RESUMEN
Mycobacterium tuberculosis is considered one of the most successful pathogens in the history of mankind, having caused 1.7â¯million deaths in 2016. The amount of resistant and extensively resistant strains has increased; BCG has been the only vaccine to be produced in more than 100â¯years though it is still unable to prevent the disease's most disseminated form in adults; pulmonary tuberculosis. The search is thus still on-going for candidate antigens for an antituberculosis vaccine. This paper reports the use of a logical and rational methodology for finding such antigens, this time as peptides derived from the Rv3587c membrane protein. Bioinformatics tools were used for predicting mycobacterial surface location and Rv3587c protein structure whilst circular dichroism was used for determining its peptides' secondary structure. Receptor-ligand assays identified 4 high activity binding peptides (HABPs) binding specifically to A549 alveolar epithelial cells and U937 monocyte-derived macrophages, covering the region between amino acids 116 and 193. Their capability for inhibiting Mtb H37Rv invasion was evaluated. The recognition of antibodies from individuals suffering active and latent tuberculosis and from healthy individuals was observed in HABPs capable of avoiding mycobacterial entry to host cells. The results showed that 8 HABPs inhibited such invasion, two of them being common for both cell lines: 39265 (155VLAAYVYSLDNKRLWSNLDT173) and 39266 (174APSNETLVKTFSPGEQVTTY192). Peptide 39265 was the least recognised by antibodies from the individuals' sera evaluated in each group. According to the model proposed by FIDIC regarding synthetic vaccine development, peptide 39265 has become a candidate antigen for an antituberculosis vaccine.
Asunto(s)
Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Proteínas de la Membrana/inmunología , Mycobacterium tuberculosis/fisiología , Fragmentos de Péptidos/inmunología , Vacunas contra la Tuberculosis/inmunología , Secuencia de Aminoácidos , Antígenos Bacterianos/metabolismo , Antígenos Bacterianos/toxicidad , Proteínas Bacterianas/síntesis química , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/toxicidad , Línea Celular Tumoral , Biología Computacional , Diseño de Fármacos , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/fisiología , Humanos , Proteínas de la Membrana/síntesis química , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/toxicidad , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/toxicidad , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Receptores de Superficie Celular/metabolismo , Vacunas contra la Tuberculosis/síntesis química , Vacunas contra la Tuberculosis/metabolismo , Vacunas contra la Tuberculosis/toxicidad , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/metabolismo , Vacunas Sintéticas/toxicidadRESUMEN
Development of novel more efficient preventive vaccines against tuberculosis (TB) is crucial to achieve TB eradication by 2050, one of the Millennium Development Goals (MDG) for the current century. MTBVAC is the first and only live attenuated vaccine based on a human isolate of Mycobacterium tuberculosis developed as BCG-replacement strategy in newborns that has entered first-in-human adult clinical trials. In this work, we characterize the safety, immunogenicity and protective efficacy of MTBVAC in a model of newborn C57/BL6 mice. Our data clearly indicate that MTBVAC is safe for newborn mice, and does not affect animal growth or organ development. In addition, MTBVAC-vaccinated mice at birth showed enhanced immunogenicity and better protection against M. tuberculosis challenge in comparison with BCG.
Asunto(s)
Mycobacterium tuberculosis/crecimiento & desarrollo , Vacunas contra la Tuberculosis/farmacología , Tuberculosis/prevención & control , Animales , Animales Recién Nacidos , Vacuna BCG/inmunología , Vacuna BCG/farmacología , Modelos Animales de Enfermedad , Interferón gamma/inmunología , Interferón gamma/metabolismo , Ratones Endogámicos C57BL , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Factores de Tiempo , Tuberculosis/inmunología , Tuberculosis/microbiología , Vacunas contra la Tuberculosis/inmunología , Vacunas contra la Tuberculosis/toxicidad , Aumento de PesoRESUMEN
In this study, a Mycobacterium bovis knockout strain in phoP-phoR and mce2 operons was tested as an antituberculosis experimental vaccine in animal models. The double mutant strain was significantly more attenuated than the wild type strain in inmunocompetent and inmunodeficient mice. Vaccination with the double mutant protected mice against challenge with a virulent M. bovis strain.
Asunto(s)
Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Mycobacterium bovis/genética , Vacunas contra la Tuberculosis/genética , Tuberculosis Bovina/prevención & control , Animales , Bovinos , Recuento de Colonia Microbiana , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Ratones Endogámicos BALB C , Ratones Desnudos , Mycobacterium bovis/crecimiento & desarrollo , Mycobacterium bovis/patogenicidad , Células TH1/inmunología , Vacunas contra la Tuberculosis/inmunología , Vacunas contra la Tuberculosis/toxicidad , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/toxicidad , Virulencia/genéticaRESUMEN
The recent advances in genetic tools to manipulate Mycobacterium tuberculosis have led to the construction of defined mutants and to the study of their role in the virulence and pathogenesis of tuberculosis. The safety and vaccine potential of a few of these M. tuberculosis mutants as candidate vaccines against tuberculosis are discussed.