Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved

Nature Genetics, advance online publication May 23, 2010
doi: 10.1038/ng.590

Iñaki Comas¹, Jaidip Chakravartti², Peter M Small³, James Galagan⁴, Stefan Niemann⁵, Kristin Kremer⁶, Joel D. Ernst² and Sebastien Gagneux<sup>1,a, b

1</sup>Medical Research Council, National Institute for Medical Research, London, UK
²New York University School of Medicine, New York, New York, USA
³The Institute for Systems Biology and the Bill and Melinda Gates Foundation, Seattle, Washington, USA
⁴Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA
⁵Research Centre Borstel, Molecular Mycobacteriology, Borstel, Germany
⁶Mycobacteria Reference Laboratory (CIb-LIS), National Institute for Public Health and the Environment, Bilthoven, The Netherlands
^aSwiss Tropical and Public Health Institute, Basel, Switzerland
^bUniversity of Basel, Basel, Switzerland

Genome Sequencing Yields Surprising Insight that Mycobacterium tuberculosis Might Benefit from Recognition by Human T cells

A Brief Overview of this Study

The immune system plays a key role in protecting the human body from invading pathogens. One of the earlier steps in the mechanism of protection involves the recognition by the immune system of particular components of pathogens. These pathogen components are known as antigens. However, many pathogens can evade this immune recognition by varying their antigens. This strategy of "immune evasion" is common to many viruses and bacteria, and is the reason, for example, that a new flu vaccine has to be developed each year.

We studied whether Mycobacterium tuberculosis, the bacterium which causes human tuberculosis, uses a similar strategy to avoid being recognized by the human immune system. Tuberculosis is primarily a disease of the lung, and the lung destruction caused by tuberculosis and the resulting cough, helps spread the bacteria through the air.

We used a novel high-throughput DNA sequencing method to analyse the whole genomes of 22 clinical strains of M. tuberculosis from different parts of the world. We then determined the number and types of mutations that occurred in antigens compared to other regions of the M. tuberculosis genome.

When we studied the genetic diversity of several globally representative strains of M. tuberculosis, we found, to our surprise, that contrary to many other human pathogens, antigens in M. tuberculosis were very homogeneous. This suggests that, rather than to escape recognition, M. tuberculosis wants to be recognized by the immune system, perhaps because the host immune mechanisms that lead to the typical lung destruction and cough in tuberculosis can contribute to the spread of M. tuberculosis. These findings are new and very unexpected.

Based on findings in bacteria and viruses, antigens of pathogens are generally thought to be highly variable. Our study demonstrates that this is not always the case and that in M. tuberculosis these antigens are very conserved. These results are counterintuitive, and will possible change the view by which researchers will approach the subject of host-pathogen interaction in tuberculosis and other diseases. Our findings suggest that M. tuberculosis employs a particular strategy of immune-subversion which is distinct from the "classical" way of immune-evasion through accumulation of antigenic diversity. Other pathogens which share a similar life style could have evolved similar strategies to manipulate the human immune system. This is a possibility which needs to be further studied.

Tuberculosis is one of the most important infectious diseases worldwide, killing someone every 15 seconds. The global epidemics of tuberculosis are worsening as a consequence of the emergence of drug resistance. New tools and strategies are urgently needed to combat these growing epidemics. Our findings have important implications for the development of new diagnostic tests and vaccines against tuberculosis. Some of the new diagnostic tests and vaccines currently under development target some of the antigens we found to be highly conserved. This is good news for the new diagnostic tests, as these tests are likely to detect tuberculosis even in region where the strains of M. tuberculosis are known to differ. By contrast, for vaccine research, our findings are more worrisome. The fact that M. tuberculosis does not need to change its antigens indicates that the immune recognition of these antigens offer a benefit to the pathogen and therefore should not be included in vaccines.

Read the news announcement by the Office of Communications and Public Affairs.


Image (top): Colorized scanning electron micrograph (SEM) depicts some of the ultrastructural details seen in the cell wall configuration of a number of Gram-positive Mycobacterium tuberculosis bacteria. The bacterium ranges in length between 2-4 microns, and a width between 0.2-0.5 microns. (Image courtesy of Centers for Disease Control and Prevention / Dr. Ray Butler, photo by Janice Haney Carr, 2006)