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Whole-genome immunoinformatic analysis of Mycobacterium tuberculosis towards large scale identification of immunodominant CD8 epitopes

Published: 02 August 2010 Publication History

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, infects ~8 million annually culminating in ~2 million deaths. Moreover, about one third of the population is latently infected, 10% of which develop disease during lifetime. Current approved prophylactic TB vaccines (BCG and derivatives thereof) are of variable efficiency in adult protection against pulmonary tuberculosis (0%--80%), and directed essentially against early phase infection. It is well established that cellular immunity plays a pivotal role against intracellular bacterial infections, such as tuberculosis. The limited knowledge existing to date on Mtb antigens recognized by T-cells in general and CD8 in particular, motivates an in-depth, genome-scale identification and analysis of potential CTL epitopes, in order to map the immunodominant determinants responsible for shaping the cellular response elicited by Mtb. Such an analysis should allow the design of a synthetic peptide library enriched for genomic regions containing promiscuous HLA-I predicted epitopes. Accordingly, we have developed a comprehensive immunoinformatic analysis for mapping of clusters of CTL epitopes. The 3989 Mtb H37Rv ORF products were scanned for putative 9-11mers binders to 12 HLA-I supertypes, using the ANN-based NetMHC-3.0 program. In order to maximize the number of "promising" epitopes in the library, a comprehensive analysis tool was developed for mapping clusters of CTL binders and visualization of "hotspots" of epitopes. The ~30,000 mapped clusters, containing at least two consecutive, overlapping predicted binders, were subsequently prioritized by employing a ranking strategy based on measures such as epitope density, median binding affinity, allelic coverage and processing. Different scoring schemes were tested, assessing the sensitivity and relative impact of each of the measures employed on the composition of the final 15mer library generated. Finally, a total score was calculated for each cluster, and the top-ranking clusters were selected as the basis for compilation of a final synthetic library of 40,000 15mer peptides. Such a library contains actually a much larger number (~140,000) of putative, promiscuous HLA-I binders, demonstrating the power of the clustering approach in enrichment of potential immune-determinants per library. Validation of these in silico preselected epitopes and antigens awaits ex vivo examination of the peptides in the library for their response with Mtb-specific T cells.

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cover image ACM Conferences
BCB '10: Proceedings of the First ACM International Conference on Bioinformatics and Computational Biology
August 2010
705 pages
ISBN:9781450304382
DOI:10.1145/1854776
Permission to make digital or hard copies of all or part of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. Copyrights for components of this work owned by others than ACM must be honored. Abstracting with credit is permitted. To copy otherwise, or republish, to post on servers or to redistribute to lists, requires prior specific permission and/or a fee. Request permissions from [email protected]

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Association for Computing Machinery

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Published: 02 August 2010

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