Abstract
Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10−10 mutations/bp/generation for recently transmitted tuberculosis and 7.3X10−11 mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10−11 mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques.
Highlights
One-third of the world’s population is asymptomatically infected with Mycobacterium tuberculosis [1]
We looked for additional ways to test whether O and S were caused by reactivation of a latent infection acquired from X around 1990, or were instead acquired more recently from Rangipo strains circulating in the community during the past decade
We found that the mutation rate during the modeled latent period at a generation time of 240 hours was lower than the mutation rate at a generation time of 18 hours during the modeled two years before disease period. These results strongly suggest that replication rates and/or mutation rates are markedly lower during the latent stage of disease compared to the two-year period up to and including active tuberculosis
Summary
One-third of the world’s population is asymptomatically infected with Mycobacterium tuberculosis [1]. Recent immunological studies of latent tuberculosis suggest that latency encompasses a disease spectrum that extends from nonreplicating persisting organisms, to replicating but asymptomatic infections, to low level-disease with higher numbers of actively replicating bacteria [2] [3]. Non-replicating organisms are much more tolerant to these drug classes [4] [5]. Another unknown feature of latency is the mutational capacity of the latent M. tuberculosis bacilli. The presumed intracellular location and prolonged exposure of latently infecting M. tuberculosis to reactive effecter molecules of the host immune system could predispose latent organisms to enhanced rates of mutation [6]. Our understanding of replication and mutagenesis in latent M. tuberculosis has clear implications for treatment strategies to eradicate latency
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