Host proteolytic enzymes are believed to play a central role in the pathogenesis of pulmonary emphysema, through degradation of alveolar connective tissue proteins. However, little is known about whether this lung disease can be either caused or exacerbated by proteinases secreted by bacterial or fungal respiratory pathogens. Significantly, none of these enzymes are known to be regulated by host proteinase inhibitors. While it is believed that their primary function is to degrade host proteins to provide nutrients for the growth and proliferation of the invading organism, we propose that they also provide a means for evasion of host defense. For these reasons, the specific aims of this project are as follows: 1) to isolate and characterize selected proteinases secreted by lung pathogens, including Aspergillus fuimigatus, Stachybotrys chartarum, Pseudomonas aeruginosa, and Staphylococcus aureus, 2) to investigate the effect of pathogen-derived proteinases on the degradation/inactivation of host bactericidal peptides and proteins utilized to maintain homeostasis within the lung, and 3) to study the effect of exposure to these proteinases on a) the responsiveness of human monocytes and neutrophils to major pro-and anti-inflammatory stimulation and b) the ability of proteinase-exposed monocytes to clear apoptotic neutrophils. Our long-term goals are to determine whether the proteinases to be investigated play major roles in host defense evasion and tissue destruction within the lung. If this is the case, then they might be considered as targets for the development of inhibitors in order to control or eradicate lung microbial infections.
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