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Studying the dynamics of pathogen transmission within wildlife populations presents an array of challenges. Where populations are socially structured, this can influence parasite transmission, impacting on the effectiveness of disease management strategies. In this thesis, I focus on a well-studied social mammal, the European badger (Meles meles) which is a key wildlife reservoir of a disease of economic importance; bovine TB (caused by infection with Mycobacterium bovis). The social structuring, characteristic of high density badger populations, is of well-established importance in the transmission of bovine TB and has resulted in unexpected management outcomes. However, little is known about the role of kin structure or host genotype on transmission dynamics. In this thesis, I combine traditional spatial epidemiology and ecological analysis of a well-studied badger population with more novel genetic and genomic approaches. Firstly, I investigate the role of kin structure within badger social groups in determining early life infection risk (Chapter 3). Using host genotype data, I demonstrate that cubs who are related to infected adults experience enhanced infection risks. I then explore the role of badger genotype on outcomes of M. bovis exposure and demonstrate that inbred badgers are more likely to show evidence of progressive infection (Chapter 4). Where the social structure of badgers is stable and unmanaged, this is predicted to result in a stable spatial distribution of M. bovis infection. Motivated by an observation of change in the spatial distribution of M. bovis infection in the study population, in the absence of management, I characterise the attrition of a spatially stable infection distribution (Chapter 5). To explore the drivers of this, I detect changes in the genetic population structure (Chapter 6) and present evidence that the population has experienced a period of demographic flux. Finally, I use a novel dataset generated by whole genome sequencing of M. bovis isolates and present evidence of spatial spread of M. bovis infection across the study population (Chapter 7). To conclude, I discuss how my findings demonstrate how genetic and genomic approaches can complement traditional wildlife epidemiology approaches, how they contribute to our understanding of heterogeneity in transmission dynamics and discuss their implications for wildlife disease management.

The significant social and economic losses as a result of bovine tuberculosis (bTB) present a continuous challenge to cattle industries in the United Kingdom (UK) and worldwide. Furthermore, as a zoonotic disease, bTB may pose a threat to humans. The potential transmission of bTB in cattle, estimated by the basic reproductive ratio (R0) was found to range between 1.0 and 1.9 in previous studies. In the UK, there has been an overall increase in bTB incidence in the last two decades despite national control and eradication programmes spanning over five decades. Such programmes mainly consist of surveillance based on the administration of skin tests and culling of animals reacting positive to these tests. Animal mobility restrictions are implemented in this case. At the same time, several studies have demonstrated that there is significant host genetic variation in individual cattle susceptibility to bTB, making the disease amenable to improvement with genetic or genomic selection. In addition, genomic analyses enhance the understanding of genetic mechanisms underlying the disease and its dynamics. The overall aim of this PhD thesis was to address existing scientific research gaps on the genetics of bTB resistance in dairy cattle. The following specific objectives were set: 1) to identify genomic regions underlying susceptibility to bTB using novel trait definitions, 2) to quantify the impact of long-term genetic selection for increased resistance to bTB on disease prevalence and dynamics and 3) to determine the consequences of genetically selecting for increased resistance to bTB on other economically important traits in dairy cattle. Genome-wide association studies (GWAS), regional heritability mapping (RHM) and chromosomal association analyses were applied in order to identify genomic regions associated with bTB (objective 1). Phenotypes comprised de-regressed estimated breeding values of 804 Holstein-Friesian sires obtain from the UK national genetic evaluation for bTB. Phenotypes pertained to three bTB trait definitions: i) positive reactors to the skin test with positive post-mortem examination results (phenotype 1); ii) positive reactors to the skin test regardless of post-mortem examination results (phenotype 2) and iii) as in (ii) plus non-reactors and inconclusive reactors to the skin test with positive post-mortem examination results (phenotype 3). In all cases, non-reactors without a subsequent positive post-mortem were considered to be healthy animals with regards to bTB. Genotypes based on a 50K SNP DNA array were available and a total of 34,874 SNPs remained after quality control. The estimated polygenic heritability for susceptibility to bTB was 0.26, 0.37 and 0.34 for phenotypes 1, 2 and 3, respectively. GWAS identified a putative SNP on Bos taurus autosomes (BTA) 2 associated with phenotype 1, and another on BTA 23 associated with phenotype 2. Genomic regions encompassing these SNPs were found to harbour potentially relevant annotated genes. RHM confirmed the effect of these genomic regions and identified new regions on BTA 18 for phenotype 1 and BTA 3 for phenotypes 2 and 3. Heritabilities of the genomic regions ranged between 0.05 and 0.08 across the three phenotypes. Chromosome