Biology of the human lung mucosa in aging and tuberculosis

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Age-associated immune defects are considered a primary risk factor for TB, but other factors such as the heightened systemic inflammatory state (inflammaging) observed in elderly individuals have not been previously considered. During infection, airborne Mycobacterium tuberculosis (M.tb) is deposited in the lung where it is exposed to different local environments over time. First, M.tb encounters the alveolar space, where it will be in direct contact with Alveolar Lining Fluid (ALF) components, notably surfactant and complement, for an undetermined period. We hypothesize that ALF, containing important innate immune determinants against M.tb infection, is functionally deficient in old age, largely as a result of oxidative stress, which negatively impacts the control of M.tb infection in the lung. ALF is generated, secreted and recycled by alveolar epithelial cells, and is essential for maintaining lung function. Some human ALF components [surfactant proteins A (SP- A) and D (SP-D), homeostatic hydrolytic enzymes (hydrolases), and lipids] are critical elements of the innate immune system during M.tb infection, playing an important role in M.tb-phagocyte encounters. Oxidative stress associated with low grade chronic inflammation that occurs during aging is expected to result in changes in ALF component production and activity. For example, alterations in surfactant lipids are predicted to negatively affect SP-A and SP-D function. We know little about how oxidative stress and low grade inflammation associated with aging impact M.tb infection progression in the lung. This knowledge gap limits our ability to design new approaches for the development of diagnostics, therapeutics and vaccines that are effective in the lung. Here we propose to determine the function of ALF components in the elderly human lung, and their impact on the establishment and progression of M.tb infection using in vitro and in vivo approaches. Our proposal is significant and innovative in the field of aging, determining how ALF soluble components in the elderly lung influence M.tb infection and outcome. Our studies are closely linked to Projects 2 & 3 (innate & adaptive responses to M.tb infection in aging, respectively) and synergize with Project 4 (circulating molecular signatures of aging).