The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs.
The Mycobacterium tuberculosis phoP mutant strain SO2 has previously been shown to have reduced multiplication in mouse macrophages and in vivo using the mouse intravenous-infection model. In this study we demonstrate that the M. tuberculosis SO2 is highly attenuated when compared with the parental M. tuberculosis MT103 strain and also more attenuated than BCG in severe combined immunodeficiency disease (SCID) mice. Complementation of the M. tuberculosis SO2 with the wild-type phoP gene restored the virulence of the strain in the SCID mice, confirming that the attenuated phenotype is due to the phoP mutation. In Balb/c mice subcutaneously vaccinated with either M. tuberculosis SO2 or BCG, the proportions of CD4+ and CD8+ populations measured in the spleen were significantly higher in the M. tuberculosis SO2 vaccinated group. In addition, the proportion of antigen-stimulated CD4+/CD8+ cells expressing IFN-gamma was significantly higher in the M. tuberculosis SO2 vaccinated group when compared with the BCG group. Balb/c mice subcutaneously vaccinated with the M. tuberculosis SO2 strain were also protected against intra-venous challenge with M. tuberculosis H37Rv at levels comparable to mice vaccinated with BCG, as measured by reduced bacterial counts in lung and spleens. Guinea pigs subcutaneously vaccinated with the M. tuberculosis SO2 strain were protected against aerosol challenge with M. tuberculosis H37Rv delivered at different doses. A high dose aerosol challenge of M. tuberculosis SO2 vaccinated guinea pigs resulted in superior levels of protection when compared with BCG vaccination, as measured by guinea pig survival and reduction in disease severity in the lung.
Martin
Carlos
C
Grupo de Genética de Micobacterias, Departamento de Microbiología, Facultad de Medicina, Universidad de Zaragoza, Spain. carlos@unizar.es
Williams
Ann
A
Hernandez-Pando
Rogelio
R
Cardona
Pere J
PJ
Gormley
Eamonn
E
Bordat
Yann
Y
Soto
Carlos Y
CY
Clark
Simon O
SO
Hatch
Graham J
GJ
Aguilar
Diana
D
Ausina
Vicente
V
Gicquel
Brigitte
B
D000818:Animals; D001500:BCG Vaccine / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006168:Guinea Pigs; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009154:Mutation; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000276:immunology
D001500:BCG Vaccine; D001426:Bacterial Proteins; D032581:Tuberculosis Vaccines; D014613:Vaccines, Attenuated; C061064:PhoP protein, Bacteria