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      Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved

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          Abstract

          Mycobacterium tuberculosis is an obligate human pathogen capable of persisting in individual hosts for decades. To determine whether antigenic variation and immune escape contribute to the success of M. tuberculosis, we determined and analyzed 22 genome sequences representative of the global diversity of the M. tuberculosis complex (MTBC). As expected, we found that essential genes in MTBC were more evolutionarily conserved than non-essential genes. Surprisingly however, most of 491 experimentally confirmed human T cell epitopes showed little sequence variation and exhibited a lower ratio of non-synonymous to synonymous changes than essential and non-essential genes. These findings are consistent with strong purifying selection acting on these epitopes, and imply that MTBC might benefit from recognition by human T cells.

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          Most cited references35

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          Genes required for mycobacterial growth defined by high density mutagenesis.

          Christopher Sassetti, Dana Boyd, Eric Rubin (2003)
          Despite over a century of research, tuberculosis remains a leading cause of infectious death worldwide. Faced with increasing rates of drug resistance, the identification of genes that are required for the growth of this organism should provide new targets for the design of antimycobacterial agents. Here, we describe the use of transposon site hybridization (TraSH) to comprehensively identify the genes required by the causative agent, Mycobacterium tuberculosis, for optimal growth. These genes include those that can be assigned to essential pathways as well as many of unknown function. The genes important for the growth of M. tuberculosis are largely conserved in the degenerate genome of the leprosy bacillus, Mycobacterium leprae, indicating that non-essential functions have been selectively lost since this bacterium diverged from other mycobacteria. In contrast, a surprisingly high proportion of these genes lack identifiable orthologues in other bacteria, suggesting that the minimal gene set required for survival varies greatly between organisms with different evolutionary histories.
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            Genetic requirements for mycobacterial survival during infection.

            C M Sassetti, E. J. Rubin (2011)
            Despite the importance of tuberculosis as a public health problem, we know relatively little about the molecular mechanisms used by the causative organism, Mycobacterium tuberculosis, to persist in the host. To define these mechanisms, we have mutated virtually every nonessential gene of M. tuberculosis and determined the effect disrupting each gene on the growth rate of this pathogen during infection. A total of 194 genes that are specifically required for mycobacterial growth in vivo were identified. The behavior of these mutants provides a detailed view of the changing environment that the bacterium encounters as infection proceeds. A surprisingly large fraction of these genes are unique to mycobacteria and closely related species, indicating that many of the strategies used by this unusual group of organisms are fundamentally different from other pathogens
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              Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature.

              G. A. Colditz, T Brewer, C S Berkey … (1994)
              To quantify the efficacy of BCG vaccine against tuberculosis (TB). MEDLINE with index terms BCG vaccine, tuberculosis, and human. Experts from the Centers for Disease Control and Prevention and the World Health Organization, among others, provided lists of all known studies. A total of 1264 articles or abstracts were reviewed for details on BCG vaccination, concurrent vaccinated and unvaccinated groups, and TB outcome; 70 articles were reviewed in depth for method of vaccine allocation used to create comparable groups, equal surveillance and follow-up for recipient and concurrent control groups, and outcome measures of TB cases and/or deaths. Fourteen prospective trials and 12 case-control studies were included in the analysis. We recorded study design, age range of study population, number of patients enrolled, efficacy of vaccine, and items to assess the potential for bias in study design and diagnosis. At least two readers independently extracted data and evaluated validity. The relative risk (RR) or odds ratio (OR) of TB provided the measure of vaccine efficacy that we analyzed. The protective effect was then computed by 1-RR or 1-OR. A random-effects model estimated a weighted average RR or OR from those provided by the trials or case-control studies. In the trials, the RR of TB was 0.49 (95% confidence interval [CI], 0.34 to 0.70) for vaccine recipients compared with nonrecipients (protective effect of 51%). In the case-control studies, the OR for TB was 0.50 (95% CI, 0.39 to 0.64), or a 50% protective effect. Seven trials reporting tuberculous deaths showed a protective effect from BCG vaccine of 71% (RR, 0.29; 95% CI, 0.16 to 0.53), and five studies reporting on meningitis showed a protective effect from BCG vaccine of 64% (OR, 0.36; 95% CI, 0.18 to 0.70). Geographic latitude of the study site and study validity score explained 66% of the heterogeneity among trials in a random-effects regression model. On average, BCG vaccine significantly reduces the risk of TB by 50%. Protection is observed across many populations, study designs, and forms of TB. Age at vaccination did not enhance predictiveness of BCG efficacy. Protection against tuberculous death, meningitis, and disseminated disease is higher than for total TB cases, although this result may reflect reduced error in disease classification rather than greater BCG efficacy.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9216904
                Journal ID (pubmed-jr-id): 2419
                Journal ID (nlm-ta): Nat Genet
                Journal ID (iso-abbrev): Nat. Genet.
                Title: Nature genetics
                ISSN (Print): 1061-4036
                ISSN (Electronic): 1546-1718
                Publication date Nihms-submitted: 1 May 2010
                Publication date (Electronic): 23 May 2010
                Publication date (Print): June 2010
                Publication date PMC-release: 01 December 2010
                Volume: 42
                Issue: 6
                Pages: 498-503
                Affiliations
                [1 ]Medical Research Council, National Institute for Medical Research, London, NW7 1AA, UK
                [2 ]New York University School of Medicine, New York, NY 10016, USA
                [3 ]The Institute for Systems Biology and the Bill and Melinda Gates Foundation, Seattle, WA 98102, USA
                [4 ]Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
                [5 ]Research Centre Borstel, Molecular Mycobacteriology, 23845 Borstel, Germany
                [6 ]Mycobacteria Reference Laboratory (CIb-LIS), National Institute for Public Health and the Environment, 3720 BA Bilthoven, The Netherlands
                [7 ]Swiss Tropical and Public Health Institute, 4002 Basel, Switzerland
                [8 ]University of Basel, 4003 Basel, Switzerland
                Author notes
                [* ]To whom correspondence should be addressed. sebastien.gagneux@ 123456unibas.ch , joel.ernst@ 123456med.nyu.edu

                AUTHOR CONTRIBUTION STATEMENTS

                I.C., J.D.E. and S.G. designed the study; P.M.S., S.N., K.K. and S.G. contributed sources of M. tuberculosis DNA and demographic information; I.C., J.C. and J.G. performed DNA sequencing and bioinformatics; I.C., P.M.S., J.D.E. and S.G. wrote the manuscript with comments from all authors.

                Article
                Manuscript ID: UKMS29888
                DOI: 10.1038/ng.590
                PMC ID: 2883744
                PubMed ID: 20495566
                SO-VID: c70f8bf3-dd6c-485d-9a02-1736faff9d61
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: Medical Research Council :
                Award ID: U117588500(88500) || MRC_
                Categories
                Subject: Article

                ScienceOpen disciplines: Genetics
                Data availability:
                ScienceOpen disciplines: Genetics

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