title: Increased pathology in lungs of mice after infection with an alpha-crystallin mutant of Mycobacterium tuberculosis: changes in cathepsin proteases and certain cytokines.
abstract: Latency and reactivation are a significant problem that contributes to the incidence, transmission and pathogenesis of tuberculosis. The mechanisms involved in these processes, at the level of both the bacillus and the host, are poorly understood. In Mycobacterium tuberculosis the alpha-crystallin (acr) gene has been linked to latency, because it is highly expressed during hypoxic growth conditions. Deletion of the acr gene in M. tuberculosis H37Rv (Deltaacr strain) was previously shown to reduce the intracellular growth of bacilli in macrophages; however, its impact on pathogenesis in vivo was unknown. This study demonstrated that infection of C57BL6 mice with Deltaacr results in lung bacillary loads 1-2 log units higher in comparison to parental H37Rv. Haematoxylin/eosin staining of lungs revealed exacerbated pathology characterized by extensive obliteration of alveolar air spaces by granulomatous inflammation. RT-PCR analysis and immunostaining of lungs showed that infection with either H37Rv or Deltaacr results in the differential expression of lysosomal cathepsin proteases. A slight increase in the expression of the matrix-degrading acidic-type cathepsins B, D and H was noted in Deltaacr-infected mice and was associated with clusters of macrophages within lung granulomas. Deltaacr-infected mice also showed high serum levels of TNF-alpha, IFN-gamma and G-CSF, suggesting that Acr may play a role in modulating the host response to infection.
authors.affiliation: Atlanta VA Medical Center Research Service, Room 12C 106, 1670 Clairmont Rd, Decatur, GA 30033, USA.
authors.forename: Julie N
authors.initials: JN
authors.lastname: Stewart
authors.affiliation: Atlanta VA Medical Center Research Service, Room 12C 106, 1670 Clairmont Rd, Decatur, GA 30033, USA.
authors.forename: Hilda N
authors.initials: HN
authors.lastname: Rivera
authors.affiliation: Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Karls
authors.affiliation: Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
authors.forename: Frederick D
authors.initials: FD
authors.lastname: Quinn
authors.affiliation: Atlanta VA Medical Center Research Service, Room 12C 106, 1670 Clairmont Rd, Decatur, GA 30033, USA.|Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Athens, GA 30602, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
authors.affiliation: Atlanta VA Medical Center Research Service, Room 12C 106, 1670 Clairmont Rd, Decatur, GA 30033, USA.|Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Athens, GA 30602, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rivera-Marrero
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D005260:Female; D006099:Granuloma / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics; D010447:Peptide Hydrolases / Q000378:metabolism; D014376:Tuberculosis / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D038201:alpha-Crystallins / Q000172:deficiency / Q000235:genetics
chemical_list: D016207:Cytokines; D038201:alpha-Crystallins; D002403:Cathepsins; D010447:Peptide Hydrolases