Deadly combination

Many factors affect the severity of tuberculosis in infected individuals. Among these are the genetic make-up of the bacterial strain, that of the host, and the interplay between the two.

A quick scan through this article might take five minutes of your time. During this period, 16 people will have died of tuberculosis, 80 will have fallen ill with it, and an astounding 800 will have become infected with the disease-causing pathogen Mycobacterium tuberculosis1. Yet, with only 1 in 10 of those infected developing tuberculosis in their lifetime, clearly most humans control the infection effectively. It is well known that resistance to tuberculosis depends on complex interactions among the host, the bacterium and the environment or culture. But the relative contributions of these factors, and the relationship between them, remain unclear. Work by Caws and colleagues2, published in PLoS Pathogens, is a first attempt at revealing the genetic contribution to interspecies communication between M. tuberculosis and its human host.

When bacteria reach human lungs — borne by tiny droplets from a cough or sneeze — they are usually engulfed and destroyed by the macrophage cells of the immune system. But M. tuberculosis has developed mechanisms to survive these assaults.

Detection of this pathogen by the pattern recognition receptor TLR-2 on the surface of macrophages (Fig. 1) induces a signalling cascade mediated by the TLR-2 adaptor protein TIRAP. Total activation of these primed macrophages is effected by soluble immune mediators, particularly IFN-γ, which is secreted by white blood cells known as T cells3. Fully activated macrophages fail to eradicate M. tuberculosis, but restrict its growth4. Consequently, the infected individual develops latent tuberculosis, remaining healthy while harbouring dormant bacteria.

Figure 1: Host and pathogen.


On reaching the host's lungs, cells of Mycobacterium tuberculosis (orange) bind to the TLR-2 receptor on the surface of a macrophage (green). Caws et al.2 speculate that polymorphisms both in the host genes (those encoding TLR-2 and its adaptor protein TIRAP) and in bacterial virulence factors (PGL and the DosR complex) affect the severity of tuberculosis. (Scale bar, 2 µm.)

Unfortunately, the pathogens can be resuscitated if the immune response diminishes, leading to pulmonary tuberculosis — the form of the disease that is confined to the lung and accounts for 80% of cases. When the bacteria reach the bronchial tree during active disease, the host becomes contagious. And once they infiltrate the bloodstream they can be dispersed to other organs. Meningeal tuberculosis, which affects the brain, is the most common (forming up to 30% of all cases) and the most hazardous form of extrapulmonary disease.

As early as the nineteenth century, it was assumed that genetic disposition contributes to the host's susceptibility to tuberculosis, but only recently were several culprit genes identified. These genes can be divided into two groups according to whether they contribute to acquired or innate immunity. Mutations in genes involved in acquired immunity, such as the IFN-γ-mediated signalling pathways3, are relatively rare but invariably lead to mycobacterial disease on infection — usually early in life. Genes modulating innate immunity operate more subtly, through natural genetic variations (polymorphisms), in both a synergistic and an antagonistic way. Examples of such genes include those encoding TLR-2 and TIRAP.

Polymorphisms are also rife among the different strains of M. tuberculosis. Different lineages of this bacterium exist that may have co-evolved in close relationship with a specific host population5. Also, separate bacterial families have developed within lineages. The Beijing family of the East Asian lineage, notorious for causing multidrug-resistant tuberculosis and spreading globally, is a noteworthy example.

Caws et al.2 analysed polymorphisms both in Vietnamese adults with pulmonary or meningeal tuberculosis and in M. tuberculosis strains isolated from these patients. Their observations are consistent with most, although not all, previous work linking6,7,8,9 polymorphisms in TLR-2/TIRAP with susceptibility to tuberculosis within the same and different ethnic groups in West Africa and Turkey. They report a close relationship between polymorphisms in the gene encoding TLR-2 and susceptibility to infection with the Beijing strain of bacterium. One particular TLR-2 polymorphism probably fails to mediate the full priming of macrophages, rendering individuals carrying it more susceptible to infection. The combination of a defective TLR-2 response and infection with the virulent Beijing strain is especially problematic, as it may increase the risk of extrapulmonary dissemination and severe meningeal tuberculosis. By contrast, Caws et al. report that the Euro-American lineage of M. tuberculosis mainly induces the less complicated pulmonary tuberculosis.