association analysis indicated a major role of BTA 23 on susceptibility to bTB. A stochastic genetic epidemiological model based on four main disease states, namely susceptible (S), exposed (E), infectious (I) and test-sensitive (T), was developed to address objective 2. Effects of selection for increased resistance to bTB were investigated in a closed, genetically heterogeneous simulated population whose structure reflected the UK national dairy herd. Disease dynamics reflected real bTB data from the UK national genetic evaluation. The proposed genetic epidemiological model was implemented to simulate breakdowns under both absence and presence of selection. Genetic selection was simulated over 20 generations in 50 replicates, while exploring various selection intensities reflecting selection of the 10, 25, 50, 70 and 100% (no selection scenario) most resistant sires. Results indicated that selection significantly reduced the average underlying susceptibility across generations. The risk of breakdown was reduced by half after 4 and 6 generations for high selection intensities (10 or 25% of sires selected) and after 9 and 15 generations for low selection intensities (50 or 70% of sires selected). The average percentage of secondary cases was reduced to less than 1% in 4 and 5 generations for high selection intensities, and in 7 and 11 generations for low selection intensities. The reduction in the number of secondary cases across generations could also be indicative of the possible impact of genetic selection on the basic reproductive ratio (R0) which is defined as the number of secondary cases that results from an infectious individual in a naive population. Genetic selection also reduced severity and duration of breakdowns across generations. Finally, with regards to objective 3, a stochastic simulation was used to investigate the long-term effects of selection for resistance to bTB on other economically important traits in the UK dairy selection programme. Selection was simulated in a genetically heterogeneous population across 10 generations in 50 replicates. Animal genetic values for bTB and other traits were simulated based on variance and genetic correlation estimates obtained from literature. Independent culling levels selection of sires was applied in every generation whereby selection was first based on increasing resistance to bTB, then improving either an overall index, milk fat yield (FY) or milk protein yield (PY). This mimics real life practices regarding the newly released national genetic evaluations for bTB resistance. The overall index comprised several traits of interest such as milk yield (MY), FY, PY, feet and legs (FL), mammary (MAM), milk somatic cell count (SCC), calving interval (CI), non-return to service at 56 days (NR56) and lifespan (LS). A fertility index (FI) consisting of CI and NR56 was also considered in the analyses. Regarding bTB, different levels of selection intensities were explored corresponding to selection of the 10, 25, 50, 70 and 100% (no selection) most resistant sires. Two levels of selection intensity on the overall index, FY or PY were considered corresponding to selecting the best 5 and 10% of sires that were left after first selecting for bTB resistance. Results indicated that selection for increased bTB resistance would generally not have far-reaching consequences on other important traits. As expected, susceptibility to bTB declined with time and increasing selection intensity. Trends for all production traits (MY, FY and PY) in the present study were affected by selection for increased bTB resistance because of their significant genetic correlations with bTB. However, body conformation traits (FL and MAM) were not affected by selection for increased bTB resistance due to zero correlation assumed between these traits and bTB in the present study. Selection on bTB hampered improvement of SCC but enhanced LS because it was correlated unfavourably with SCC but favourably with LS. In all selection scenarios, the overall index improved and was generally not affected by selection for bTB resistance. Similarly, the FI was not affected by selection on bTB in all cases. However, secondary selection on production traits only (FY or PY) led to a decline in FI. Results presented in this thesis add insight into the genetic architecture of bTB and offer a prediction of potential effects of genetic selection for increased resistance to bTB in dairy cattle. The genomic regions and candidate genes identified to be associated with susceptibility to bTB will assist to further elucidate pathways critical to cattle susceptibility to bTB. / Consistent with previous studies of other populations and trait definitions, results from genomic association analyses suggest that susceptibility of cattle to bTB is heritable and likely a polygenic trait, amenable to improvement by genetic and/or genomic selection. Embarking on routine selection for resistance to bTB will reduce future bTB prevalence and severity of breakdowns across selection generations, as manifested by results of this thesis. The results also highlight the importance of considering selection as a complementary strategy to existing interventions. This has the potential to accelerate control and ultimate eradication of bTB. This strategy could assist the UK to achieve the national goal of being officially bTB free by 2038. Furthermore, as indicated by results of this thesis, selection against bTB in the national breeding programme will not adversely affect other economically important traits. Assimilation of bTB into the overall index will better manage possible antagonistic correlations between bTB susceptibility and some of the other traits.

