DNA Metabolism in Mycobacterial Pathogenesis

Abstract

Fundamental aspects of the lifestyle of Mycobacterium tuberculosis implicate DNA metabolism in bacillary survival and adaptive evolution. The environments encountered by M. tuberculosis during successive cycles of infection and transmission are genotoxic. Moreover, as an obligate pathogen, M. tuberculosis has the ability to persist for extended periods in a subclinical state, suggesting that active DNA repair is critical to maintain genome integrity and bacterial viability during prolonged infection. In this chapter, we provide an overview of the major DNA metabolic pathways identified in M. tuberculosis, and situate key recent findings within the context of mycobacterial pathogenesis. Unlike many other bacterial pathogens, M. tuberculosis is genetically secluded, and appears to rely solely on chromosomal mutagenesis to drive its microevolution within the human host. In turn, this implies that a balance between high versus relaxed fidelity mechanisms of DNA metabolism ensures the maintenance of genome integrity, while accommodating the evolutionary imperative to adapt to hostile and fluctuating environments. The inferred relationship between mycobacterial DNA repair and genome dynamics is considered in the light of emerging data from whole-genome sequencing studies of clinical M. tuberculosis isolates which have revealed the potential for considerable heterogeneity within and between different bacterial and host populations.

DNA Replication in Mycobacterium tuberculosis

“…Similarly, although it has not been directly investigated, it is tempting to speculate that the filamentous mycobacteria that develop during infection of macrophages (111, 112) might also be polyploid. It is worth noting, too, that separating concepts of cell division from chromosomal replication appears consistent with the idea that it may be simplistic to assume that mycobacterial metabolism (including DNA metabolism) has been selected to generate maximal bacillary numbers within a given microenvironment during host infection (23). As discussed previously, bacillary numbers determined from individual pulmonary lesions in a non-human primate model of TB suggest that the infecting population maintains a fairly consistent bacterial load throughout active disease (14), and that maximal growth may even be detrimental to the immediate fate of the infecting bacillus (individual host outcome) or to its long-term survival (evolutionary persistence within the human population).…”

“…It seems certain that intracellular dNTP concentrations must also play a critical role in determining the rate and fidelity of DNA replication in M. tuberculosis . However, while numerous studies have investigated the ribonucleotide reductase and thymidylate synthase enzymes responsible for the provision of dATP/dCTP/dGTP and dTTP, respectively (117–130), the measurement of dNTP pool sizes remains an elusive (23), but high-priority, research focus.…”

Deficiency of Double-Strand DNA Break Repair Does Not Impair Mycobacterium tuberculosis Virulence in Multiple Animal Models of Infection

“…These experiments were motivated by the attenuation phenotypes of other DNA repair-deficient M. tuberculosis strains in mice (3,4,36) and in other bacterial pathogens (37)(38)(39). In addition, the documented role of the mycobacterial NHEJ system in the repair of DSBs that arise in nonreplicating cells has logical potential relevance to latency, during which M. tuberculosis is thought to be nonreplicating.…”

DNA Replication in Mycobacterium tuberculosis

“…Finally, given that the regulation of DNA replication and its coordination with cell division are critical to cell cycle progression, we consider the impact of transient interruptions of DNA replication on mycobacterial drug susceptibility as well as the emergence and fixation of genetic mutations in a pathogen increasingly associated with multidrug resistance. As applies to all specialist review articles, the treatment in this case of DNA replication in M. tuberculosis and its potential role in pathogenesis is neither exhaustive nor definitive: the reader is encouraged to consult the large number of related articles on this subject, some of which are cited here as well (8,(20)(21)(22)(23)(24).…”