Wild Animal Tuberculosis: Stakeholder Value Systems and Management of Disease

When human health is put at risk from the transmission of animal diseases, the options for intervention often require input from stakeholders whose differing values systems contribute to decisions on disease management. Animal tuberculosis (TB), caused principally by Mycobacterium bovis is an archetypical zoonotic pathogen in that it can be transmitted from animals to humans and vice versa. Although elimination of zoonotic transmission of TB to humans is frequently promoted as the raison d'être for TB management in livestock, in many countries the control strategies are more likely based on minimizing the impact of sustained infection on the agricultural industry. Where wild animals are implicated in the epidemiology of the disease, the options for control and eradication can require involvement of additional stakeholder groups. Conflict can arise when different monetary and/or societal values are assigned to the affected animals. This may impose practical and ethical dilemmas for decision makers where one or more species of wild animal is seen by some stakeholders to have a greater value than the affected livestock. Here we assess the role of stakeholder values in influencing TB eradication strategies in a number of countries including Ireland, the UK, the USA, Spain, France, Australia, New Zealand and South Africa. What it reveals is that the level of stakeholder involvement increases with the complexity of the epidemiology, and that similar groups of stakeholders may agree to a set of control and eradication measures in one region only to disagree with applying the same measures in another. The level of consensus depends on the considerations of the reservoir status of the infected host, the societal values assigned to each species, the type of interventions proposed, ethical issues raised by culling of sentient wild animals, and the economic cost benefit effectiveness of dealing with the problem in one or more species over a long time frame. While there is a societal benefit from controlling TB, the means to achieve this requires identification and long-term engagement with all key stakeholders in order to reach agreement on ethical frameworks that prioritize and justify control options, particularly where culling of wild animals is concerned

DNA Typing of Mycobacterium bovis Isolates from Badgers (Meles meles) Culled from Areas in Ireland with Different Levels of Tuberculosis Prevalence

Badgers (Meles meles) have been implicated in the transmission of Mycobacterium bovis infection to cattle in Ireland and UK. Recent studies in Ireland have shown that although the disease is endemic in badgers, the prevalence of disease is not uniform throughout the country and can vary among subpopulations. The extent to which the prevalence levels in badgers impact on the prevalence in cattle is not known. Previously, DNA fingerprinting has shown that M. bovis strain types are shared between badgers and cattle, and that there are a large number of strain types circulating in the two species. In this study we have carried out spoligotyping and variable number tandem repeat (VNTR) analysis of M. bovis isolates from two groups of badgers, representing a wide geographic area, with different tuberculosis prevalence levels. The results of the typing show that there is no geographic clustering of strain types associated with prevalence. However, two VNTR profiles were identified that appear to be associated with high- and low-prevalence M. bovis infection levels, respectively. In addition, spoligotyping and VNTR analysis has provided evidence, for the first time, of multiple infections of individual badgers with different M. bovis strains

Antigen stimulation of peripheral blood mononuclear cells from Mycobacterium bovis infected cattle yields evidence for a novel gene expression program

<p>Abstract</p> <p>Background</p> <p>Bovine tuberculosis (BTB) caused by <it>Mycobacterium bovis </it>continues to cause substantial losses to global agriculture and has significant repercussions for human health. The advent of high throughput genomics has facilitated large scale gene expression analyses that present a novel opportunity for revealing the molecular mechanisms underlying mycobacterial infection. Using this approach, we have previously shown that innate immune genes in peripheral blood mononuclear cells (PBMC) from BTB-infected animals are repressed <it>in vivo </it>in the absence of exogenous antigen stimulation. In the present study, we hypothesized that the PBMC from BTB-infected cattle would display a distinct gene expression program resulting from exposure to <it>M. bovis</it>. A functional genomics approach was used to examine the immune response of BTB-infected (<it>n </it>= 6) and healthy control (<it>n </it>= 6) cattle to stimulation with bovine tuberculin (purified protein derivative – PPD-b) <it>in vitro</it>. PBMC were harvested before, and at 3 h and 12 h post <it>in vitro </it>stimulation with bovine tuberculin. Gene expression changes were catalogued within each group using a reference hybridization design and a targeted immunospecific cDNA microarray platform (BOTL-5) with 4,800 spot features representing 1,391 genes.</p> <p>Results</p> <p>250 gene spot features were significantly differentially expressed in BTB-infected animals at 3 h post-stimulation contrasting with only 88 gene spot features in the non-infected control animals (<it>P </it>≤ 0.05). At 12 h post-stimulation, 56 and 80 gene spot features were differentially expressed in both groups respectively. The results provided evidence of a proinflammatory gene expression profile in PBMC from BTB-infected animals in response to antigen stimulation. Furthermore, a common panel of eighteen genes, including transcription factors were significantly expressed in opposite directions in both groups. Real-time quantitative reverse transcription PCR (qRT-PCR) demonstrated that many innate immune genes, including components of the TLR pathway and cytokines were differentially expressed in BTB-infected (<it>n </it>= 8) versus control animals (<it>n </it>= 8) after stimulation with bovine tuberculin.</p> <p>Conclusion</p> <p>The PBMC from BTB-infected animals exhibit different transcriptional profiles compared with PBMC from healthy control animals in response to <it>M. bovis </it>antigen stimulation, providing evidence of a novel gene expression program due to <it>M. bovis </it>exposure.</p

