Lungs sit at a critical interface between the environment and the mucosal immune system where abundant particulates and microbes are inhaled. If these agents transit to the lower airways, specialized alveolar innate immune responses play a key role in their clearance while maintaining integrity of the thin alveolar membrane. The initial interaction of innate immune cells with microbes is critical to the ultimate outcome of infection, particularly for Mycobacterium tuberculosis (M.tb) which survives within alveolar macrophages (AMs). Pattern Recognition Receptors on AMs efficiently detect microbes; however, the immune responses following detection are highly regulated to enable dampening of potentially damaging inflammation. This ability of AMs to generate a balanced inflammatory response (both pro- and anti-) is characteristic of alternatively activated macrophages (aaMs) of which AMs are a prototype. While AMs effectively eradicate routinely encountered microbes, they often fail to do so for host-adapted intracellular pathogens due to reduced or slowed microbial killing mechanisms. Thus we believe that aaMs play an important role in the pathogenesis of M.tb and other air-borne infectious agents, yet their development, maintenance and biology within the alveoli remain poorly understood, especially for human macrophages and the effect of the local environment, e.g. surfactant components. Our failure to completely understand the molecular events underlying lung macrophage development and biology creates a critical barrier in our attempts to develop new treatment and vaccine strategies that target the lung. Based on our recently published work and new preliminary data that both M.tb and alveolar surfactant components up-regulate a major negative regulator of pro-inflammation, i.e. PPAR?, and that this transcription factor in turn regulates several innate immune determinants, we hypothesize that 1) the lung microenvironment, specifically surfactant components, directs the differentiation of AMs toward the aaM state by increasing PPAR? activity and its downstream effectors; and 2) M.tb acts in concert with surfactant components to increase PPAR? activity which results in a dampened early protective immune response to M.tb in the lung.
Our aims are to: 1) determine the biochemical pathways that increase PPAR? expression and its immune-related functions in human macrophages in response to surfactant and virulent M.tb; 2) characterize the role of novel PPAR? effectors in the regulation of human macrophage responses to M.tb infection; and 3) determine whether perturbations in PPAR? in macrophages alter the growth of virulent M.tb and coincident inflammatory and microbicidal responses. We will use human AMs and monocyte-derived macrophages (MDMs), biochemical and genetic techniques, and a new mouse model to accomplish our goals. The broad, long-term objectives of this continuing program are to identify the key signaling pathways and intracellular master regulators that dictate macrophage immunobiology in response to surfactant during health and to M.tb during air-borne infection; and to ultimately target these determinants to boost lung immunity.
As the lungs are constantly bombarded by inhaled particles and microbes, they have developed a highly regulated, dampened immune system driven by macrophages in this environment that is effective in clearing routinely encountered infectious agents but not adapted intracellular bacteria like the one that causes the worldwide scourge tuberculosis. We seek to identify the molecular events underlying this process in an effort to develop new strategies to boost lung immunity as an adjunct to therapies and vaccines. This is essential as current therapies and vaccines for air-borne infectious agents have limited activity in the lung.
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