L’infection par le virus de l’hépatite C est fréquente chez les patients infectés par le VIH. Chez les patients co-infectés VIH-VHC, les lésions hépatiques sont plus sévères et évoluent plus rapidement vers la cirrhose et ses complications. Cette thèse est consacrée à la description des patients co-infectés pris en charge, en France (2006-2008), à l’évaluation de la prévalence et des facteurs de stéatose hépatique chez ces patients, et à la question de l’évaluation non invasive de la fibrose hépatique. La prise en charge des patients co-infectés VIH-VHC devrait inclure un dépistage systématique de la stéatose hépatique. L’évaluation de la fibrose hépatique par l’utilisation de deux scores non invasifs (Fibroscan-Apri, Fibroscan-Fibrotest, par exemple) pourrait être envisagée. En cas de discordance entre les résultats de ces scores, une biopsie hépatique doit être réalisée. / Chronic hepatitis C virus (HCV) infection is common in patients with human immunodeficiency virus (HIV). HIV-HCV Co-infection is associated with more severe and more rapid progression of HCV, leading to increased incidence of fibrosis, cirrhosis, and end-stage liver disease. Our work is devoted to the description of HIV-HCV co-infected patients (2006-2008). We also evaluated the prevalence and factors associated with liver steatosis in these patients. Lastly, we addressed the issue of the non-invasive assessment of liver fibrosis. The management of HIV-HCV co-infected patients should comprise a systematic screening of liver steatosis. The assessment of liver fibrosis using two non-invasive tests (eg Fibroscan-Apri, Fibroscan-Fibrotest) should be considered. In case of discordance between the results of these tests, a liver biopsy must be performed.

The protozoan parasites Trypanosoma brucei brucei, Trypanosoma congolense and Trypanosoma vivax cause Animal African Trypanosomiasis, a disease responsible for costly livestock pathology and economic losses in Africa. Each of these African trypanosomes are vector-borne and transmitted by the blood-feeding tsetse fly. Additional blood-feeding vectors can spread T. vivax, extending its range into South America. T. b. brucei infection of the mammalian host progresses in waves, with periodic clearance of antigenic variants. Accumulation of slender parasites in the blood is accompanied by accumulation of the density-sensing factor, SIF (stumpy induction factor). SIF drives differentiation from the proliferative slender form to the growth arrested stumpy form at the peak of parasitaemia. This differentiation step aids host survival, and the stumpy form is pre-adapted for continuation of development in the tsetse fly, ensuring transmissibility. Despite facing challenges comparable to T. b. brucei during their life cycle, T. congolense and T. vivax are not found to have morphologically distinguishable slender and stumpy forms. The growth control mechanisms used by these important veterinary pathogens have been investigated in this thesis. Particular focus has been placed on the conservation of quorum sensing pathways within the African Trypanosomes. The potential for cross-species communication has implications for co-infections. T. congolense was found to undergo growth arrest at peak parasitaemia, and transcriptomic changes occurring between ascending and peak parasitaemia were identified and comparisons made to T. b. brucei slender and stumpy transcriptomes. In an examination of the conservation of the SIF-responsive pathway, expression of a T. congolense orthologue was found to rescue stumpy formation in an otherwise SIF-resistant null mutant for the corresponding T. b. brucei gene. The capacity for cross-talk between density-sensing signals in different trypanosome species was tested using conditioned medium from T. congolense bloodstream form cultures. This could activate the expression of a stumpy specific reporter protein in T. b. brucei. A cell line deficient in a SIF-responsive gene showed resistance to the conditioned medium with a delay in reporter expression. These results highlight the unanticipated capacity for different trypanosome species to exhibit intra and inter specific cell-cell communication in the mammalian bloodstream, with possible consequences for their virulence, transmission and evolution.

