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

Abstract

The neutrophil serine proteases cathepsin G (CG) and neutrophil elastase (NE) are involved in immune-regulatory processes and exert antibacterial activity against various pathogens. To date, their role and their therapeutic potential in pulmonary host defense against mycobacterial infections are poorly defined. In this work, we studied the roles of CG and NE in the pulmonary resistance against Mycobacterium bovis bacillus Calmette-Guérin (BCG). CG-deficient mice and even more pronounced CG/NE-deficient mice showed significantly impaired pathogen elimination to infection with M. bovis BCG in comparison to wild-type mice. Moreover, granuloma formation was more pronounced in M. bovis BCG-infected CG/NE-deficient mice in comparison to CG-deficient and wild-type mice. A close 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. Therapeutically applied human CG/NE encapsulated in liposomes colocalized with mycobacteria in alveolar macrophages, as assessed by laser scanning and electron microscopy. Importantly, therapy with CG/NE-loaded liposomes significantly reduced mycobacterial loads in the lungs of mice. Together, neutrophil-derived CG and NE critically contribute to deceleration of pathogen replication during the early phase of antimycobacterial responses. In addition, to our knowledge, we show for the first time that liposomal encapsulated CG/NE exhibit therapeutic potential against pulmonary mycobacterial infections. These findings may be relevant for novel adjuvant approaches in the treatment of tuberculosis in humans.

• Authors: Kathrin Steinwede, Regina Maus, Jennifer Bohling, Sabrina Voedisch, Armin Braun, Matthias Ochs, Andreas Schmiedl, Florian Länger, Francis Gauthier, Jürgen Roes, Tobias Welte, Franz C Bange, Michael Niederweis, Frank Bühling, Ulrich A Maus
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 188 Issue 9 Pg. 4476-87 (May 01 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22461690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cathepsin G
• Ctsg protein, mouse
• Leukocyte Elastase

Topics

• Animals
• Cathepsin G (genetics, immunology, metabolism)
• Female
• Humans
• Leukocyte Elastase (genetics, immunology, metabolism)
• Macrophages, Alveolar (enzymology, immunology, microbiology)
• Mice
• Mice, Mutant Strains
• Mycobacterium bovis (immunology)
• Tuberculosis, Pulmonary (drug therapy, enzymology, immunology, microbiology)