The Beijing strains also seem to have evolved additional virulence mechanisms to induce meningeal tuberculosis. These strains produce abundant phenolic glycolipids, which suppress innate immune responses10. Also, the activity of their DosR protein complex is increased. This complex regulates the expression of some 50 genes involved in facilitating the persistence of M. tuberculosis under conditions of stress11 — yet another survival factor enabling Beijing strains to resist the hostile milieu of activated macrophages. Thus, infection of a person who has an impaired TLR-2/TIRAP signalling system (through polymorphisms in genes encoding these proteins) with a more virulent strain of M. tuberculosis such as the Beijing strains (resulting from polymorphisms that lead to better chances of bacterial survival) could be a deadly combination.

Does the improved survival of the Beijing strains mean they are more likely to lead to meningeal tuberculosis? The number of subjects Caws et al. examined was too small to provide any conclusive evidence, but other studies have indicated an association between members of this family of bacteria and extrapulmonary tuberculosis12. Future studies of larger subject groups should unequivocally clarify the interrelationship between M. tuberculosis, host genotypes and the disease characteristics.

Many years after the discovery of the first antituberculosis drug streptomycin, and despite the availability of a childhood vaccine for the disease, M. tuberculosis is once again emerging as a deadly pathogen across the world. The dangerous liaison between AIDS and tuberculosis continues, and incidences of multidrug-resistant, and even extensively drug-resistant, tuberculosis are on the rise. The pipeline for new tuberculosis drugs is dry, and there is no sign that a vaccine for adult tuberculosis will be available for at least a decade.

It is to be hoped, therefore, that studies such as those of Caws et al.2 will further elucidate the multigenic interplay between humans and M. tuberculosis. Research will be aimed at deciphering the unknown factors underlying the transmission of M. tuberculosis from a patient with active tuberculosis to an uninfected individual. The development of new technologies enabling large-scale genetic screens is certainly timely. Perhaps differential gene expression will be found to contribute to both pathogen virulence and human susceptibility. Correlational studies of gene expression with analysis of functional gene products may provide definitive answers. Such studies will help to identify new drug targets and biomarkers.


  1. 1

  2. 2

    Caws, M. et al. PLoS Pathog. 4, e1000034 (2008).

  3. 3

    Quintana-Murci, L., Alcaïs, A., Abel, L. & Casanova, J.-L. Nature Immunol. 8, 1165–1171 (2007).

  4. 4

    Kaufmann, S. H. E. Nature Rev. Microbiol. 5, 491–504 (2007).

  5. 5

    Gagneux, S. & Small, P. M. Lancet Infect. Dis. 7, 328–337 (2007).

  6. 6

    Khor, C. C. et al. Nature Genet. 39, 523–528 (2007). | Article |

  7. 7

    Ogus, A. C. et al. Eur. Respir. J. 23, 219–223 (2004).

  8. 8

    Hawn, T. R. et al. J. Infect. Dis. 194, 1127–1134 (2006).

  9. 9

    Nejeutsev, S. et al. Nature Genet. 40, 261–262 (2007).| Article |

  10. 10

    Reed, M. B. et al. Nature 431, 84–87 (2004).

  11. 11

    Reed, M. B. et al. J. Bacteriol. 189, 2583–2589 (2007).

  12. 12

    Kong, Y. et al. J. Clin. Microbiol. 45, 409–414 (2007).

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kaufmann, S. Deadly combination. Nature 453, 295–296 (2008) doi:10.1038/453295a

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.