Defining mechanisms of mycobacterial protective immunity using human experimental medicine and murine models

Progress in the development of an effective TB vaccine is hindered by an incomplete understanding of protective immunity, and by a lack of knowledge as to which proteins from Mycobacterium tuberculosis (M.tb) are protective. Most of our understanding has come from studies in mice, and studies using blood from patients with TB. The lung is the primary site of infection in TB. Lung and blood responses may differ, and murine and human responses can also differ. I have developed a safe human infection model in which BCG, a replicating mycobacterial strain, is delivered by aerosol directly to the lungs of healthy volunteers. I will use this model to define the innate and adaptive, systemic and mucosal immune responses, in humans. I will then use an in-vitro mycobacterial growth inhibition assay to assess whether these responses are protective. I will use this information to identify which components of host immunity are important in protection in humans. We will also use state-of-the-art mass spectrometry to identify which M.tb proteins are naturally presented to the human immune system, and determine if these proteins confer protection in a murine M.tb challenge study. This information will facilitate the development of effective vaccines.