The overall objective of this thesis is to provide an enhanced understanding of the epidemiology of Mycobacterium bovis in the Greater Riding Mountain Ecosystem (GRME) and provide a scientific basis for disease management from a systems perspective now and into the future. M. bovis prevalence has been consistently higher in elk compared to white-tailed deer, and higher within a defined Core area compared to areas outside. Prevalence in both species declined significantly between 2003 and 2013. Only one infected elk was detected in 2013; the last infected white-tailed deer was detected in 2009 and the last infected cattle herd was detected in 2008. Parallel interpretation of three blood-based assays resulted in effective selective culling of elk within Riding Mountain National Park (RMNP) with predictive value negative of 100%. A lymphocyte stimulation test (LST) was the most sensitive single blood-based assay, but was difficult to perform under field conditions. Combinations of humoral antibody tests and cell-mediated tests performed better than any single test, likely detecting the broad spectrum of host pathology present. Seven of 14 risk factors were identified for wild cervids testing culture positive with the three being most strongly associated with culture positivity being geographical location (within core area), elk density and year category (sampling phase). Age, sex, and surveillance method were also significant factors, but species was not. A rapid decline in elk density in combination with fencing of hay storage yard and non-selective culling were likely key factors resulting in the M. bovis prevalence decline observed in elk, and an overall decline in prevalence from 1997 for both species. Elk were the primary reservoir species in this episystem, but are now considered a spillover host, while white-tailed deer have always been a spillover host due to lower densities and shorter life expectancy. Very limited strain diversity exists within the GRME with one spoligotype restricted to cattle and associated with a limited outbreak in five herds in the early 1990’s, and three other shared strains between cattle and wildlife. A single monomorphic type was present in white-tailed deer. Significant spatial overlap of wildlife and cattle isolates delineated a core area where management activities are now focused. The relative simplicity of this episystem has allowed significant progress on control and management to be achieved, despite being located within a national park. Wildlife surveillance will need to continue until at least 2022 in order to achieve a 95% probability of freedom using three different surveillance streams. Latent cases are likely to be extremely rare in future and unlikely to result in ongoing transmission as the factors that created this wildlife reservoir no longer exist. Wild cervids should not be considered ideal maintenance hosts for M. bovis in North America but rather facultative hosts; acting either as a reservoir or spillover host dependent on regional/local density and presence/absence of baiting and feeding.

