title: Aerosol infection of mice with recombinant BCG secreting murine IFN-gamma partially reconstitutes local protective immunity.
abstract: To better understand the contribution of interferon-gamma (IFN-gamma) to the immune response during the first 60 days of mycobacterial infection in the lungs, IFN-gamma gene disrupted (IFN-gamma-/-) mice were infected via aerosol with recombinant Mycobacterium bovis Bacillus Calmette-Guerin (BCG) secreting murine IFN-gamma (BCG-IFN-gamma) and compared to mice infected with recombinant BCG containing the vector only (BCG-vector). When IFN-gamma-/- mice were infected with BCG-vector, increasing bacillary loads and large undifferentiated granulomas that did not express inducible nitric oxide synthase (iNOS) were observed in the lungs. In contrast, infection with BCG-IFN-gamma resulted in reduced bacillary load and better differentiated granulomas containing epithelioid macrophages expressing iNOS as well as reduced levels of interleukin 10 (IL-10) mRNA. However, local production of IFN-gamma by the recombinant BCG did not protect IFN-gamma-/- mice from subsequent challenge with M. tuberculosis. Infection of IFN-gamma-/- peritoneal macrophages in vitro with BCG-IFN-gamma led to induction of iNOS expression and lower IL-10 mRNA levels. Nevertheless, the growth of the intracellular BCG was unaffected. Since IFN-gamma induced-iNOS protein and reduced IL-10 production were insufficient to control mycobacterial growth in vitro, the results suggest that additional mediator(s) present in vivo are required for control of mycobacterial growth.
authors.affiliation: Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Moreira
authors.forename: L
authors.initials: L
authors.lastname: Tsenova
authors.forename: P J
authors.initials: PJ
authors.lastname: Murray
authors.forename: S
authors.initials: S
authors.lastname: Freeman
authors.forename: A
authors.initials: A
authors.lastname: Bergtold
authors.forename: L
authors.initials: L
authors.lastname: Chiriboga
authors.forename: G
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000336:Aerosols; D000818:Animals; D015169:Colony Count, Microbial; D016207:Cytokines / Q000378:metabolism; D004274:DNA, Recombinant; D005260:Female; D005822:Genetic Vectors; D006099:Granuloma / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009163:Mycobacterium bovis / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
chemical_list: D000336:Aerosols; D016207:Cytokines; D004274:DNA, Recombinant; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse