title: Mouse model of pulmonary cavitary tuberculosis and expression of matrix metalloproteinase-9.
abstract: Cavitation is a key pathological feature of human tuberculosis (TB), and is a well-recognized risk factor for transmission of infection, relapse after treatment and the emergence of drug resistance. Despite intense interest in the mechanisms underlying cavitation and its negative impact on treatment outcomes, there has been limited study of this phenomenon, owing in large part to the limitations of existing animal models. Although cavitation does not occur in conventional mouse strains after infection with Mycobacterium tuberculosis, cavitary lung lesions have occasionally been observed in C3HeB/FeJ mice. However, to date, there has been no demonstration that cavitation can be produced consistently enough to support C3HeB/FeJ mice as a new and useful model of cavitary TB. We utilized serial computed tomography (CT) imaging to detect pulmonary cavitation in C3HeB/FeJ mice after aerosol infection with M. tuberculosis Post-mortem analyses were performed to characterize lung lesions and to localize matrix metalloproteinases (MMPs) previously implicated in cavitary TB in situ A total of 47-61% of infected mice developed cavities during primary disease or relapse after non-curative treatments. Key pathological features of human TB, including simultaneous presence of multiple pathologies, were noted in lung tissues. Optical imaging demonstrated increased MMP activity in TB lesions and MMP-9 was significantly expressed in cavitary lesions. Tissue MMP-9 activity could be abrogated by specific inhibitors. In situ, three-dimensional analyses of cavitary lesions demonstrated that 22.06% of CD11b+ signal colocalized with MMP-9. C3HeB/FeJ mice represent a reliable, economical and tractable model of cavitary TB, with key similarities to human TB. This model should provide an excellent tool to better understand the pathogenesis of cavitation and its effects on TB treatments.
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Ordonez
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Rokeya
authors.initials: R
authors.lastname: Tasneen
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Pokkali
authors.affiliation: Center for Infectious Disease Imaging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Converse
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Mariah H
authors.initials: MH
authors.lastname: Klunk
authors.affiliation: Center for Infectious Disease Imaging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Mollura
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA enuermb@jhmi.edu sjain5@jhmi.edu.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA enuermb@jhmi.edu sjain5@jhmi.edu.
authors.forename: Sanjay K
authors.identifier: 0000-0001-9620-7070
authors.initials: SK
authors.lastname: Jain
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000000981:diagnostic imaging / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D014057:Tomography, X-Ray Computed; D014397:Tuberculosis, Pulmonary / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology*
chemical_list: D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9
keywords: Cavity; Computed tomography; Matrix metalloproteinases; Mice; Tuberculosis