Signatures of selection at drug resistance loci in<i>Mycobacterium tuberculosis</i>

Mortimer, Tatum D; Weber, Alexandra M.; Pepperell, Caitlin S.

doi:10.1101/173229

Cited by 15 publications

(19 citation statements)

References 63 publications

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“…However, one study showed that an M. tuberculosis strain harboring a deletion in pncA conferring pyrazinamide resistance was estimated to be endemic longer before the use of pyrazinamide for TB treatment [26]. This finding supports the idea that purifying selection on pncA is relatively weak, which would contribute to its exceedingly high diversity and broaden the adaptive paths to resistance [27].…”

Section: Discussionmentioning

confidence: 95%

Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

et al. 2020

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Background: Pyrazinamide still may be a useful drug for treatment of rifampin-resistant (RR-TB) or multidrugresistant tuberculosis (MDR-TB) in China while awaiting scale up of new drugs and regimens including bedaquiline and linezolid. The level of pyrazinamide resistance among MDR-TB patients in China is not well established. Therefore, we assessed pyrazinamide resistance in a representative sample and explored determinants and patterns of pncA mutations. Methods: MDR-TB isolates from the 2007 national drug resistance survey of China were sub-cultured and examined for pyrazinamide susceptibility by BACTEC MGIT 960 method. pncA mutations were identified by sequencing. Characteristics associated with pyrazinamide resistance were analyzed using univariable and multivariable logbinominal regression. Results: Of 401 MDR-TB isolates, 324 were successfully sub-cultured and underwent drug susceptibility testing. Pyrazinamide resistance was prevalent in 40.7% of samples, similarly among new and previously treated MDR-TB patients. Pyrazinamide resistance in MDR-TB patients was associated with lower age (adjusted OR 0.54; 95% CI, 0.34-0.87 for those aged ≧60 years compared to < 40 years). Pyrazinamide resistance was not associated with gender, residential area, previous treatment history and Beijing genotype. Of 132 patients with pyrazinamide resistant MDR-TB, 97 (73.5%) had a mutation in the pncA gene; with 61 different point mutations causing amino acid change, and 11 frameshifts in the pncA gene. The mutations were scattered throughout the whole pncA gene and no hot spot region was identified. Conclusions: Pyrazinamide resistance among MDR-TB patients in China is common, although less so in elderly patients. Therefore, pyrazinamide should only be used for treatment of RR/MDR-TB in China if susceptibility is confirmed. Molecular testing for detection of pyrazinamide resistance only based on pncA mutations has certain value for the rapid detection of pyrazinamide resistance in MDR-TB strains but other gene mutations conferring to pyrazinamide resistance still need to be explored to increase its predictive ability .

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Section: Discussionmentioning

confidence: 95%

Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

et al. 2020

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“…Such studies can benefit from an understanding of the selection pressures shaping genetic diversity and the identification of sites under positive selection because often that selection is driven by drug therapy (e.g. Pepperell et al 2013;Zhang et al 2013;Farhat et al 2013;Osório et al 2013;Lee et al 2015;Koch et al 2017;Mortimer et al 2018).…”

Section: Figurementioning

confidence: 99%

GenomegaMap: within-species genome-wided_N/d_Sestimation from over 10,000 genomes

Wilson

2019

Preprint

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The d N /d S ratio provides evidence of adaptation or functional constraint in protein-coding genes by quantifying the relative excess or deficit of amino acid-replacing versus silent nucleotide variation. Inexpensive sequencing promises a better understanding of parameters such as d N /d S , but analysing very large datasets poses a major statistical challenge. Here I introduce genomegaMap for estimating within-species genome-wide variation in d N /d S , and I apply it to 3,979 genes across 10,209 tuberculosis genomes to characterize the selection pressures shaping this global pathogen. GenomegaMap is a phylogeny-free method that addresses two major problems with existing approaches: (i) it is fast no matter how large the sample size and (ii) it is robust to recombination, which causes phylogenetic methods to report artefactual signals of adaptation. GenomegaMap uses population genetics theory to approximate the distribution of allele frequencies under general, parent-dependent mutation models. Coalescent simulations show that substitution parameters are well-estimated even when genomegaMap's simplifying assumption of independence among sites is violated. I demonstrate the ability of genomegaMap to detect genuine signatures of selection at antimicrobial resistance-conferring substitutions in M. tuberculosis and describe a novel signature of selection in the cold-shock DEAD-box protein A gene deaD/csdA. The genomegaMap approach helps accelerate the exploitation of big data for gaining new insights into evolution within species.

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“…If some of the identified polymorphisms indeed lead to a modulation of cytokine induction, we would expect signatures of selection acting upon them. Homoplastic positions, those appearing multiple times and independently in the phylogeny, are generally good surrogates of the action of positive selection 17,18 . By comparing the identified polymorphisms to a collection of 4528 strain genomes representative of the global diversity of the MTBC, we found that five SNP positions from our Porto dataset also emerged in unrelated strains in the phylogeny more than one time.…”

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confidence: 99%

Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production

et al. 2020

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Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1β is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1β production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.

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Signatures of selection at drug resistance loci inMycobacterium tuberculosis

Abstract: Abstract-2509

Cited by 15 publications

References 63 publications

Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

GenomegaMap: within-species genome-wided_N/d_Sestimation from over 10,000 genomes

Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production

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Signatures of selection at drug resistance loci inMycobacterium tuberculosis

Abstract: Abstract-2509

Cited by 15 publications

References 63 publications

Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

Value of pyrazinamide for composition of new treatment regimens for multidrug-resistant Mycobacterium tuberculosis in China

GenomegaMap: within-species genome-widedN/dSestimation from over 10,000 genomes

Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production

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Product

Resources

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GenomegaMap: within-species genome-wided_N/d_Sestimation from over 10,000 genomes