title: The BCGΔBCG1419c strain, which produces more pellicle in vitro, improves control of chronic tuberculosis in vivo.
abstract: Mycobacterium tuberculosis (Mtb) has been a threat to humans since ancient times, and it is the main causative agent of tuberculosis (TB). Until today, the only licensed vaccine against Mtb is the live attenuated M. bovis Bacillus Calmette-Guérin (BCG), which has variable levels of protection against the pulmonary form of infection. The quest for a new vaccine is a priority given the rise of multidrug-resistant Mtb around the world, as well as the tremendous burden imposed by latent TB. The objective of this study was to evaluate the immunogenicity and capacity of protection of a modified BCG strain (BCGΔBCG1419c) lacking the c-di-GMP phosphodiesterase gene BCG1419c, in diverse mice models. In a previous report, we have shown that BCGΔBCG1419c was capable of increasing biofilm production and after intravenous infection of immunocompetent mice; this strain persisted longer in lungs than parental BCG Pasteur. This led us to hypothesize that BCGΔBCG1419c might therefore possess some advantage as vaccine candidate. Our results in this report indicate that compared to conventional BCG, vaccination with BCGΔBCG1419c induced a better activation of specific T-lymphocytes population, was equally effective in preventing weight loss despite being used at lower dose, reduced tissue damage (pneumonic scores), increased local IFNγ(+) T cells, and diminished bacterial burden in lungs of BALB/c mice infected intratracheally with high dose Mtb H37Rv to induce progressive TB. Moreover, vaccination with BCGΔBCG1419c improved resistance to reactivation after immunosuppression induced by corticosterone in a murine model of chronic infection similar to latent TB. Furthermore, despite showing increased persistence in immunocompetent mice, BCGΔBCG1419c was as attenuated as parental BCG in nude mice. To our knowledge, this is the first demonstration that a modified BCG vaccine candidate with increased pellicle/biofilm production has the capacity to protect against Mtb challenge in chronic and reactivation models of infection.
authors.affiliation: Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y diseño del Estado de Jalisco, A.C., Av. Normalistas No. 800, Col. Colinas de la Normal, 44270 Guadalajara, Jalisco, Mexico.
authors.forename: César
authors.initials: C
authors.lastname: Pedroza-Roldán
authors.affiliation: Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Vasco de Quiroga 15, Tlalpan, México, D.F. 14000, Mexico.
authors.forename: Carolina
authors.initials: C
authors.lastname: Guapillo
authors.affiliation: Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Vasco de Quiroga 15, Tlalpan, México, D.F. 14000, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barrios-Payán
authors.affiliation: Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Vasco de Quiroga 15, Tlalpan, México, D.F. 14000, Mexico.
authors.forename: Dulce
authors.initials: D
authors.lastname: Mata-Espinosa
authors.affiliation: Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y diseño del Estado de Jalisco, A.C., Av. Normalistas No. 800, Col. Colinas de la Normal, 44270 Guadalajara, Jalisco, Mexico.
authors.forename: Michel de Jesús
authors.initials: Mde J
authors.lastname: Aceves-Sánchez
authors.affiliation: Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Vasco de Quiroga 15, Tlalpan, México, D.F. 14000, Mexico.
authors.forename: Brenda
authors.initials: B
authors.lastname: Marquina-Castillo
authors.affiliation: Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Vasco de Quiroga 15, Tlalpan, México, D.F. 14000, Mexico. Electronic address: rhdezpando@hotmail.com.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Hernández-Pando
authors.affiliation: Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y diseño del Estado de Jalisco, A.C., Av. Normalistas No. 800, Col. Colinas de la Normal, 44270 Guadalajara, Jalisco, Mexico. Electronic address: floresv@ciatej.mx.
authors.forename: Mario Alberto
authors.initials: MA
authors.lastname: Flores-Valdez
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000276:immunology*; D058491:Bacterial Load; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000235:genetics; D005260:Female; D055985:Latent Tuberculosis / Q000517:prevention & control*; D008168:Lung / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009169:Mycobacterium tuberculosis / Q000145:classification* / Q000472:pathogenicity; D013601:T-Lymphocytes / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000517:prevention & control*; D014774:Virulence
chemical_list: D001500:BCG Vaccine; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP
keywords: Bacillus-Calmette Guerin; Biofilm; Pellicle; Tuberculosis; Vaccine