Role of cathepsin G and neutrophil elastase in the lung host defense against mycobacterial infections

Background: Tuberculosis remains to be a major health threat with ˜ 8–10 million new infections and 2–3 million deaths per year worldwide. The current study aimed at elucidating the role of neutral serine proteases cathepsin G and neutrophil elastase in the lung host defense against mycobacterial infections. Methods and Results: We found that cathepsin G deficient mice responded with a significantly decreased survival and significantly impaired pathogen elimination to infection with either M. tuberculosis or M. bovis BCG. Moreover, an even more accentuated disturbation of the pathogen elimination process was observed in the lungs of mice deficient of both cathepsin G and neutrophil elastase. Among the examined professional phagocyte subsets, exclusively neutrophils were observed to abundantly express serine proteases cathepsin G and neutrophil elastase. Importantly, detection of immunoreactivity of cathepsin G and neutrophil elastase in the bronchoalveolar space of mice infected with M. bovis BCG coincided with the appearance of neutrophils in this compartment. Moreover, chimeric wild-type mice lacking cathepsin G and neutrophil elastase in their hematopoietic system responded with a significantly decreased lung bacterial clearance after challenge with M. bovis BCG, relative to wild-type mice. In vitro, we found that incubation of M. bovis BCG with cathepsin G, but not cathepsin B resulted in a significantly impaired bacterial outgrowth, suggesting a direct antimycobacterial effect of cathepsin G on mycobacterial pathogens. Summary: This study for the first time demonstrates that both cathepsin G and neutrophil elastase are central to the pathogen elimination process during the early phase of protective immunity against inhaled mycobacterial pathogens.