Human Metapneumovirus and Chronic Obstructive Pulmonary Disease

Merchant et al., by using ung+ and ung– Escherichia coli strains, demonstrated that total nitric oxide exposures in the μmol/L range can lead to C→T mutations by a mechanism probably involving cytosine deamination (8). On the other hand, in M. smegmatis, the abrogation of the Ung activity leads not only to increased mutator phenotype but also to growth inhibition by reactive nitrogen intermediates (7). In summary, I speculate that mutations in ung that do not completely impair function, but do decrease synthesis of its product, might tolerably increase the spontaneous C→T mutations, including those in the respective positions in the rpoB codons 531 and 526. This assumption seems likely because both of the aforementioned particular mutations were described in spontaneous mutants of H37Rv obtained in vitro and had a Darwinian fitness slightly less than or equal to that of the rpoB wild-type-susceptible parental strain (9). In contrast, the translesion synthesis-based pathways appear less likely to contribute to emergence of such mutants, although at least one of the translesion synthesis genes (dinP) is present in the genome of M. tuberculosis. In the E. coli in vitro model, a translesion synthesis enzyme (dinB encoded DNA polymerase IV) activity clearly promoted more important frameshift mutations (single-base deletions) in two thirds of the spontaneous mutants (10). From an evolutionary point of view, the multiple rpoB mutations in M. tuberculosis have been hypothesized to arise as a compensatory mechanism to ameliorate the fitness costs of the original resistance mutation by a secondary mutation (11). The process of adaptation to the fitness costs of chromosomally encoded resistance has been studied in E. coli and Salmonella enterica serovar Typhi for mutations that affect translation in the rpsL and fusR genes (11) and for rpoB mutations in E. coli K12 strain (11). In the last instance, the rpoB multiple mutants were selected in vitro in a stepwise fashion, and one double mutant, L511Q+D516G (also described in M. tuberculosis strain [3]), exhibited a relative fitness either greater than or equal to either single mutant or the wild type. Reynolds (11) suggested that this allele is favored not merely as a combination of two low-level resistance mutations but also because these mutations together boost resistance and preserve fitness. Whether the same is true for other multiple mutant alleles in M. tuberculosis rpoB remains to be seen. Studying the costs of resistance of multiple rpoB mutations in a more realistic environment of animal models of TB infection seems promising.