Clinical and epidemiological studies have provided a large body of evidence supporting a link between HIV and other sexually transmitted co-infections. Co-infections have been associated with promoting HIV transmission and acquisition. One of the closest studied interactions is the co-infection with N. gonorrhoeae, the etiological agent of gonorrhea, yet a clear understanding of this relationship is still elusive. Studies aimed at deciphering how N. gonorrhoeae mediates these effects have provided mixed results with some suggesting co-infection promotes HIV replication, and others suggesting the opposite. The aim of this thesis is to uncover molecular mechanisms that explain these results through in vitro co-infection studies using a combination of mixed peripheral mononuclear blood cells (PBMCs) and isolated human cell types. The results presented here demonstrate that gonococcal co-infection profoundly inhibits HIV replication in co-infected PBMCs. This inhibition is due to both the release of anti-HIV IFN via TLR9-mediated activation of plasmacytoid dendritic cells (pDCs), and the activation of  T cells. In addition, I show that responses between CD4+ T cell lines, such as the Jurkat cell line, and primary CD4+ T cells can differ, which may explain some of the contrasting results seen in published literature. The results in this thesis have implications for understanding the relationship between gonococci and HIV, providing new insight into molecular and immunological interactions that influence viral transmission, and reveal new opportunities to combat HIV.

Clinical and epidemiological studies have provided a large body of evidence supporting a link between HIV and other sexually transmitted co-infections. Co-infections have been associated with promoting HIV transmission and acquisition. One of the closest studied interactions is the co-infection with N. gonorrhoeae, the etiological agent of gonorrhea, yet a clear understanding of this relationship is still elusive. Studies aimed at deciphering how N. gonorrhoeae mediates these effects have provided mixed results with some suggesting co-infection promotes HIV replication, and others suggesting the opposite. The aim of this thesis is to uncover molecular mechanisms that explain these results through in vitro co-infection studies using a combination of mixed peripheral mononuclear blood cells (PBMCs) and isolated human cell types. The results presented here demonstrate that gonococcal co-infection profoundly inhibits HIV replication in co-infected PBMCs. This inhibition is due to both the release of anti-HIV IFN via TLR9-mediated activation of plasmacytoid dendritic cells (pDCs), and the activation of  T cells. In addition, I show that responses between CD4+ T cell lines, such as the Jurkat cell line, and primary CD4+ T cells can differ, which may explain some of the contrasting results seen in published literature. The results in this thesis have implications for understanding the relationship between gonococci and HIV, providing new insight into molecular and immunological interactions that influence viral transmission, and reveal new opportunities to combat HIV.

The two main causes of child mortality and morbidity in Africa are malaria and invasive bacterial diseases. In addition, co-infections in sub-Saharan Africa are the rule rather than the exception. However, not much is known about the host-pathogen interaction during a concomitant infection or how it affects the outcome of disease. In order to study the immunological responses during malaria and bacterial co-infections, we established a co-infection mouse model. In these studies we used two pathogenic bacteria found in malaria co-infected patients: Streptococcus pneumoniae and Relapsing fever Borrelia duttonii. Hosts co-infected with malaria and Borrelia showed greatly increased spirochetal growth but low parasite densities. In addition, the co-infected hosts presented symptoms of experimental-cerebral malaria, in an otherwise unsusceptible mouse model. This was found to be a consequence of a dysregulated immune response due to loss of timing and control over regulatory mechanisms in antigen presenting cells thus locking the host in an inflammatory response. This results in inflammation, severe anemia, internal organ damage and pathology of experimental cerebral malaria. On the other hand, in the malaria - S. pneumoniae co-infection model we found that co-infected hosts cleared the bacterium much more efficiently than the single infected counterpart. This efficiency of clearance showed to be neutrophil dependent. Furthermore, in vitro studies revealed that neutrophils isolated from malaria-infected hosts present an altered migratory effect together with a significantly increased capacity to kill S. pneumoniae. This suggests that a malaria infection primes neutrophils to kill S. pneumoniae more efficiently. Furthermore, a study was carried out on plasma samples from Rwandan children under the age of five, on which a full metabolomics profile was performed. We showed that these children could be divided in different disease categories based on their metabolomics profile and independent of clinical information. Additionally, the mild malaria group could further be divided in two sub-groups, in which one had a metabolomic profile resembling that of severe malaria infected patients. Based on this, metabolite profiling could be used as a diagnostic tool to determine the distinct phase, or severity of a malaria infection, identify risk patients and provide helpful and correct therapy.

