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    Assessment of the Genetic Diversity of Mycobacterium tuberculosis esxA, esxH, and fbpB Genes among Clinical Isolates and Its Implication for the Future Immunization by New Tuberculosis Subunit Vaccines Ag85B-ESAT-6 and Ag85B-TB10.4
    (Hindawi Ltd, 2010) Davila, Jose; Zhang, Lixin; Marrs, Carl F.; Durmaz, Riza; Yang, Zhenhua
    The effort to develop a tuberculosis (TB) vaccine more effective than the widely used Bacille Calmette-Guerin (BCG) has led to the development of two novel fusion protein subunit vaccines: Ag85B-ESAT-6 and Ag85B-TB10.4. Studies of these vaccines in animal models have revealed their ability to generate protective immune responses. Yet, previous work on TB fusion subunit vaccine candidate, Mtb72f, has suggested that genetic diversity among M. tuberculosis strains may compromise vaccine efficacy. In this study, we sequenced the esxA, esxH, and fbpB genes of M. tuberculosis encoding ESAT-6, TB10.4, and Ag85B proteins, respectively, in a sample of 88 clinical isolates representing 57 strains from Ark, USA, and 31 strains from Turkey, to assess the genetic diversity of the two vaccine candidates. We found no DNA polymorphism in esxA and esxH genes in the study sample and only one synonymous single nucleotide change (C to A) in fbpB gene among 39 (44.3%) of the 88 strains sequenced. These data suggest that it is unlikely that the efficacy of Ag85B-ESAT-6 and Ag85B-TB10.4 vaccines will be affected by the genetic diversity of M. tuberculosis population. Future studies should include a broader pool of M. tuberculosis strains to validate the current conclusion.
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    DNA polymorphisms in the pepA and PPE18 genes among clinical strains of Mycobacterium tuberculosis
    (Amer Soc Microbiology, 2007) Hebert, Andrea M.; Talarico, Sarah; Yang, Dong; Durmaz, Riza; Marrs, Carl F.; Zhang, Lixin; Foxman, Betsy
    Tuberculosis continues to be a leading cause of death worldwide. Development of an effective vaccine against Mycobacterium tuberculosis is necessary to reduce the global burden of this disease. Mtb72F, consisting of the protein products of the pepA and PPE18 genes, is the first subunit tuberculosis vaccine to undergo phase I clinical trials. To obtain insight into the ability of Mtb72F to induce an immune response capable of recognizing different strains of M. tuberculosis, we investigated the genomic diversity of the pepA and PPE18 genes among 225 clinical strains of M. tuberculosis from two different geographical locations, Arkansas and Turkey, representing a broad range of genotypes of M. tuberculosis. A combination of single nucleotide polymorphisms (SNPs) and insertion/deletions resulting in amino acid changes in the PPE18 protein occurred in 47 (20.9%) of the 225 study strains, whereas SNPs resulted in amino acid changes in the PepA protein in 14 (6.2%) of the 225 study strains. Of the 122 Arkansas study strains and the 103 Turkey study strains, 32 (26.2%) and 15 (14.6%), respectively, had at least one genetic change leading to an alteration of the amino acid sequence of the PPE18 protein, and many of the changes occurred in regions previously reported to be potential T-cell epitopes. Thus, immunity induced by Mtb72F may not recognize a proportion of M. tuberculosis clinical strains.