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|Title:||Investigating the role of memory alveolar macrophages in early innate immune control of pulmonary tuberculosis|
|Abstract:||Mycobacterium tuberculosis (M.tb) is the causative agent of pulmonary tuberculosis (TB). Over 25% of the world’s population is estimated to be infected with tuberculosis, yielding over 10 million new cases and over 1.5 million deaths in 2017 alone. This is all despite the near universal implementation of bacille Calmette-Guérin (BCG) vaccination across TB endemic areas. BCG is capable of preventing childhood disseminated forms of disease but fails to induce potent immunity within the lung. We expect this to in part play a role in the lack of protection against pulmonary TB. Our lab has developed a human adenovirus serotype 5 vaccine expressing the M.tb antigen Ag85A (AdHu5Ag85A). When delivered directly to the respiratory mucosa (RM), AdHu5Ag85A has proven to be safe and immunogenic, generating both CD4 and CD8 T cell responses within the lung. We have found that RM AdHu5Ag85A vaccination also generates a long-lasting population of memory macrophages in the airway and lung, that are primed to better control early M.tb infection. Importantly, this was a vaccination route-dependent mechanism. Memory macrophages express a trained innate immune phenotype as they express high levels of MHC II, are highly glycolytic, and produce more IL-12 upon re-stimulation. Importantly, utilization of an in vivo T cell depletion approach allowed us to show that these memory macrophages are capable of limiting early M.tb infection independent of T cells. Our findings indicate that RM vaccination may be advantageous to parenteral routes by not only drawing antigen specific T cells into immunologically restricted lung mucosa but also generating a memory macrophage population within the lung. Induction of memory macrophages within the airway helps overcome early innate immune suppression by M.tb.|
|Appears in Collections:||Open Access Dissertations and Theses|
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|D'Agostino_Michael_R_2019August_MSc.pdf||6.74 MB||Adobe PDF||View/Open|
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