with an animal's VTEC O157 status in the multivariable logistic regression, as was detection of VTEC O157 in the pooled faecal pats at the previous visit. © Copyright Cambridge University Press 2016.


Gale P.,Animal and Plant Health Agency APHA | Kelly L.,Animal and Plant Health Agency APHA | Mearns R.,Animal and Plant Health Agency APHA | Duggan J.,Public Health England | Snary E.L.,Animal and Plant Health Agency APHA
Journal of Applied Microbiology | Year: 2015

Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii which is endemic in cattle, sheep and goats in much of the world, including the United Kingdom (UK). There is some epidemiological evidence that a small proportion of cases in the developed world may arise from consumption of unpasteurised milk with less evidence for milk products such as cheese. Long maturation at low pH may give some inactivation in hard cheese, and viable C. burnetii are rarely detected in unpasteurised cheese compared to unpasteurised milk. Simulations presented here predict that the probability of exposure per person to one or more C. burnetii through the daily cumulative consumption of raw milk in the UK is 0·4203. For those positive exposures, the average level of exposure predicted is high at 1266 guinea pig intraperitoneal infectious dose 50% units (GP_IP_ID50) per person per day. However, in the absence of human dose-response data, the case is made that the GP_IP_ID50 unit represents a very low risk through the oral route. The available evidence suggests that the risks from C. burnetii through consumption of unpasteurised milk and milk products (including cheese) are not negligible but they are lower in comparison to transmission via inhalation of aerosols from parturient products and livestock contact. © 2015 The Society for Applied Microbiology.


PubMed | Animal and Plant Health Agency APHA, Public Health England and University of Liverpool
Type: Journal Article | Journal: Vaccine | Year: 2016

Despite the availability of safe and effective human vaccines, rabies remains a global threat, with an estimated 60,000 human deaths annually attributed to rabies. Pre-exposure prophylaxis against rabies infection is recommended for travelers to countries where rabies is endemic, and also for those with a higher risk of exposure. In this study, the rabies-specific neutralising antibody responses in a cohort of rabies-vaccinated recipients over a period of twenty years have been assessed. In particular, the antibody response to primary vaccinations and boosters, and the waning of antibody post primary vaccination and post booster were investigated. The significance of gender, age at vaccination, vaccine manufacturer and vaccination intervals were also evaluated. These data confirm that rabies vaccination can elicit a neutralising antibody response that can remain at detectable levels for a number of years, without additional booster vaccinations. The antibody response following both primary vaccination and booster was significantly influenced by the gender of the subject (p=0.002 and 0.03 respectively), with supportive data that suggests an effect by the make of vaccine administered following primary vaccination, with significantly higher VNA titres observed for one vaccine manufactured prior to 2006 (p<0.001) in a small subset of recipients (n=5). Additionally, the decay rate was demonstrated through the overall decline in antibody titre for all individuals, which was a 37% and 27% reduction per 2-fold change in time following primary and booster vaccination respectively. Individuals within older age groups demonstrated a significantly faster decline in antibody titre following the primary vaccination course (p=0.012). Rate of decline in antibody titre was also significantly influenced by the vaccine make following primary course (p<0.001). The assessment of neutralising antibody titre decline has also provided an insight into the most appropriate timing for booster administration, and enabled the prediction of long term titres from post-vaccination antibody titres.


PubMed | Animal and Plant Health Agency APHA
Type: | Journal: Preventive veterinary medicine | Year: 2016

European surveillance for Bovine Spongiform Encephalopathy (BSE), initiated in 2001, has shown a steady exponential decline in the number of infected cattle, demonstrating that control measures have been effective. In 2016 23 European countries out of 28 demonstrated negligible risk status for the disease. The international standard setting body, the World Organization for Animal Health (OIE), prescribes that for countries where there is a non-negligible BSE risk, surveillance should allow the detection of one case per 100,000 in the adult cattle population with 95% confidence (Type A surveillance). The Cattle TSE Monitoring Model (C-TSEMM) was developed to estimate the sensitivity of surveillance systems to detect BSE in cattle. The model includes a cohort-based back calculation model to estimate the number and age of infected animals, the subset of those that are detectable by the diagnostic test, and the stream by which infected animals exit the standing population, that is, healthy slaughter, emergency slaughter, fallen stock and clinical suspects. Data collected by the European Commission (EC) and European Food Safety Authority (EFSA), containing the details of over 91 million cattle tested within the European Member States (EU25) surveillance scheme from 2002 to 2011, was used to populate the model. When considering the EU25 surveillance scheme as a single epidemiological unit, the model estimated that the surveillance scheme in place exceeded the OIE required threshold for Type A surveillance, and that a revised monitoring system excluding all healthy slaughter animals would also exceed this threshold. Results indicated a variation in individual country sensitivity of surveillance with seven countries (Germany, Spain, France, Ireland, Italy, Poland and the UK) exceeding the required threshold individually. Key assumptions included the fitting of an exponential distribution for all countries to describe the decline in prevalence over time and, for those members with no detected cases of BSE, an estimated area prevalence was used as a proxy. These results were part of the evidence base that lifted the testing requirement for healthy slaughter animals in European countries in 2013. The model has been maintained and updated by EFSA each year with the addition of new member states, and updated surveillance data.

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