Lessons from molecular epidemiology and comparative genomics

Molecular biology has revolutionized the field of tuberculosis (TB) research. Comparative genomics and molecular epidemiology are providing revelations about the evolutionary origins of Mycobacterium tuberculosis and phylogenetic relationships between different strains and strain families. Accumulating evidence indicates that distinct strains of M tuberculosis (genotype) may be associated with differential transmissibility, virulence, and/or clinical manifestations (phenotype). As advances in our understanding of the relationships between genotype and phenotype progress, this knowledge will have important ramifications for TB control and the development of novel vaccines and improved diagnostics. Some of the greatest advantages of molecular epidemiological methods include our abilities to follow transmission of particular strains within communities, track epidemics, and recognize the presence of historic outbreaks. Moreover, there are critical questions about TB that are essentially unanswerable in the absence of molecular techniques. These include our capacity to distinguish exogenous reinfection from endogenous reactivation in recurrent TB cases and to recognize primary transmission of drug resistant strains versus the acquisition of drug resistance via de novo mutations. Finally, an elucidation of the phylogenetic structure and evolutionary history of M. tuberculosis provides a necessary background for understanding the underlying mechanisms responsible for the continued success of this deadly pathogen.