Tuberculosis (TB) is caused by a group of closely related Gram-positive bacilli, collectively known as the Mycobacterium tuberculosis
complex (MTBC). MTBC comprises the typical human pathogens M. tuberculosis
and Mycobacterium africanum
, as well as variants affecting various animal species. These animal pathogens include Mycobacterium bovis
(a pathogen of cattle), Mycobacterium caprae
(goats and sheep), Mycobacterium microti
(voles), and Mycobacterium pinnipedii
(seals and sea lions) [1
]. Contrary to many other pathogenic bacteria, MTBC does not have classical virulence factors such as recently acquired pathogenecity islands, nor does it produce any toxin. Yet, MTBC is able to efficiently infect, survive and transmit among hosts. According to estimates by the World Health Organization, one-third of the world’s human population is latently infected with MTBC, and 1.7 million people die of TB each year [2
]. The outcome of TB infection and diseases is highly variable, ranging from complete elimination of the bacteria by innate immunity to classical pulmonary disease, disseminated TB, and death. In 90% of the cases, the infection remains latent, while 10% will develop active disease at some point during their lifetime [3
]. The intimate cross-talk between the bacteria and the host immune system is one of the main complexities determining these variable outcomes [4
]. In order to better control TB globally, new tools are urgently needed, in particular better diagnostics, new antibiotics, and better vaccines [5
In most parts of the world, active TB is still being diagnosed by sputum microscopy [5
]. However, this technique has a limited sensitivity, and up to 50% of cases are routinely missed. Although bacterial culture is the current gold standard for detecting TB, this technique takes up to 4 weeks, and requires skilled technicians and well-equipped laboratories, all of which are rarely available in developing countries. Fortunately, novel and highly sensitive molecular tools are being developed which show great promise for rapid detection of active TB [6
]. One additional difficulty in diagnosing TB is to reliably differentiate between latent and active disease. Contrary to the traditional view considering TB as a simple binary state of active versus latent disease, the manifestation of TB is currently thought to represent a whole spectrum of infection [7
] (). Ideally, biomarkers should be available that allow classifying patients according to this spectrum [8
]. Such biomarkers would be particularly valuable if they allowed identifying infected individuals most likely to progress to active TB. A recent study suggests this may become possible [9
MTBC strain variation and the spectrum of responses to TB
Apart from the difficulties in diagnosing TB, the standard treatment against TB is also complicated, as it involves a six month regimen with multiple antibiotics. Long-term treatments are inherently problematic, as patient non-adherence or drug shortages can lead to the development of drug resistance [10
]. Drug-resistant strains of MTBC started to appear shortly after the introduction of streptomycin in 1943 [11
]. Today, many regions of the world report increases in multidrug-resistant TB, and some MTBC strains are now resistant to all available drugs [12
]. Adding to the problem of drug-resistant TB is that no new anti-TB drug has been licensed since the discovery of ethambutol in the 1960s. Following the onset of the HIV epidemic in the early 1980s, overconfidence regarding old antibiotics combined with long-term neglect in TB research and surveillance led to a re-emergence of the disease in the developed world [13
]. While in the developing world TB presumably never had actually declined, HIV had a dramatic impact on TB incidence, particularly in sub-Saharan Africa. Fortunately, the development of new drugs and shorter treatment regimens against TB are back on the agenda [14
In addition to new diagnostics and new antimicrobials, a better vaccine against TB is urgently needed. Considering the large pool of latently infected individuals [3
], prevention of TB infection and disease through vaccination might be the only realistic way of controlling global TB in the long run. However, the Bacille Calmette-Guérin (BCG) vaccine is the only currently approved vaccine against TB and it has a questionable efficiency against pulmonary TB in adults, ranging from 0 to 80% [15
]. Yet, BCG remains the most widely used vaccine in the world because it protects children against TB meningitis, the most severe form of the disease [16
]. BCG was derived in the first quarter of the 20th century from a virulent strain of M. bovis
. The reasons for the observed variation in protective efficacy of BCG are unclear, although differences among BCG strains, exposure to environmental mycobacteria, and human genetic diversity have been invoked [15
]. Currently, several new vaccine candidates are at various stages of development [17
]. Yet, despite significant progress over the past 20 years, a new and broadly effective vaccine against TB will not be available any time soon. A significant hurdle in TB vaccinology is our limited understanding of what constitutes protective immunity (Box 1
). This, as well as many other important gaps of knowledge will need to be filled before an effective TB vaccine can become a reality [18
BOX 1. Outstanding questions
- What is latent TB?
- What constitutes protective immunity in TB?
- How can individuals be categorized within the spectrum of latent and active TB?
- How does infection with different strains affect the likelihood of being in a different state of the spectrum?
- What is the role of CD4+ and CD8+ responses in promoting TB transmission?
- How will the ongoing changes in human demography influence the evolution of MTBC in the future?
There is increasing consensus among the TB research community that systems biology will play an important role in generating new insights relevant to the development of new diagnostics, drugs, and vaccines against TB [5
]. The chronic nature of the disease, characterized by a complex dialog between the host immune system and the pathogen, combined with features such as latency, a complex mycobacterial cell wall, and the phenomenon of antimicrobial persistence, all call for more comprehensive approaches to study the biology of TB (Box 1
). In this review, we start by briefly reviewing recent advances in applying systems biology to TB research. We then discuss why systems biology should be combined with complementary approaches to understand and control TB globally. Finally, we review recent data on the genetic diversity and evolution of MTBC, and end by proposing a new hypothesis on the evolution of virulence in MTBC, which, if confirmed, could impact the future spread and control of TB in the world..