title: Vaccination with a Sindbis virus-based DNA vaccine expressing antigen 85B induces protective immunity against Mycobacterium tuberculosis.
abstract: To improve DNA vaccination against Mycobacterium tuberculosis, we evaluated the effectiveness of a Sindbis virus-based DNA construct expressing the tuberculosis antigen 85B (Sin85B). The protective efficacy of Sin85B was initially assessed by aerogenically challenging immunized C57BL/6 mice with virulent Mycobacterium tuberculosis. At 1 and 7 months postinfection, the lung bacterial burdens were considerably reduced and the lung pathology was improved in vaccinated mice compared to naive controls. Furthermore, the mean survival period for Sin85B-immunized mice (305 +/- 9 days) after the tuberculous challenge was extended 102 days relative to the naive mice (203 +/- 13 days) and was essentially equivalent to the survival time of Mycobacterium bovis BCG-vaccinated mice (294 +/- 15 days). The essential role of gamma interferon (IFN-gamma) in Sin85B-mediated protection was established by showing that significantly increased levels of IFN-gamma mRNA were present postinfection in lung cells from vaccinated mice relative to control mice and by demonstrating that IFN-gamma depletion prior to challenge abolished the vaccine-induced protection. The substantial antituberculosis protective responses induced by Sin85B immunization of CD4-/- mice strongly suggested that CD8 cells partially mediate Sin85B-induced protective immunity. Interestingly, Sin85B vaccination did not protect RNase L-/- (a key enzyme in the innate antiviral response) mice while significant protection was detected in RNase L-/- mice immunized with either BCG or a conventional DNA plasmid expressing antigen 85B. These data show that immunization with Sin85B offers protection similar to BCG in a murine model of pulmonary tuberculosis and suggest that Sin85B-induced protection is dependent upon both innate and acquired immune mechanisms.
authors.affiliation: Laboratory of Mycobacterial Diseases and Cellular Immunology, Building 29/Room 511, CBER/FDA, 29 Lincoln Dr., Bethesda, MD 20892, USA. derrick@cber.fda.gov
authors.forename: Steven C
authors.initials: SC
authors.lastname: Derrick
authors.forename: Amy Li
authors.initials: AL
authors.lastname: Yang
authors.forename: Sheldon L
authors.initials: SL
authors.lastname: Morris
mesh_terms: D000336:Aerosols; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics; D016827:CD8 Antigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D012845:Sindbis Virus / Q000235:genetics*; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000235:genetics / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000235:genetics* / Q000276:immunology*
chemical_list: D000336:Aerosols; D000942:Antigens, Bacterial; D015704:CD4 Antigens; D016827:CD8 Antigens; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; C071448:antigen 85B, Mycobacterium leprae; D007371:Interferon-gamma; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease