MRC National Institute for Medical Research, London
Science for Health
Mycobacterium tuberculosis does not change its spots
25 May 2010
Infection with M. tuberculosis causes enormous worldwide morbidity and mortality. Attempts to control tuberculosis through improved identification and treatment of infectious cases have been successful in some settings but similar approaches in other contexts have resulted in increasing rates of resistance to available antituberculosis drugs. New approaches to controlling tuberculosis are therefore needed and an improved understanding of the biology of the bacteria and their interactions with their human hosts would help the search for new approaches. In particular, understanding the factors that drive the evolution of M. tuberculosis and allow it to evade host defenses may suggest unique opportunities to develop novel strategies against tuberculosis.
The immune system plays a key role in protecting the human body from invading pathogens. One of the early 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.
Sebastien Gagneux (pictured) in NIMR’s Division of Mycobacterial Research, together with collaborators from the USA, Germany and the Netherlands, have studied whether Mycobacterium tuberculosis, the bacterium which causes human tuberculosis, uses a strategy of evasion to avoid being recognised by the human immune system. Using a novel high-throughput DNA sequencing method they analysed the whole genomes of 22 clinical strains of M. tuberculosis from different parts of the world. They then determined the number and types of mutations that occurred in antigens compared to other regions of the M. tuberculosis genome.
When they studied the genetic diversity of these strains of M. tuberculosis they were surprised to find that unlike many other human pathogens, antigens in M. tuberculosis were very homogeneous. This suggests that rather than trying 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.
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 that we have 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 it seems to be using our immune response to its own advantage as the lung damage and coughing which follows acts as an aerosol machine, spraying germs into the air and spreading the disease. They say a leopard never changes its spots!
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-cycle could have evolved similar strategies to manipulate the human immune system. This is a possibility which needs to be further studied.
Sebastien Gagneux
MTBC neighbour-joining phylogeny
Neighbour-joining phylogeny based on 9,037 variable common nucleotide positions across 21 human M. tuberculosis complex genome sequences. The tree is rooted with M. canettii, the closest known outgroup.
Original article
Iñaki Comas, Jaidip Chakravartti, Peter M Small, James Galagan, Stefan Niemann, Kristin Kremer, Joel D Ernst & Sebastien Gagneux. (2010)
Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved.
Nature Genetics , epub ahead of print. Publisher abstract
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