Ethical Issues in the New Digital Era: The Case of Assisting Driving

Mobility is associated with driving a vehicle. Age-related declines in the abilities of older persons present certain obstacles to safe driving. The negative effects of driving cessation on older adults’ physical, mental, cognitive, and social functioning are well reported. Automated driving solutions represent a potential solution to promoting driver persistence and the management of fitness to drive issues in older adults. Technology innovation influences societal values and raises ethical questions. The advancement of new driving solutions raises overarching questions in relation to the values of society and how we design technology (a) to promote positive values around ageing, (b) to enhance ageing experience, (c) to protect human rights, (d) to ensure human benefit and (e) to prioritise human well-being. To this end, this chapter reviews the relevant ethical considerations in relation to assisted driving solutions. Further, it presents a new ethically aligned system concept for assisted driving. It is argued that human benefit, well-being and respect for human identity and rights are important goals for new automated driving technologies. Enabling driver persistence is an issue for all of society and not just older adult

Driver Persistence, Safety and Older Adult Self-efficacy: Addressing Driving Challenges Using Innovative Multimodal Communication Concepts

New assisted driving technology provides a solution to enabling driver persistence while also addressing older adult fitness to drive issues. The proposed driver assistance system follows a detailed literature review, an analysis of secondary data, and the specification of a solution using human machine interaction (HMI) design methods. Overall, the assisted driving concept follows from a principled/ethical perspective in relation to promoting self-efficacy and enablement for older adults. The system is conceptualized as a supportive friend or ‘co-pilot’. It is argued that the use of new car-based sensors, along with machine learning intelligence and novel multimodal HMI communication methods will enable driver persistence while also promoting older adult self-efficacy and positive ageing

Innate gene repression associated with Mycobacterium bovis infection in cattle: toward a gene signature of disease

<p>Abstract</p> <p>Background</p> <p>Bovine tuberculosis is an enduring disease of cattle that has significant repercussions for human health. The advent of high-throughput functional genomics technologies has facilitated large-scale analyses of the immune response to this disease that may ultimately lead to novel diagnostics and therapeutic targets. Analysis of mRNA abundance in peripheral blood mononuclear cells (PBMC) from six <it>Mycobacterium bovis </it>infected cattle and six non-infected controls was performed. A targeted immunospecific bovine cDNA microarray with duplicated spot features representing 1,391 genes was used to test the hypothesis that a distinct gene expression profile may exist in <it>M. bovis </it>infected animals <it>in vivo</it>.</p> <p>Results</p> <p>In total, 378 gene features were differentially expressed at the <it>P </it>≤ 0.05 level in bovine tuberculosis (BTB)-infected and control animals, of which 244 were expressed at lower levels (65%) in the infected group. Lower relative expression of key innate immune genes, including the Toll-like receptor 2 (<it>TLR2</it>) and <it>TLR4 </it>genes, lack of differential expression of indicator adaptive immune gene transcripts (<it>IFNG, IL2, IL4</it>), and lower <it>BOLA </it>major histocompatibility complex – class I (<it>BOLA</it>) and class II (<it>BOLA-DRA</it>) gene expression was consistent with innate immune gene repression in the BTB-infected animals. Supervised hierarchical cluster analysis and class prediction validation identified a panel of 15 genes predictive of disease status and selected gene transcripts were validated (<it>n </it>= 8 per group) by real time quantitative reverse transcription PCR.</p> <p>Conclusion</p> <p>These results suggest that large-scale expression profiling can identify gene signatures of disease in peripheral blood that can be used to classify animals on the basis of <it>in vivo </it>infection, in the absence of exogenous antigenic stimulation.</p

Investigation of the association between the Enferplex bovine tuberculosis antibody test and the future risk of bovine tuberculosis in irish cattle in infected herds: a pilot field study

