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The emergence of multiple drug resistant tuberculosis (MDR-TB) together with extensively drug resistant (XDR-TB) and now totally drug resistant tuberculosis (TDR-TB) presents a significant public health challenge. Yet, we still have a poor understanding of the finer details of the dynamics underlying this phenomenon. One of the group research interests is to make use of whole genome sequencing to describe the processes underlying the acquisition and dynamics of antimicrobial resistance in TB at various scales ranging from the within-host to the outbreak and even more global level.
• Mycobacterium tuberculosis (Mtb) is characterised by a low mutation rate and a lack of genetic recombination. Yet, the rise of extensively resistant strains paints a picture of a microbe with an impressive adaptive potential. To investigate further the evolutionary potential of Mtb at the within-host scale we recently took advantage of whole-genome sequences of nine serial Mtb isolated from the same patient. Interestingly, we describe the first documented case of extensively drug-resistant tuberculosis that evolved from a susceptible ancestor within a single patient. Further genomic investigations uncovered a dramatic turnover of competing lineages driven by the emergence, and subsequent fixation or loss of single nucleotide polymorphisms. We show that for most drugs, resistance arose through independent emergence of mutations in more than one clone, of which only one ultimately prevailed as the clone carrying it expanded, displacing the other clones in the process. The vast majority of mutations identified over 3.5 years were either involved in drug resistance or hitchhiking in the genetic background of these. This has major implications for inferring tuberculosis transmission events in situations where drug resistance evolves within transmission chains.
• Little is known about the extent of resistance in early years of chemotherapy and when transmission of resistant strains on a larger scale became a major public health issue. We recently used WGS to reconstruct the trajectory of drug resistance evolution within a major ongoing outbreak of multidrug-resistant TB in Argentina. By applying a Bayesian phylogenetic tip-dating approach, we were able to finely reconstruct the time-line of the acquisition of antimicrobial resistance at the outbreak scale. We find that the progenitor of the outbreak strain acquired resistance to isoniazid, streptomycin and rifampicin by 1973, demonstrating the continuous circulation of a multidrug-resistant TB strain for four decades. Five years later, the strain had acquired additional resistance to ethambutol, kanamycin and pyrazinamide. These results suggest that resistance to the most efficient drugs available at the time occurred at low rates about 15 years before the outbreak was detected among HIV co-infected patients, and about one decade before the earliest documented transmission of Mtb strains with such extensive resistance profiles globally. To prevent history from repeating itself over and over again with the evolution and transmission of new clones of drug resistant TB, the development and implementation of methods for rapid and accurate identification of resistance mutations are dearly needed for appropriate treatment of TB patients, optimally from day one following diagnosis.
• Mtb has been infecting humans for a long time, although no consensus has been reached yet on the age of this association. Previous models hypothesised that the human-adapted pathogen evolved from a zoonotic transfer of M. bovis following animal domestication during the Neolithic age. Comparative genomic analyses, however, suggest that the bovine form and those adapted to other animal hosts are in fact derived from human strains. This supports a rather different disease history where humans may have been the most susceptible host species for early progenitors of strains currently circulating. In two recent studies, the analyse of ancient genome obtained from 1000 year old Peruvian skeletons and 18th-century mummified human remains from Hungary respectively, suggested that the most recent common ancestor for the Mtb complex would have existed less than 6,000 years ago, which support a Holocene dispersal of the disease. This is in variance with the recovery of Mtb specific PCR-amplification products from Neolithic samples (ranging from between 9.000 to 17.000 years BP). By generating and analysing new genetic data for Mtb isolated from the Middle Ages to today, we aim to shed light on the historical evolution and spread of the disease over time.
