title: Mycobacterium bovis BCG-mediated protection against W-Beijing strains of Mycobacterium tuberculosis is diminished concomitant with the emergence of regulatory T cells.
abstract: Despite issues relating to variable efficacy in the past, the Mycobacterium bovis BCG vaccine remains the basis for new-generation recombinant vaccines currently in clinical trials. To date, vaccines have been tested mostly against laboratory strains and not against the newly emerging clinical strains. In this study, we evaluated the ability of BCG Pasteur to protect mice from aerosol infections with two highly virulent W-Beijing clinical strains, HN878 and SA161. In a conventional 30-day protection assay, BCG was highly protective against both strains, but by day 60 of the assay, this protection was diminished. Histological examination of the lungs of vaccinated animals showed reduced lung consolidation and smaller and more-organized granulomas in the vaccinated mice after 30 days, but in both cases, these tissues demonstrated worsening pathology over time. Effector T cell responses were increased in the vaccinated mice infected with HN878, but these diminished in number after day 30 of the infections concomitant with increased CD4(+) Foxp3(+) T cells in the lungs, draining lymph nodes, and the spleen. Given the concomitant decrease in effector immunity and continued expansion of regulatory Foxp3(+) cells observed here, it is reasonable to hypothesize that downregulation of effector immunity by these cells may be a serious impediment to the efficacy of BCG-based vaccines.
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682. D.Ordway-Rodriguez@colostate.edu
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Ordway
authors.forename: Shaobin
authors.initials: S
authors.lastname: Shang
authors.forename: Marcela
authors.initials: M
authors.lastname: Henao-Tamayo
authors.forename: Andres
authors.initials: A
authors.lastname: Obregon-Henao
authors.forename: Laura
authors.initials: L
authors.lastname: Nold
authors.forename: Megan
authors.initials: M
authors.lastname: Caraway
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Shanley
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Basaraba
authors.forename: Colleen G
authors.initials: CG
authors.lastname: Duncan
authors.forename: Ian M
authors.initials: IM
authors.lastname: Orme
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity*; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D014611:Vaccination; D014774:Virulence
chemical_list: D001500:BCG Vaccine; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse