title: Mycobacterial antigens exacerbate disease manifestations in Mycobacterium tuberculosis-infected mice.
abstract: To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used, Mycobacterium bovis BCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with prior M. tuberculosis infection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viable M. tuberculosis mixed with heat-killed Mycobacterium tuberculosis (1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. When M. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-alpha, and to a lesser extent, IL-2 and gamma interferon (IFN-gamma), caused a significant increase in granuloma size in the lungs. Moreover, treatment of M. tuberculosis-infected mice with recombinant murine TNF-alpha resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with prior M. tuberculosis infection leads to immune activation that may exacerbate lung pathology via TNF-alpha-induced inflammation without reducing the bacillary load.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Andre L
authors.initials: AL
authors.lastname: Moreira
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.forename: Melles Haile
authors.initials: MH
authors.lastname: Aman
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.forename: Sherry
authors.initials: S
authors.lastname: Freeman
authors.forename: Bande
authors.initials: B
authors.lastname: Mangaliso
authors.forename: Ulf
authors.initials: U
authors.lastname: Schröder
authors.forename: Jaishree
authors.initials: J
authors.lastname: Jagirdar
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.forename: Michael G
authors.initials: MG
authors.lastname: Tovey
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Freedman
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001500:BCG Vaccine / Q000276:immunology; D005260:Female; D015850:Interleukin-6 / Q000235:genetics; D008168:Lung / Q000473:pathology*; D008213:Lymphocyte Activation; D051379:Mice; D009161:Mycobacterium / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology; D014376:Tuberculosis / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology; D014611:Vaccination
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha