Abstract:Mycobacterium tuberculosis remains a leading cause of death worldwide, especially among individuals infected with HIV1. While phylogenetic analysis has revealed M. tuberculosis spread throughout history2–5 and in local outbreaks6–8, much less is understood about its dissemination within the body. Here, we report genomic analysis of 2693 samples collected postmortem from lung and extrapulmonary biopsies of 44 subjects in KwaZulu-Natal, South Africa who received minimal antitubercular treatment and most of whom … Show more
“…The majority of the detected sequence heterogeneity therefore resulted from an abundance of rare alleles in the population—approximately 80% of the total heterogeneity was accounted for by v-SNPs with a frequency of less than 20%. This degree of variation is higher than reported previously [54–56] and shows that MTBC might explore its mutational space to a greater extent than previously thought. Importantly, the intra-patient SFS was very similar to the inter-host SFS reported by Pepperell and colleagues [57], suggesting that forces shaping the diversity at the host population level are already prominent within patients, before the bottleneck of transmission.Fig.…”
BackgroundCombination therapy is one of the most effective tools for limiting the emergence of drug resistance in pathogens. Despite the widespread adoption of combination therapy across diseases, drug resistance rates continue to rise, leading to failing treatment regimens. The mechanisms underlying treatment failure are well studied, but the processes governing successful combination therapy are poorly understood. We address this question by studying the population dynamics of Mycobacterium tuberculosis within tuberculosis patients undergoing treatment with different combinations of antibiotics.ResultsBy combining very deep whole genome sequencing (~1000-fold genome-wide coverage) with sequential sputum sampling, we were able to detect transient genetic diversity driven by the apparently continuous turnover of minor alleles, which could serve as the source of drug-resistant bacteria. However, we report that treatment efficacy has a clear impact on the population dynamics: sufficient drug pressure bears a clear signature of purifying selection leading to apparent genetic stability. In contrast, M. tuberculosis populations subject to less drug pressure show markedly different dynamics, including cases of acquisition of additional drug resistance.ConclusionsOur findings show that for a pathogen like M. tuberculosis, which is well adapted to the human host, purifying selection constrains the evolutionary trajectory to resistance in effectively treated individuals. Nonetheless, we also report a continuous turnover of minor variants, which could give rise to the emergence of drug resistance in cases of drug pressure weakening. Monitoring bacterial population dynamics could therefore provide an informative metric for assessing the efficacy of novel drug combinations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1196-0) contains supplementary material, which is available to authorized users.
“…The majority of the detected sequence heterogeneity therefore resulted from an abundance of rare alleles in the population—approximately 80% of the total heterogeneity was accounted for by v-SNPs with a frequency of less than 20%. This degree of variation is higher than reported previously [54–56] and shows that MTBC might explore its mutational space to a greater extent than previously thought. Importantly, the intra-patient SFS was very similar to the inter-host SFS reported by Pepperell and colleagues [57], suggesting that forces shaping the diversity at the host population level are already prominent within patients, before the bottleneck of transmission.Fig.…”
BackgroundCombination therapy is one of the most effective tools for limiting the emergence of drug resistance in pathogens. Despite the widespread adoption of combination therapy across diseases, drug resistance rates continue to rise, leading to failing treatment regimens. The mechanisms underlying treatment failure are well studied, but the processes governing successful combination therapy are poorly understood. We address this question by studying the population dynamics of Mycobacterium tuberculosis within tuberculosis patients undergoing treatment with different combinations of antibiotics.ResultsBy combining very deep whole genome sequencing (~1000-fold genome-wide coverage) with sequential sputum sampling, we were able to detect transient genetic diversity driven by the apparently continuous turnover of minor alleles, which could serve as the source of drug-resistant bacteria. However, we report that treatment efficacy has a clear impact on the population dynamics: sufficient drug pressure bears a clear signature of purifying selection leading to apparent genetic stability. In contrast, M. tuberculosis populations subject to less drug pressure show markedly different dynamics, including cases of acquisition of additional drug resistance.ConclusionsOur findings show that for a pathogen like M. tuberculosis, which is well adapted to the human host, purifying selection constrains the evolutionary trajectory to resistance in effectively treated individuals. Nonetheless, we also report a continuous turnover of minor variants, which could give rise to the emergence of drug resistance in cases of drug pressure weakening. Monitoring bacterial population dynamics could therefore provide an informative metric for assessing the efficacy of novel drug combinations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1196-0) contains supplementary material, which is available to authorized users.
“…Similar results were recently published that reveal evidence of both purifying selection and genome diversification in M . tuberculosis isolates obtained from distinct lesions and organs of HIV-coinfected humans that succumbed to infection[39]. Thus, in another context, prolonged infection leads to increased M .…”
Molecular epidemiological assessments, drug treatment optimization, and development of immunological interventions all depend on understanding pathogen adaptation and genetic variation, which differ for specific pathogens. Mycobacterium tuberculosis is an exceptionally successful human pathogen, yet beyond knowledge that this bacterium has low overall genomic variation but acquires drug resistance mutations, little is known of the factors that drive its population genomic characteristics. Here, we compared the genetic diversity of the bacteria that established infection to the bacterial populations obtained from infected tissues during murine M. tuberculosis pulmonary infection and human disseminated M. bovis BCG infection. We found that new mutations accumulate during in vitro culture, but that in vivo, purifying selection against new mutations dominates, indicating that M. tuberculosis follows a dominant lineage model of evolution. Comparing bacterial populations passaged in T cell-deficient and immunocompetent mice, we found that the presence of T cells is associated with an increase in the diversity of the M. tuberculosis genome. Together, our findings put M. tuberculosis genetic evolution in a new perspective and clarify the impact of T cells on sequence diversity of M. tuberculosis.
“…Recent studies using both animal models of TB 14,37 and surgically resected tissue from humans with TB 38,39 support these findings and reiterate the inherent complexity of the disease. Importantly, this granuloma-specific heterogeneity is crucial in determining host outcome, as only one or a few granulomas that poorly contain their bacteria are probably responsible for allowing bacterial dissemination, worsening pathology and driving the onset of active disease 37,40–42 . In a macaque model of TB, Lin et al 37 demonstrated that animals with clinically active disease had both sterile granulomas and regions of severe pathology (that is, consolidations and TB-associated pneumonia) that had very different profiles of bacterial killing.…”
Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as a clinically asymptomatic, contained state that is termed latent TB infection (LTBI); a smaller subset of infected individuals present with symptomatic, active TB. Within these two seemingly binary states, there is a spectrum of host outcomes that have varying symptoms, microbiologies, immune responses and pathologies. Recently, it has become apparent that there is diversity of infection even within a single individual. A good understanding of the heterogeneity that is intrinsic to TB — at both the population level and the individual level — is crucial to inform the development of intervention strategies that account for and target the unique, complex and independent nature of the local host–pathogen interactions that occur in this infection. In this Review, we draw on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease.
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