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Vaccine v.36 no.16, 2018년, pp.2069 - 2078   SCI SCIE SCOPUS
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Immune response elicited by two rBCG strains devoid of genes involved in c-di-GMP metabolism affect protection versus challenge with M. tuberculosis strains of different virulence

Segura-Cerda, Cristian Alfredo (Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y diseño del Estado de Jalisco, A.C., Guadalajara, Jalisco, Mexico ) ; Aceves-Sánchez, Michel de Jesús (Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y diseño del Estado de Jalisco, A.C., Guadalajara, Jalisco, Mexico ) ; Marquina-Castillo, Brenda (Departamento de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico ) ; Mata-Espinoza, Dulce (Departamento de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico ) ; Barrios-Payán, Jorge (Departamento de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico ) ; Vega-Domínguez, Perla Jazmín (Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en ) ; Pedroza-Roldán, César ; Bravo-Madrigal, Jorge ; Vallejo-Cardona, Alba Adriana ; Hernández-Pando, Rogelio ; Flores-Valdez, Mario Alberto ;
  • 초록  

    Abstract Pellicles, a type of biofilm, have gathered a renewed interest in the field of tuberculosis as a structure that mimics some characteristics occurring during M. tuberculosis infection, such as antibiotic recalcitrance and chronicity of infection, and as a source of antigens for humoral response in infected guinea pigs. In other bacteria, it has been well documented that the second messenger c-di-GMP modulates the transition from planktonic cells to biofilm formation. In this work, we used the live vaccine Mycobacterium bovis BCG to determine whether deletion of genes involved in c-di-GMP metabolism would affect interaction with macrophages, capacity to induce immune response in a murine cell line and mice, and how the protein profile was modified when grown as surface pellicles. We found that deletion of the BCG1419c (Delta c-di-GMP phosphodiesterase, ΔPDE) gene, or deletion of the BCG1416c (Delta c-di-GMP diguanylate cyclase, ΔDGC) gene, altered production of TNF-α, IL-6, and IL-1β, in murine macrophages, and resulted in attenuation in intra-macrophage replication. Moreover, in addition to the improved immunogenicity of the BCGΔBCG1419c mutant already reported, deletion of the BCG1416c gene leads to increased T CD4 + and T CD8 + activation. This correlated with protection versus lethality in mice infected with the highly virulent M. tuberculosis 5186 afforded by vaccination with all the tested BCG strains, and controlled the growth of the mildly virulent M. tuberculosis H37Rv in lungs by vaccination with BCGΔBCG1419c during chronic late infection from 4 to 6 months after challenge. Furthermore, when grown as surface pellicles, a condition used to manufacture BCG vaccine, in comparison to BCG wild type, both rBCGs changed expression of antigenic proteins such as DnaK, HbhA, PstS2, 35KDa antigen, GroEL2, as well as AcpM, a protein involved in synthesis of mycolic acids, molecules relevant to modulate inflammatory responses. Highlights BCG strains devoid of genes involved in c-di-GMP metabolism modify TNFα, IL-6 & IL-10. Immunization with a BCG1416c mutant increases IFNγ + in T CD4 and CD8 lymphocytes. Immunization with BCG mutants in BCG1416c or BCG1419c protects vs Mtb challenge. BCG mutants in BCG1416c or BCG1419c differentially express antigenic proteins.


  • 주제어

    Tuberculosis .   BCG .   Pellicle .   Proteome .   T-cell activation .   Cytokines.  

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