title: Protective immunity afforded by attenuated, PhoP-deficient Mycobacterium tuberculosis is associated with sustained generation of CD4+ T-cell memory.
abstract: Definition of protective immunity induced by effective vaccines is important for the design of new pathogen control strategies. Inactivation of the PhoP response-regulator in Mycobacterium tuberculosis results in a highly attenuated strain that demonstrates impressive protective efficacy in pre-clinical models of tuberculosis. In this report we demonstrate that the protection afforded by the M. tuberculosis phoP mutant strain is associated with the long-term maintenance of CD4(+)  T-cell memory. Immunization of mice with SO2 resulted in enhanced expansion of M. tuberculosis-specific CD4(+)  T cells compared with vaccination with the BCG vaccine, with an increased frequency of these cells persisting at extended time-points after vaccination. Strikingly, vaccination with SO2 resulted in sustained generation of CD4(+)  T cells displaying a central memory phenotype, a property not shared by BCG. Further, SO2 vaccination markedly improved the generation of polyfunctional cytokine-secreting CD4(+)  T cells compared with BCG vaccination. The improved generation of functionally competent memory T cells by SO2 correlated with augmented recall responses in SO2-vaccinated animals after challenge with virulent M. tuberculosis. This study defines a mechanism for the protective effect of the SO2 vaccine and suggests that deletion of defined virulence networks may provide vaccine strains with potent immuno-stimulatory properties.
authors: Microbial Pathogenesis and Immunity Group, Discipline of Infectious Diseases and Immunology, University of Sydney, Sydney, Australia.
authors: Jonathan K
authors: JK
authors: Nambiar
authors: Rachel
authors: R
authors: Pinto
authors: Juan I
authors: JI
authors: Aguilo
authors: Kiyoshi
authors: K
authors: Takatsu
authors: Carlos
authors: C
authors: Martin
authors: Warwick J
authors: WJ
authors: Britton
authors: James A
authors: JA
authors: Triccas
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007111:Immunity, Cellular; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology; D014611:Vaccination; D014613:Vaccines, Attenuated; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D011948:Receptors, Antigen, T-Cell; D014613:Vaccines, Attenuated; C061064:PhoP protein, Bacteria