Bovine Tuberculosis is a chronic debilitating disease of cattle and other animals with a worldwide distribution and transmitted mainly through the inhalation of aerosols. The aim of this study was to determine the prevalence of BTB in the cattle population of selected dip tanks in Swaziland. Furthermore, the zoonotic risk to farmers whose cattle are infected with BTB was assessed by means of a questionnaire survey. Abattoir surveillance identified 16 dip tanks of study where at least 10 % of the cattle were tested for BTB using the comparative intra-dermal skin. In five of these dip tanks, the same cattle were tested for BTB using the IFN-γ Test. Eight BTB skin test positive animals were slaughtered and a detailed post mortem examination was conducted and samples collected for the isolation of M. bovis. Concurrent with BTB testing, a questionnaire survey was conducted to determine risk factors for humans. The prevalence of BTB was found to be 6.75 % in the study population and 20 % of BTB positive animals were diagnosed by both the CIST and IFN-γ, indicating a correlation for the test positive animals in the two tests. M. bovis was isolated from seven of the eight animals slaughtered. Farmers’ knowledge of BTB as a cattle disease and serious zoonosis is insufficient and inadequate while consumption practices of products of bovine origin exposes them to the risk of infection by M. bovis. There is a need to investigate the extent of M. bovis infections in the human population. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Veterinary Tropical Diseases / unrestricted

This study was conducted to confirm the presence of bovine tuberculosis (BTB) and determine its prevalence, based on skin test reactivity, in cattle reared under extensive farming conditions in the Govuro district, Inhambane province, Mozambique. The study was comprised of a primary screening test using the single intradermal test (SIT) in randomly selected animals from Colonato and Sede dip tanks in Govuro. Positive reactors to the SIT were tested again with bovine and avian tuberculin using the single intradermal comparative test (SICTT) 7 weeks after the SIT. The sample size was calculated using Win Episcope 2.0 based on 95% confidence to detect a 2% expected prevalence using the SIT, with a 1% accepted error and accounting for a total population size of 7208. The calculated sample size was 682 animals. To compensate for the probability of 20% default in reading, the sample size was increased to 853. During the testing process (SIT), it was evident from the first 3 reading days that the apparent prevalence (61, 94%) was higher than expected (2%), hence we decided to stop when the total number of cattle was 530. During the testing process (SIT), it was evident from the first 3 reading days that the apparent prevalence (61.94%) was far higher than expected (2%), hence we decided to stop when the total number of cattle was 530. This was due to the fact that, at such a high prevalence, it would not be necessary to achieve as high a precision as 1% accepted error. A sample size of 530 would be sufficient to achieve a precision of 4% accepted error, which was regarded as more than adequate. The 530 cattle, 3 or more years of age, were selected using systematic random sampling from the two dip tanks (Colonato 371 and Sede 159 animals). All animals were identified by numbers painted, dorsally on the sacral region. Out of 530 tested cattle by SIT, 268 were read, and 166/268 (61.94% with 95% confidence interval [CI]: 55.8 – 67.8%) were found positive, with visible swallow at the injection site. Apparent prevalence (AP) was found to be 61.94% while the true prevalence (TP) was 75.92%. The predictive value of a positive result (PV+) was found to be 87.9%. No significant difference in apparent prevalence between the two areas was detected by Fisher’s exact test (P = 0.11). By SICTT, out of 28 animals positive reactors to SIT, 21 were possible to read, and 13/21 (61.9%; 95% CI: 55.1 – 89.3%) were found positive. A three year old bull, positive reactor to the SIT, was slaughtered, and a detailed post mortem was carried out and organs with visible lesions were collected for further laboratory testing (histopathology, culture and isolation of M. Bovis and PCR). Later on, 30 more positive reactors to the SIT test were slaughtered: 25/30 (83.3%) showed visible lesions compatible with BTB, and total condemnation of carcass was made in 3/25 (12%) due to generalized lesions. The high prevalence rate of skin test positive animals as well as gross lesions and histopathology were confirmed to be BTB by the isolation and identification of M. Bovis by culture and PCR. Our results suggest that bovine tuberculosis is highly prevalent in Govuro district and may thus represent a potential health problem of zoonotic tuberculosis in humans. Our results suggest that BTB has reached the plateau phase of endemicity in cattle in Govuro district. In this context, the positive predictive value of the SIT is very high and thus the use of the SICTT as a confirmatory test has a limited value and should not be advocated. Our results further indicate that no other prevalence study of BTB should be conducted in the next few years in Govuro district, unless comprehensive control measures are implemented. The focus of further studies should be on the isolation and the molecular characterization of M. Bovis from cattle and humans in order to assess transmission routes and the role played by BTB in human TB cases in Govuro district. Copyright / Dissertation (MSc (Veterinary Tropical Diseases))--University of Pretoria, 2009. / Veterinary Tropical Diseases / unrestricted