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Cathepsin G and neutrophil elastase contribute to lung protective immunity against mycobacterial infections in mice

: Steinwede, Kathrin; Maus, Regina; Bohling, Jennifer; Voedisch, Sabrina; Braun, Armin; Ochs, Matthias; Schmiedl, Andreas; Walter, Kerstin; Bange, Franz; Welte, Tobias; Ehlers, Stefan; Maus, Ulrich A.

American Journal of Respiratory and Critical Care Medicine 185 (2012), Abstract A3267
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2012, San Francisco/Calif.>
Fraunhofer ITEM ()

Rationale: Tuberculosis remains to be a global health threat. The observed increase of MDR-TB and XDR-TB cases necessitates the development of novel antibiotic-independent therapeutic strategies. The current study aimed at elucidating the role and the therapeutic potential of the two neutral serine proteases cathepsin G (CG) and neutrophil elastase (NE) in the lung host defense against mycobacterial infections.
Methods: CG deficient, CG/NE double deficient, and wild-type mice were infected with M. bovis BCG, and bacterial loads in BAL fluids and lung tissue as well as lung leukocyte recruitment profiles, lung histopathology and cytokine profiles were determined over time. In selected experiments, M. bovis BCG infected wild-type mice received repetitive intratracheal applications of liposomal encapsulated human CG and NE to evaluate the antimycobacterial efficacy of these serine proteases as novel therapeutic approach in vivo.
Results: CG deficient mice and even more so CG/NE deficient mice responded with significantly impaired pathogen elimination to infection with M. bovis BCG, relative to wild-type mice. Moreover, granuloma formation was more pronounced in M. bovis BCG challenged CG/NE deficient mice compared to CG deficient and wild-type mice. Examination of professional phagocyte subsets revealed that exclusively neutrophils shuttled CG and NE into the bronchoalveolar space of M. bovis BCG infected mice. Accordingly, chimeric wild-type mice with a CG/NE deficient hematopoietic system displayed significantly increased lung bacterial loads in response to M. bovis BCG infection. Liposomal encapsulated human CG/NE instilled into the lungs of wild-type mice co-localized with mycobacteria in the same phagosomal compartment of alveolar macrophages, as assessed by laser scanning and electron microscopy. Such liposomal CG/NE therapy resulted in significantly reduced mycobacterial loads in the lungs of mice.
Conclusion: The data show that neutrophils are the primary cellular shuttle transporting CG and NE into the lungs during the early phase of mycobacterial infections. Moreover, CG/NE critically contribute to the early mycobacterial pathogen elimination in the lungs of infected mice. In addition, we show for the first time that liposomal encapsulated CG and NE exhibit therapeutic potential against lung mycobacterial infections. These findings may be relevant for novel adjuvant approaches in the treatment of tuberculosis in humans.