Les macrophages sont une cible cellulaire du VIH-1, et jouent un rôle important dans la pathogenèse virale. Au cours de ma thèse, je me suis intéressée au rôle des macrophages dans la pathogenèse du VIH-1, mais aussi au cours de la co-infection avec Mycobacterium tuberculosis (Mtb), l'agent étiologique de la tuberculose. J'ai tout d'abord participé à une étude mettant en évidence que l'infection par le VIH-1 reprogramme la migration des macrophages, favorisant notamment le mode migratoire protéolytique. Cet effet est médié par l'interaction de la protéine virale Nef avec les protéines de l'hôte Hck et WASP, ce qui conduit à une modification de l'organisation et de la fonction des podosomes, structures impliquées dans la dégradation de la matrice extracellulaire et la migration dépendante des protéases. La meilleure capacité à migrer des macrophages infectés par le VIH-1 in vitro se traduit in vivo par une augmentation du recrutement des macrophages dans différents tissus de souris transgéniques qui expriment la protéine Nef. Ces travaux ont ainsi révélé un nouveau mécanisme par lequel le VIH-1 dissémine dans les tissus, via l'action de Nef dans les macrophages. L'association fréquente du VIH-1 avec Mtb complique le problème de santé publique posé par l'infection virale. En effet, Mtb aggrave la pathogenèse du VIH-1 chez les patients co-infectés. L'étude des mécanismes impliqués et le rôle des macrophages dans ce phénomène constituent les objectifs principaux de ma thèse. J'ai révélé que les macrophages infectés par Mtb génèrent un microenvironnement qui active les macrophages voisins vers un programme de polarisation anti-inflammatoire dit M(IL-10). J'ai mis en évidence que ces macrophages M(IL-10) sont particulièrement efficaces pour la production de VIH-1. J'ai démontré que le microenvironnement associé à la tuberculose entraîne la formation de nanotubes entre les macrophages, grâce à l'activation de la signalisation cellulaire médiée par l'axe IL-10/STAT3. Ces nanotubes, qui favorisent le transfert du virus d'un macrophage à un autre, sont à l'origine de la spectaculaire production de VIH-1 par les macrophages. Nous avons également constaté que ces cellules M(IL-10) s'accumulent dans la circulation sanguine des patients co-infectés ainsi que dans les poumons de primates non-humains co-infectés. Dans l'ensemble, mes travaux identifient les nanotubes comme des acteurs clés dans l'aggravation de la pathogenèse du VIH-1 lors de la co-infection avec Mtb. Ainsi, les nanotubes et la voie de signalisation IL-10/STAT3 pourraient représenter des cibles pour développer de nouvelles thérapies de lutte contre la comorbidité VIH/Mtb. Les résultats obtenus lors de ma thèse contribuent à une meilleure compréhension du rôle des macrophages dans la pathogenèse et la dissémination du VIH-1 dans un contexte de mono-infection, ou lors d'une co-infection avec Mtb. / Macrophages are both crucial host effector cells for HIV-1 and important leukocytes involved in viral pathogenesis. For my doctoral thesis, I was interested in further characterizing the role of macrophages in HIV-1 pathogenesis, and during co-infection with Mycobacterium tuberculosis (Mtb), the etiological agent for tuberculosis (TB). I first participated in a study that provided evidence that HIV-1 infection reprograms the migration of macrophages, particularly by triggering the protease-dependent migration mode. This effect was mediated by the interaction of the viral protein Nef with the host proteins Hck and WASP, which leads to modification in the organization and proteolytic activity of podosomes, important structures for protease-dependent migration. The higher migration capacity of HIV-1-infected macrophages translated in vivo by an increase in the recruitment of macrophages in several tissues of Nef-transgenic mice. This work revealed a novel mechanistic understanding of how HIV-1 infection drives macrophages into tissues, contributing to viral dissemination and possibly creating a hidden cellular reservoir of virus. Worsening this public health issue posed by the HIV-1 epidemic is the frequent association of the virus with Mtb. Indeed, Mtb aggravates HIV-1 pathogenesis in co-infected individuals. Yet, the mechanisms involved in this process are still poorly understood, including the contribution of macrophages. To investigate how Mtb exacerbates the HIV-1 infection in human macrophages was the main focus of my thesis. First, I revealed