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No description available.

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Bovine tuberculosis (TB), caused by Mycobacterium bovis, is increasing in incidence in the United Kingdom and detailed knowledge of host-pathogen interactions in the natural host is essential to facilitate disease control. Vaccination of neonatal calves with Bacille Calmette Guerin (BCG) induces a significant level of protection from infection with M. bovis. Since neonatal vaccination of humans with BCG induces activation of natural killer (NK) cells, and neonatal calves have high circulating numbers of these cells, it is proposed that NK cells are important in the response to BCG. Furthermore, NK cells play an important role in shaping adaptive immune responses through interactions with dendritic cells (DCs). The overall hypothesis of this project was that the enhanced efficacy of BCG in neonates is due to the increased number of NK cells, which through interactions with DCs can polarise Th1-type CD4+ and CD8+ T cell responses, both of which are involved in protection against M. bovis infection. Initially, the frequency and phenotype of NK cells across the blood, afferent lymph and the lymph nodes in steady-state conditions were compared. CD2- NK cells were the principal subset of NK cells migrating from the skin to the draining lymph node and were highly activated in afferent lymph and lymph nodes, compared with peripheral blood. It was also demonstrated that CD2- NK cells were the main subset of NK cells egressing from the lymph node via the efferent lymphatic vessel to return to circulation. Since many vaccines including BCG are delivered subcutaneously, NK cell responses in the blood and the skin draining afferent lymphatic vessel, lymph nodes and efferent lymphatic vessel were determined after BCG vaccination. Alterations in the frequency and receptor repertoire were evident following vaccination, supporting a role for NK cells during BCG vaccination of neonatal calves. To investigate the interactions of NK cells and BCG-infected DCs, in vitro co-cultures were established. CD2- NK cells were preferentially activated following culture with BCG-infected DCs and secreted high levels of IFN-γ. Overall, this thesis provides novel evidence that NK cells may re-circulate in steady-state conditions, play a role in BCG vaccination of neonatal calves, and that through interactions with BCG-infected DCs, may be involved in driving protective Th1-type adaptive immune responses.

Cutaneous leishmaniasis (CL) is usually a self-limiting lesion on the skin while visceral leishmaniasis is a progressive, systemic disease with high mortality even if treated. The problem associated with treatment and vector control justifies a search for an effective vaccine which seems to be the only practical means to control the disease. The aim of this study is to identify immunological surrogate marker(s) associated with protection against Leishmania infection. The results indicate that a single dose of ALM+BCG induced Thl-like response but the level of such response is not sufficient for full protection. Accordingly, further evaluation of the vaccine is necessary other strategies multiple injections or changing the adjutant.

La méthylation de l'ADN est une marque épigénétique importante chez les mammifères. Malgré le fait que la méthylation de la cytosine en 5' (5mC) soit reconnue comme une modification épigénétique stable, il devient de plus en plus reconnu qu'elle soit un processus plus dynamique impliquant des voies de méthylation et de déméthylation actives. La dynamique de la méthylation de l'ADN est désormais bien caractérisée dans le développement et dans le fonctionnement cellulaire des mammifères. Très peu est cependant connu concernant les implications régulatrices dans les réponses immunitaires. Pour se faire, nous avons effectué des analyses du niveau de transcription des gènes ainsi que du profilage épigénétique de cellules dendritiques (DCs) humaines. Ceux-ci ont été faits avant et après infection par le pathogène Mycobacterium tuberculosis (MTB). Nos résultats fournissent le premier portrait génomique du remodelage épigénétique survenant dans les DCs en réponse à une infection bactérienne. Nous avons constaté que les changements dans la méthylation de l'ADN sont omniprésents, identifiant 3,926 régions différentiellement méthylées lors des infections par MTB (MTB-RDMs). Les MTB-RDMs montrent un chevauchement frappant avec les régions génomiques marquées par les histones associées avec des régions amplificatrices. De plus, nos analyses ont révélées que les MTB-RDMs sont activement liées par des facteurs de transcription associés à l'immunité avant même d'être infecté par MTB, suggérant ces domaines comme étant des éléments d'activation dans un état de dormance. Nos données suggèrent que les changements actifs dans la méthylation jouent un rôle essentiel pour contrôler la réponse cellulaire des DCs à l'infection bactérienne. / DNA methylation is an important epigenetic mark in mammals. Although methylation at the 5’ position of cytosine (5mC) is recognized as a stable epigenetic modification, it is becoming increasingly viewed as a more dynamic process that involves both active methylation and demethylation pathways. While the dynamics of DNA methylation has been well characterized in mammalian development and normal cellular function, little is known about its regulatory implications in immune responses. To that end, we performed comprehensive transcriptional and epigenetic profiling of primary dendritic cell (DC) samples from humans, before and after infection with Mycobacterium tuberculosis (MTB). Our results provide the first complete genomic portrait of the extensive epigenetic remodeling occurring in primary DCs in response to a bacterial infection. We found that active changes in DNA methylation are pervasive, identifying 3,926 MTB-induced differentially methylated regions (MTB-DMRs). MTB-DMRs show a striking overlap with genomic regions marked by histones associated with enhancer activity. ATAC-seq footprinting analysis revealed that regions that change methylation were actively bound by immune-related TFs prior to MTB-infection suggesting that these domains are likely to represent enhancer elements in a poised state. Our data suggests that active changes in DNA methylation play an essential and previously unappreciated role at controlling of the regulatory programs engaged by DCs in response to a bacterial infection.