RESUMO
BACKGROUND: The extent to which individuals exhibit genetic susceptibility to tuberculosis (TB) is still unclear. Genetic variations in chemokine genes might influence the early clearance of Mycobacterium tuberculosis, affecting TB susceptibility. OBJECTIVES: To study single nucleotide polymorphisms (SNPs) of chemokine genes CCL2, CXCL9, CXCL10 and CXCL11, and their association with TB susceptibility. DESIGN: Of 248 participants enrolled, 49 had active TB, 43 had latent tuberculous infection (LTBI) and 156 were non-infected, including 24 healthy controls with no known TB exposure. These populations were divided into two groups based on TB exposure: susceptible (n = 92) and resistant (early clearance) (n = 132). RESULTS: Only CCL2 SNPs (-2518A/G) were significantly associated with increased TB susceptibility. Based on adjusted multivariate analysis, persons with the GG genotype at this SNP were twice as susceptible to TB as those with the AA genotype (P = 0.018, OR 2.880, 95%CI 1.201-6.903). Risk of LTBI was three times higher among those with GG (P = 0.003, OR 3.358, 95%CI 1.525-7.396 for AA+AG vs. GG and P = 0.012, OR 3.706, 95%CI 1.340-10.254 for AA vs. GG). Persons with the GG genotype produced significantly lower CCL2 levels in response to M. tuberculosis antigen stimulation (AA+AG vs. GG, P = 0.038). CONCLUSION: The CCL2 polymorphism (-2518A/G) was associated with susceptibility to LTBI in a North-East Thai populations.
Assuntos
Quimiocina CCL2/genética , Predisposição Genética para Doença , Tuberculose Latente/genética , Adulto , Antígenos de Bactérias/sangue , Povo Asiático/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Quimiocina CXCL10/genética , Quimiocina CXCL11/genética , Quimiocina CXCL9/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , TailândiaRESUMO
A gene designated varR (for virginiae antibiotic resistance regulator) was identified in Streptomyces virginiae 89 bp downstream of a varS gene encoding a virginiamycin S (VS)-specific transporter. The deduced varR product showed high homology to repressors of the TetR family with a conserved helix-turn-helix DNA binding motif. Purified recombinant VarR protein was present as a dimer in vitro and showed clear DNA binding activity toward the varS promoter region. This binding was abolished by the presence of VS, suggesting that VarR regulates transcription of varS in a VS-dependent manner. Northern blot analysis revealed that varR was cotranscribed with upstream varS as a 2.4-kb transcript and that VS acted as an inducer of bicistronic transcription. Deletion analysis of the varS promoter region clarified two adjacent VarR binding sites in the varS promoter.
Assuntos
Proteínas de Bactérias , Proteínas de Ligação a DNA/genética , Genes Reguladores , Proteínas Repressoras/genética , Streptomyces/efeitos dos fármacos , Streptomyces/genética , Virginiamicina/farmacologia , Sequência de Aminoácidos , Sequência de Bases , Sítios de Ligação , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Resistência Microbiana a Medicamentos/genética , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Análise de Sequência de DNA , Streptomyces/crescimento & desenvolvimento , Streptomyces/metabolismo , Transcrição GênicaRESUMO
OBJECTIVE: To develop and use a polymerase chain reaction (PCR) method for studying the genetic diversity of Mycobacterium tuberculosis. DESIGN: Two polymorphic DNA segments of M. tuberculosis H37Rv were identified and sequenced. Primers were then designed for simultaneous amplification of both polymorphic segments. The method was used for studying 179 clinical isolates of M. tuberculosis that had been previously characterized by Southern hybridization with IS6110. RESULTS: Both polymorphic segments contained direct repetitive sequences. In one segment the direct repetitive sequences were within the putative coding sequence of alpha-isopropylmalate synthase gene. After amplifying both segments of the 179 isolates, 40 patterns of PCR products could be identified. The method was able to differentiate 38 IS6110-single-banded isolates into 23 types. Most of the isolates belonging to the Beijing family had PCR products identical to the H37Rv strain. The PCR products of the members of the Nonthaburi group were similar to each other. CONCLUSION: These results agree with the hypothesis that the members of the Beijing family and the Nonthaburi group descended from two common ancestors. The PCR method might be useful for differentiating strains of M. tuberculosis that contain a single copy of IS6110.