that Mtb-infected macrophages generate a microenvironment that drives bystander macrophages towards phenotypic and functional features of the so-called M(IL-10) anti-inflammatory program. I found that these M(IL-10) macrophages are highly efficient for HIV-1 production. I demonstrated that the TB-associated microenvironment induces the formation of macrophage-to-macrophage connecting tunneling nanotubes (TNTs) through the IL- 10/STAT3 axis, a phenomenon that is responsible for the dramatic increase of HIV-1 production in M(IL-10) macrophages. Moreover, I provided evidence that M(IL-10) cells are expanded in the peripheral blood of co-infected patients and accumulate in the lungs of co-infected non-human primates. Altogether, this central part of my PhD thesis sheds light to TNTs as key players in the aggravation of HIV-1 pathogenesis in human macrophages during co-infection with Mtb. Thus, this cellular mechanism (together with the IL- 10/STAT3 axis) could represent an unexpected target to develop novel therapeutics against AIDS/TB co-morbidity. Collectively, the results obtained during my thesis contribute to a better understanding of the role of macrophages during HIV-1 pathogenesis and their ability to disseminate the virus in a mono-infection context, or during co-infection with Mtb.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-02-04T15:52:03Z No. of bitstreams: 1 Lais da Silva Pereira Co-infecção...2015.pdf: 2458556 bytes, checksum: 23a6b27a228ed08f29d7e68206a6a31d (MD5) / Approved for entry into archive by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-02-04T15:52:14Z (GMT) No. of bitstreams: 1 Lais da Silva Pereira Co-infecção...2015.pdf: 2458556 bytes, checksum: 23a6b27a228ed08f29d7e68206a6a31d (MD5) / Made available in DSpace on 2016-02-04T15:52:14Z (GMT). No. of bitstreams: 1 Lais da Silva Pereira Co-infecção...2015.pdf: 2458556 bytes, checksum: 23a6b27a228ed08f29d7e68206a6a31d (MD5) Previous issue date: 2015 / Fundação Oswaldo Cruz, Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia, Faculdade de Medicina. Salvador, BA, Brasil / Os resultados das co-infecções nas leishmanioses cutânea (LC) são variáveis. Neste estudo, demonstramos o desfecho da co-infecção com Trypanosoma brucei brucei sobre a LC, causada por L. major. Infectamos camundongos C57BL/6 com T. b. brucei e estes foram tratados com o Berenil para controlar a infecção antes da transmissão da L. major por picadas de Lutzomyia longipalpis infectados. Nossos resultados revelam que, a infecção ativa com o T. b. brucei controla a patologia da LC causada por L. major. Comparados aos controles, camundongos coinfectados mostraram uma diminuição significativa do tamanho da lesão até 6 semanas após infecção. Adicionalmente, uma diminuição significativa da carga parasitária foi observada 3 semanas após a infecção. É importante salientar que a proteção observada não foi devido a reação cruzada entre os antígenos do T. b. brucei e L. major, mas por uma ativação não específica das células T efetoras, tanto sistemicamente como localmente no sítio da infecção, induzindo uma resposta inflamatória intensa, em particular com a produção de IFN-γ e em menor concentração de IL-10. Concluímos que a ativação das células T pelo curso da infecção com T. b. brucei, modulou a infecção com L. major, resultando em proteção. / The outcome of co-infections on cutaneous leishmaniasis (CL) is variable. Here, we determined the outcome of a co-infection with Trypanosoma brucei brucei on CL caused by L. major. We infected C57BL/6 mice with T. b. brucei and treated them with Berenil to control parasite growth prior to L. major transmission by infected Lutzomyia longipalpis bites. Our results revealed that an active infection with T. b. brucei controls the pathology of CL by L. major. Compared to controls, co-infected mice show a significant decrease in lesion size up to 6 weeks post-infection. Additionally, a significant decrease in the parasite load was observed at 3 weeks post-infection. Importantly, the observed protection was not due to cross-reactivity between antigens of T. b. brucei and L. major but to a non-specific activation of effector T cells, both at the site of infection and systemically, that induces a strong inflammatory response, in particular IFN-γ and at a lower IL-10 level. We conclude that activation of T cells by an ongoing T. b. brucei infection modulates the outcome of infection with L. major resulting in protection.

