| Summary: | <p>There remains much that we do not understand about the interaction between Mycobacterium tuberculosis (M.tb) and the host immune response. Development of an effective vaccine is hampered by an incomplete understanding of the immunoprotective mechanisms, no biomarker of infection and no validated correlate of protection. Initial immune events driven by the innate system play an important role in the development of adaptive immunity and protection. This thesis describes the development of an aerosol BCG human infection challenge and demonstrates that this model is safe and well tolerated in BCG and M.tb naïve UK adults. This novel challenge model is then used to describe the initial innate and adaptive immune events at the site of infection, the airway parenchymal interface. The response is characterised by a local innate and adaptive lymphocytosis by day 7, and rapid upregulation of MHC-II antigen presentation differential gene expression pathways and Th1 effector function. There is a corresponding peak in antigen-specific IFN-y production at day 7 in the peripheral circulation, and improved mycobacterial growth control by peripheral blood mononuclear cells at day 14 on an ex-vivo functional assay. By describing underlying early immune responses to a mycobacterial airway infection in humans, this thesis provides an invaluable contribution to the field. This body of work has created a rich resource of early immune variables from which new hypotheses can be drawn for further investigation. Novel immune mechanisms, if correlated with growth control, could be used for rational tuberculosis vaccine design, to help tackle this pervasive disease. </p>
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