Science for Health
03 January 2013
NIMR researchers have explored a novel means to identify antigenic targets that might contribute to a vaccine against TB. The research is published in Journal of Immunology and is a featured article.
Tuberculosis (TB) is a major killer. In 2010, there were 8.8 million cases of TB and nearly 1.5 million deaths from TB. Furthermore, one third of the world’s population is infected with Mycobacterium tuberculosis (Mtb), the causative organism of TB, but shows no symptoms. This pool of latent infection forms a reservoir from which active TB disease will continue to develop, forming a major obstacle to achieving control.
Lack of understanding of the biology of Mtb is a major obstacle to vaccine development. Therefore, studying Mtb antigens (Ags) is a priority in order to identify vaccine candidates that might elicit a protective immune response.
Several studies have shown that M. tuberculosis adapts to oxygen limitation by adoption of a non-replicating persistent state. These observations led to the models of latency and reactivation that suggest a prominent role for oxygen status in the biology of M. tuberculosis. In vitro culture models represent conditions that tubercle bacilli are thought to encounter in vivo during persistence in the immune-competent host.
Robert Wilkinson, from NIMR's Division of Mycobacterial Research and the University of Cape Town, worked with NIMR's Douglas Young and collaborators from Cape Town, Seattle and Imperial College London. The researchers analysed whole genome–based transcriptional profiles of Mycobacterium tuberculosis that had been subjected to prolonged hypoxia. They identified what they called the "enduring hypoxic response" (EHR) and identified a set of genes as potential Ags, by using a combined bioinformatic and immunological approach. This showed that Ags could be predicted, providing transcriptomic data were combined with peptide-binding prediction adjusted by population-specific MHC class II allele frequency.
This is the first evaluation of the ability of EHR genes to induce a human T cell response. We have identified novel immunodominant molecules that could be characterized further to better understand the mechanism and importance of hypoxia in vivo. Overall, our findings support the hypothesis that it is possible to predict Ags using genomic data, provided that combinations are taken into account. This approach may be applicable to other pathogens.
The article is featured in the "In This Issue" section of Journal of Immunology, which highlights articles that are among the top 10% of articles published in the journal. A corresponding ImmunoCast of "In This Issue" is also produced for each issue and can be found on the journal's web site.
Bioinformatic and Empirical Analysis of Novel Hypoxia-Inducible Targets of the Human Antituberculosis T Cell Response
Hannah P. Gideon, Katalin A. Wilkinson, Tige R. Rustad, Tolu Oni, Heinner Guio, David R. Sherman, H. Martin Vordermeier, Brian D. Robertson, Douglas B. Young and Robert J. Wilkinson (2012)Journal of Immunology, 189(12):5867-76 PubMed abstract
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