L’infection des cellules cibles par le Virus de l’Immunodéficience Humaine de type 1(VIH-1) suit une succession d’étapes finement régulées par de nombreux facteurs cellulaires et viraux. Mon travail de thèse a consisté à étudier certains aspects de cette régulation, en particulier la protéine virale Nef et son impact sur l’infectivité des virus, mais aussi la susceptibilité des cellules cibles à l’infection. Tout d’abord, nous nous sommes intéressés aux mécanismes selon lesquels Nef augmente l’infectivité virale. Pour cela, nous avons identifié les différences entre le protéome des virus sauvages et des virus dépourvus du gène nef (Δnef) grâce à deux méthodes protéomiques, laDIGE et l’iTRAQ. Nous avons pu mettre en évidence que les protéines Ezrine et EHD4 sont impliquées dans des processus qui rendent les virus sauvages plus infectieux que les virusΔnef. L’augmentation de l’infectivité virale par Nef dépend des glycoprotéines d’enveloppes avec lesquelles les particules virales sont pseudotypées. Dans le but d’identifier les bases moléculaires de ce mécanisme, nous avons généré des constructions chimériques entre des glycoprotéines d’enveloppes qui permettent (enveloppes permissives) ou ne permettent pas(enveloppes non permissives) au phénotype Nef de se manifester. Cette approche a permis démontrer que le domaine cytoplasmique de la protéine d’enveloppe est un des déterminants qui dictent l’acquisition du phénotype Nef. Mon travail s’est aussi axé sur le mécanisme de co-infection cellulaire par le VIH-1.Après co-incubation des cellules avec des virus VIH rapporteur GFP et DsRed, nos résultats ont montré que les événements de co-infection sont plus fréquents qu’attendus dans le cas d’une infection stochastique. Nous montrons que ce biais qui semble favoriser la co-infection et qui suggère l’hétérogénéité de la population cible en terme de susceptibilité à l’infection par le VIH-1 provient en fait d’une sous-estimation des fréquences de cellules infectées en raison d’un phénomène de latence post-intégrative. Ainsi, mes études ont permis de mieux comprendre les mécanismes permettant à Nef d’augmenter l’infectivité des particules virales ouvrant de nouvelles perspectives à ce sujet, de même qu’elles ont permis de mettre en évidence que la co-infection était bien un processus aléatoire mais qui permettait de révéler des cellules arborant un provirus silencieux. / Pas de résumé en anglais

Magister Curationis - MCur / As early as 1993, the World Health Organisation declared Tuberculosis (TB) a global emergency and the South African Department of Health confirmed that TB was a national emergency. The primary cause of the rise in TB cases has been attributed to co-infection with HIV. TB is the leading opportunistic infection worldwide and the primary cause of mortality among people living with Human Immunodeficiency Virus (HIV). TB and HIV are two of the highest health threats globally and in South Africa. Tuberculosis and HIV combined are responsible for the deaths of over 4 million people annually. More than 65% of individuals diagnosed with TB in South Africa are co-infected with HIV. The importance of providing quality health services is a human right and non-negotiable. Better quality of health care is fundamental in improving South Africa's poor health outcomes and in restoring patient and staff confidence in the public and private health system. In 1996, the South African Department of Health introduced the topic of quality to raise its awareness and to make it an inherent part of the health care system. The South African health care consumers (patients) are increasingly becoming aware of their rights as patients and the gap between the actual and ideal health practices. They have broad knowledge and great expectations with regard to available care including effectiveness of service and treatment. Patients have desires for quality services when visiting a health care facility, and these desires are directly linked to the success of the healthcare system. If the desires are not met, they can negatively influence the outcome of healthcare processes such as treatment adherence and retention of patients on the system. This could possibly further escalate the TB/HIV co-infection rate in South Africa. The need to address TB and HIV together in the light of quality care is urgent so as to improve the provision of quality health services rendered to people co-infected with TB and HIV. The Institute of Medicine developed a framework that could guide on healthcare dimensions that need to be met for quality of care to be achieved and it is the underpinning theoretical framework for this study. The patients play a critical role in the healthcare system as they are the customers and therefore, the opinions of the patients need to be recognised to ensure that strategies and programmes that are developed are relevant. The purpose of this research was to explore and describe the perceptions of patients co-infected with TB and HIV regarding the quality of care at the Primary Health Care facilities, in the Chris Hani District. A qualitative, explorative and descriptive design was used which enabled the researcher to understand the perceptions of TB and HIV co-infected patients regarding quality of care. The population studied in this research consisted of TB and HIV co-infected patients attending the Primary Health Care facilities at the Lukhanji Sub-district within the Chris Hani District. Purposive sampling was used to select participants with the assistance of nurses working at the selected facilities. The sample size was determined by data saturation, which was reached after 18 semi-structured interviews were conducted. Data analysis was carried out simultaneously with data collection. In consensus discussions, the researcher and the co-coder reached an agreement on the main theme, sub-theme and sub-categories. From the research findings, two main themes were identified namely; satisfaction with delivered services and impediments to quality of care. These were further divided in sub themes and categories. The conclusion that could be made on the quality of care provided to the TB and HIV co-infected patients in this study is that the nurses in the facilities aim to provide four of the six IOM aims of quality of care to the TB and HIV co-infected patients namely: equitable, effective, efficient and patient-centred domains. Therefore, the quality of care provided to these patients is partial as they are not provided with all the six aims that are needed to achieve quality of care. Recommendations are made for the field of community health nursing practice and nursing research on how to improve quality of care provided to TB and HIV co-infected patients at Primary Health Care facilities.

