title: High Sequence Variability of the ppE18 Gene of Clinical Mycobacterium tuberculosis Complex Strains Potentially Impacts Effectivity of Vaccine Candidate M72/AS01E.
abstract: The development of an effective vaccine is urgently needed to fight tuberculosis (TB) which is still the leading cause of death from a single infectious agent worldwide. One of the promising vaccine candidates M72/AS01E consists of two proteins subunits PepA and PPE18 coded by Rv0125 and Rv1196. However, preliminary data indicate a high level of sequence variability among clinical Mycobacterium tuberculosis complex (MTBC) strains that might have an impact on the vaccine efficacy. To further investigate this finding, we determined ppE18 sequence variability in a well-characterized reference collection of 71 MTBC strains from 23 phylogenetic lineages representing the global MTBC diversity. In total, 100 sequence variations consisting of 96 single nucleotide polymorphisms (SNPs), three insertions and one deletion were detected resulting in 141 variable positions distributed over the entire gene. The majority of SNPs detected were non-synonymous (n = 68 vs. n = 28 synonymous). Strains from animal adapted lineages, e.g., M. bovis, showed a significant higher diversity than the human pathogens such as M. tuberculosis Haarlem. SNP patterns specific for different lineages as well as for deeper branches in the phylogeny could be identified. The results of our study demonstrate a high variability of the ppE18 gene even in the N-terminal domains that is normally highly conserved in ppe genes. As the N-terminal region interacts with TLR2 receptor inducing a protective anti-inflammatory immune response, genetic heterogeneity has a potential impact on the vaccine efficiency, however, this has to be investigated in future studies.
authors.affiliation: Molecular and Experimental Mycobacteriology, Research Center Borstel, Schleswig-Holstein, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Homolka
authors.affiliation: Molecular and Experimental Mycobacteriology, Research Center Borstel, Schleswig-Holstein, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Ubben
authors.affiliation: Molecular and Experimental Mycobacteriology, Research Center Borstel, Schleswig-Holstein, Germany.|German Centre for Infection Research (DZIF), Partner Site Borstel, Schleswig-Holstein, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Niemann
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D018740:Genetic Heterogeneity; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D020641:Polymorphism, Single Nucleotide; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C544170:Rv1196 protein, Mycobacterium tuberculosis; D051195:Toll-Like Receptor 2; D032581:Tuberculosis Vaccines