title: Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice.
abstract: The hallmark of human Mycobacterium tuberculosis infection is the presence of lung granulomas. Lung granulomas can have different phenotypes, with caseous necrosis and hypoxia present within these structures during active tuberculosis. Production of NO by the inducible host enzyme NOS2 is a key antimycobacterial defense mechanism that requires oxygen as a substrate; it is therefore likely to perform inefficiently in hypoxic regions of granulomas in which M. tuberculosis persists. Here we have used Nos2-/- mice to investigate host-protective mechanisms within hypoxic granulomas and identified a role for host serine proteases in hypoxic granulomas in determining outcome of disease. Nos2-/- mice reproduced human-like granulomas in the lung when infected with M. tuberculosis in the ear dermis. The granulomas were hypoxic and contained large amounts of the serine protease cathepsin G and clade B serine protease inhibitors (serpins). Extrinsic inhibition of serine protease activity in vivo resulted in distorted granuloma structure, extensive hypoxia, and increased bacterial growth in this model. These data suggest that serine protease activity acts as a protective mechanism within hypoxic regions of lung granulomas and present a potential new strategy for the treatment of tuberculosis.
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany. reece@mpiib-berlin.mpg.de
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Reece
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: David J
authors.initials: DJ
authors.lastname: Askew
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zedler
authors.forename: Sandra
authors.initials: S
authors.lastname: Schommer-Leitner
authors.forename: Maik
authors.initials: M
authors.lastname: Stein
authors.forename: Fayaz Ahmad
authors.initials: FA
authors.lastname: Mir
authors.forename: Anca
authors.initials: A
authors.lastname: Dorhoi
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.forename: Gary A
authors.initials: GA
authors.lastname: Silverman
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D056649:Cathepsin G / Q000378:metabolism; D006099:Granuloma / Q000201:enzymology* / Q000382:microbiology*; D000860:Hypoxia; D008168:Lung / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000254:growth & development*; D009336:Necrosis; D011658:Pulmonary Fibrosis / Q000201:enzymology; D057057:Serine Proteases / Q000502:physiology*; D014397:Tuberculosis, Pulmonary / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology*
chemical_list: D057057:Serine Proteases; D056649:Cathepsin G