The Infectious Diseases of East African Livestock (IDEAL) project followed 548 East African Shorthorn Zebu (EASZ) calves in Western Kenya for the first year of life and monitored the sequelae of infections by multiple parasites. More than 50 different parasites were identified during this time. The IDEAL project also gathered environmental information about the farm and collected phenotypic data on the calf and its dam. Calves were also genotyped for 55,777 single nucleotide polymorphisms (SNPs). Recent research has looked at coinfection in rodents and humans but not in indigenous cattle. Here I investigate the evidence for coinfection in EASZ and study the associations occurring between coinfecting parasites. In addition, I examine the genetic and phenotypic factors which predispose an individual to infection with multiple parasites. Using information gathered by the IDEAL project, my thesis consists of the following chapters. An investigation of the nature of concurrent associations and of lagged effects between different parasites. Using the parasites Theileria spp., Coccidia spp., Strongyloides spp., strongyles and Calicophoron spp. I show that the patterns of association between different parasites are complex: there is evidence for both positive and negative associations. For example, infection with Strongyloides spp. increased the risk of strongyle infection. Conversely, in other cases, being infected with one parasite decreased the calf’s risk of infection with another parasite: for example, infection with Strongyloides spp. decreased the risk of infection with Calicophoron spp. A study of the relationship between different respiratory viruses and their effect upon the host. I confirm that positive associations exist between Infectious Bovine Rhinotracheitis (IBR), Bovine Viral Diarrhoea Virus (BVDV) and Bovine Parainfluenza Virus Type 3 (PIV3) in a previously unstudied setting; being seropositive for any one of these three viruses means that an individual is more likely to be seropositive for the other two viruses than expected by chance. Being seropositive for IBR, BVDV or PIV3 did not affect the average daily weight gain of the calf, nor did PIV3 and BVDV serostatus have an effect on the calf ever experiencing a clinical episode. However, IBR seropositive calves were less likely to experience a clinical episode of some form, suggestive of some protective aspect of IBR. An examination of the sources of variation in faecal strongyle egg counts (EPG), and their association with body weight, host genetics and a suite of haematological measures. Using estimates of relatedness derived from the SNP data, I established that strongyle EPG has a genetic basis in EASZ, with a heritability of 23.9% (S.E. = 11.8%) and showed a consistently strong negative association between strongyle infection and the haematological parameters white blood cell count, red blood cell count, total serum protein and absolute eosinophil count. Furthermore, calf body weight at 1 week old was a significant predictor of strongyle EPG at 16-51 weeks, with smaller calves being predisposed to a higher strongyle EPG later in life. A genome-wide association study (GWAS) to investigate if there is a genetic predisposition to East Coast Fever (ECF) death and a genetic basis to the packed cell volume at the time of seroconversion to Theileria parva (PCVTP). I found no robust evidence for a relationship between genotyped single nucleotide polymorphisms (SNPs) and ECF death or PCVTP. The effect of sample size upon GWAS and significance thresholds was investigated further through simulations. I conclude that the small number of cases influences the probability of association between a SNP and the phenotypic trait. Smaller case numbers produce more artifactual associations with SNPs, an effect not fully compensated for by the standard Bonferroni correction, suggesting that an empirical significance threshold should be used to directly account for sample size. The results of this thesis provide an understanding of the associations occurring between different parasites, and of their causes and consequences. I discuss the results in the context of their implications for disease control strategies, suggesting the benefits of an integrated approach to control worm and T. parva alongside the possible genetic selection for parasite resistance and supplementary feeding of lightweight individuals to improve the health of EASZ.