Mycobacterium Tuberculosis Evolutionary Pathogenesis and its Putative Impact on Drug Development

Fabien Le Chevalier; Alessandro Cascioferro; Laleh Majlessi; Jean Louis Herrmann; Roland Brosch


Future Microbiol. 2014;9(8):969-985. 

In This Article

Future Perspective

In order to predict future trends, it might be useful to look back some years and evaluate whether the current situation of research and development could have been predicted. Research within the last 20 years since TB was declared a global emergency by the WHO in 1993[26] has contributed to the enormous gain of knowledge regarding the causative agent of TB and its interactions with its host. Apart from the fact that some of these recent advances of mycobacterial research and technology have already been translated into applications with direct impact on diagnosis (e.g., IFN-γ release assays) or treatment (e.g., bedaquiline), the situation concerning TB research has profoundly changed in recent years concerning our knowledge regarding the evolution, genomics and genetics of M. tuberculosis, the disease-causing processes related to host–pathogen interactions and the discovery of new molecules, immunogens and drug targets. For example, today it is very difficult to imagine biological and medical research without access to genome data and all of the data produced by follow-up strategies, such as genome-wide transposon insertion screens, transcriptome analyses and structural biology approaches, among others. The broad impact of the genome sequence for the mycobacterial research community is reflected in the fact that the publication presenting the first complete genome sequence of M. tuberculosis (H37Rv)[11] represents the most cited article in the field of TB research at more than 4000 citations. The use of genome sequencing has been refined in recent years, as NGS approaches have allowed the cost of genome sequencing to be dramatically reduced. The reduced costs and technical advances opened the NGS technologies up for use in the sequencing of the genomes of many different M. tuberculosis isolates, thereby allowing the phylogenetic reconstruction of the global M. tuberculosis strains to be refined.[28] NGS also showed that epidemiological tracing of M. tuberculosis-caused outbreaks could be carried out in much greater detail than with the previously used molecular typing methods,[115,116] a finding that could revolutionize epidemiological studies of M. tuberculosis outbreaks in the near future.

Recent research on virulence factors and the fate of M. tuberculosis in the phagosome has elucidated many of the key features of mycobacterial host–pathogen interactions. While M. tuberculosis was considered until very recently to be a pathogen that, during the infection of phagocytic cells, resides exclusively in the phagovacuole, technical advances in cryoelectron microscopy and single-cell assays based on fluorescence imaging suggested that M. tuberculosis breaks the phagosomal membrane and accesses the cytosol of the host cell at later stages of infection.[84,85,89] Future research will certainly further refine these observations and link them to the survival strategy of M. tuberculosis, with central importance being given for the induction of host-cell death and bacterial spread. Future therapeutic strategies that would prevent the rupture of M. tuberculosis-containing phagovacuoles could have a strong impact on the outcome of infection. In order to identify new molecules with such activity, phenotypic cell-based assays, which use automated confocal fluorescence microscopy for the high-throughput screening of chemicals that interfere with the replication of M. tuberculosis within macrophages,[43] could be used. An adaptation of this method, which was successfully employed to identify acyl-trehalose-containing glycolipids involved in phagosome remodeling,[114] might well be used for finding factors that might interfere with the induction of phagosomal rupture and related cellular processes. As mentioned above, this method has the great advantage of simultaneously observing the behavior of the bacterial invader and the defense strategies of the host cell, which is thus a very promising technology for future applications.

Looking at the advances in biomedical research of the last few years, which would have been difficult to foresee 20 years ago, the outlook for the future may only be very vague. In order to cope with the global problem of TB, combination strategies might be most advantageous. The trend in human medicine is to individualize treatment, and this might also apply for the prevention and treatment of TB cases. TB is a highly complex disease, with the complexity arising from the varied immunological and nutritional status of the individual, the type of M. tuberculosis strains circulating in the community, the presence of drug resistance and the social environment, among other factors. In this context, it might be best to combine treatment with immunotherapies (i.e., immunization strategies that would add an additional layer of immune defense to the action of conventional or novel anti-TB drugs). However, care has to be taken in order to avoid inducing a so-called Koch phenomenon, which corresponds to the development of necrotic lesions as a result of hypersensitivity to products of the tubercle bacillus. In addition, the use of molecules that would act against the pathogenicity factors of M. tuberculosis might be a very useful addition to such combinatorial treatment strategies. The last 20 years of TB research have unravelled numerous new details regarding the pathogen and its interactions with the host that are beginning to find practical applications for patients. Apart from increasing the social standards of the populations that are most affected by high infection rates with M. tuberculosis, it is to be hoped that the next 20 years of TB research will reveal even more secrets of the TB pathogen that can be used in the continued fight against TB. We should not make the mistake of the 1970s again, which would be to underestimate the adaptability of this pathogen, whose evolution is directly linked with human evolution. High-quality TB research will have to continue to cope with today's situation and find novel innovative solutions for future trends.