When Mycobacterium tuberculosis (M.tb) infection occurs by airiaorne transmission, bacilli are deposited in the alveolar spaces of the lungs. Within the alveolar space and proximal to it exist a number of innate immune mechanisms that are critical in maintaining pulmonary homeostasis. M.tb, a highly host-adapted intracellular pathogen of macrophages, may use these mechanisms to its advantage during infection. Little is known about how M.tb is affected by the immune pressure that it encounters in the alveolar microenvironment outside of the macrophage. In addition to alveolar macrophages, major constituents of lung defense in the alveolar space are type I and II epithelial cells, monocytes, and neutrophils, and their secreted products to the alveolar lumen (I.e., surfactant). Each of these alveolar compartment cells contains its own unique array of hydrolases that are released to the alveolar environment and sequestered in surfactant. When M.tb is initially deposited in the terminal bronchioles and alveoli, as well as following release from lysed macrophages, the bacilli are in close contact with these hydrolases. During the K99/R00 NIH Pathway to Independence Award, Dr. Torrelles will examine the effects of the human alveolar environment on the cell envelope of M.tb and how these effects dictate the fate of M.tb within the host. Using labeled virulent M.tb H37Rv and/or M.tb Erdman, and biochemical, molecular and cell biology approaches, we propose: 1) To characterize specific hydrolases derived from alveolar compartment cells and pulmonary surfactant that affect the cell envelope of virulent M.tb. To ensure that the studies remain focused, we will prioritize candidate hydrolases and restrict our experiments to the study of the 3-5 hydrolases in total;2) To characterize the effects of our selected human lung hydrolases on the integrity of the virulent M.tb cell envelope;and 3) To determine how hydrolase-derived modifications on the cell envelope of virulent M.tb affect the bacillus sun/ival within alveolar compartment cells.
Since components of the M.tb cell envelope dictate the host innate immune response against the bacterium via their interaction with surface receptors on myeloid cells, the identification of alveolar enzymatic activities (hydrolases) that shape the surface of the M.tb cell envelope will enable more predictive in vitro models to be developed and novel drug targets to be identified.
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|Arcos, J; Sasindran, S J; Moliva, J I et al. (2017) Mycobacterium tuberculosis cell wall released fragments by the action of the human lung mucosa modulate macrophages to control infection in an IL-10-dependent manner. Mucosal Immunol 10:1248-1258|
|Scordo, Julia M; Knoell, Daren L; Torrelles, Jordi B (2016) Alveolar Epithelial Cells in Mycobacterium tuberculosis Infection: Active Players or Innocent Bystanders? J Innate Immun 8:3-14|
|Arcos, Jesús; Diangelo, Lauren E; Scordo, Julia M et al. (2015) Lung Mucosa Lining Fluid Modification of Mycobacterium tuberculosis to Reprogram Human Neutrophil Killing Mechanisms. J Infect Dis 212:948-58|
|Moliva, Juan I; Turner, Joanne; Torrelles, Jordi B (2015) Prospects in Mycobacterium bovis Bacille Calmette et Guérin (BCG) vaccine diversity and delivery: why does BCG fail to protect against tuberculosis? Vaccine 33:5035-41|
|Yang, Lanhao; Sinha, Tejas; Carlson, Tracy K et al. (2013) Changes in the major cell envelope components of Mycobacterium tuberculosis during in vitro growth. Glycobiology 23:926-34|
|Torrelles, Jordi B; Sieling, Peter A; Zhang, Nannan et al. (2012) Isolation of a distinct Mycobacterium tuberculosis mannose-capped lipoarabinomannan isoform responsible for recognition by CD1b-restricted T cells. Glycobiology 22:1118-27|
|Torrelles, Jordi B; Sieling, Peter A; Arcos, Jesús et al. (2011) Structural differences in lipomannans from pathogenic and nonpathogenic mycobacteria that impact CD1b-restricted T cell responses. J Biol Chem 286:35438-46|
|Arcos, Jesus; Sasindran, Smitha J; Fujiwara, Nagatoshi et al. (2011) Human lung hydrolases delineate Mycobacterium tuberculosis-macrophage interactions and the capacity to control infection. J Immunol 187:372-81|
|Torrelles, Jordi B; Schlesinger, Larry S (2010) Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the host. Tuberculosis (Edinb) 90:84-93|
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