The Single Intradermal Comparative Tuberculin Test (SICTT) and the interferon-gamma (IFN-γ) assay are the approved diagnostic tests for bovine tuberculosis (bTB) in Ireland. The aim of this pilot study was to explore if there was any added diagnostic benefit from applying the Enferplex bTB test (an antibody test) in severe bTB herd breakdowns after the removal of cattle that had tested positive to the SICTT and the IFN-γ test. In addition to the normal bTB testing and management protocols, the animals in these herds that tested negative to SICTT and the IFN-γ test were followed forward for a period of two years. All animals were tested by Enferplex at enrolment. The time to subsequent bTB detection (diagnosed with SICTT/IFN-γ tests or detection of visible lesions at routine slaughter) for animals that tested positive or negative to the Enferplex bTB test at the start of the study was compared using Kaplan–Meier survival curves and Cox based survival models. Of the 484 enrolled animals (from 11 herds), 171 (35.3%) and 151 (31.1%) initially tested positive in the Enferplex assay under the high sensitivity and high specificity interpretation settings respectively. The results of the survival analysis showed that there was no difference in the survival time to a positive diagnosis with bTB during the follow-up period between animals initially classified as positive and negative by the Enferplex test. Further research is warranted to explore the potential benefit of using the Enferplex test in other scenarios.Department of Agriculture, Food and the MarineOpen Access funding provided by the IReL ConsortiumTo check citing and date details in 6

New serological platform for detecting antibodies against Mycobacterium tuberculosis complex in European badgers

[EN]European badgers (Meles meles) have been identified as wildlife reservoirs for Mycobacterium bovis in the UK and Ireland, and may also have a role in the epidemiology of animal tuberculosis in other European regions. Thus, detection of M. bovis-infected badgers may be required for the purposes of surveillance and monitoring of disease levels in infected populations. Current serological assays to detect M. bovis infection in live badgers, while rapid and inexpensive, show limited diagnostic sensitivity. Here we describe and evaluate new ELISA platforms for the recognition of the P22 multiprotein complex derived from the purified protein derivative (PPD) of M. bovis. The recognition of IgG against P22 multiprotein complex derived from PPD-B was tested by ELISA in the serum of badgers from the UK, Ireland and Spain. TB infection in the badgers was indicated by the presence of M. bovis in tissues by culture and histology at post-mortem examination and TB-free status was established by repeated negativity in the interferon c release assay (IGRA). In experimentally infected badgers, humoral antibody responses against P22 developed within 45 days post-infection. The ELISA tests showed estimated sensitivity levels of 74–82% in experimentally and naturally infected badgers with specifici-ties ranging from 75% to 100% depending on the badger population tested. The P22 multi-antigen based ELI-SAs provide a sensitive and specific test platform for improved tuberculosis surveillance in badgers.SIThis work was supported by the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria of Spain (INIA; RTA2015-00043-C02-02) and the TAVS-CM Programme of the Comunidad de Madrid (S2013/ABI-2747), cofinanced by the FEDER fund ‘A way to build Europe’. This work was partially supported by a FEDER co-funded grant from INIA (RTA2014-00002-C02-01). Jose Antonio Infantes-Lorenzo was supported by an FPU contract-fellowship (Formación de Profesorado Universitario) from the Ministerio de Educación, Cultura y Deporte of the Spanish Government (FPU2013/6000)

Key Hub and Bottleneck Genes Differentiate the Macrophage Response to Virulent and Attenuated Mycobacterium bovis

Mycobacterium bovis is an intracellular pathogen that causes tuberculosis in cattle. Following infection, the pathogen resides and persists inside host macrophages by subverting host immune responses via a diverse range of mechanisms. Here, a high-density bovine microarray platform was used to examine the bovine monocyte-derived macrophage transcriptome response to M. bovis infection relative to infection with the attenuated vaccine strain, M. bovis Bacille Calmette–Guérin. Differentially expressed genes were identified (adjusted P-value ≤0.01) and interaction networks generated across an infection time course of 2, 6, and 24 h. The largest number of biological interactions was observed in the 24-h network, which exhibited scale-free network properties. The 24-h network featured a small number of key hub and bottleneck gene nodes, including IKBKE, MYC, NFKB1, and EGR1 that differentiated the macrophage response to virulent and attenuated M. bovis strains, possibly via the modulation of host cell death mechanisms. These hub and bottleneck genes represent possible targets for immuno-modulation of host macrophages by virulent mycobacterial species that enable their survival within a hostile environment