The Use of Genomics in Microbiology: From Vaccines to Drug Resistance (original) (raw)
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Whole genome sequencing: A new paradigm in the surveillance and control of human tuberculosis
Tuberculosis (Edinburgh, Scotland), 2014
Whole Genome Sequencing (WGS) is emerging as a very powerful tool for the management, outbreak analyses, surveillance and determining drug resistance of human infectious pathogens including Mycobacterium tuberculosis and MRSA. WGS can also discriminate relapse TB from re-infection and the resolution provided by WGS has no comparison to conventional technologies. With current cost coming down to <£70 per bacterial genome, WGS has emerged as an alternative to all the existing technologies put together. We discuss the advantage and disadvantages of WGS and whether it can become a point of care tool in not just developed countries but also in developing countries which have a huge TB burden. The likely utility of WGS for other pathogens and also in characterizing holobionts is also discussed.
BMJ Global Health, 2020
The global spread of antimicrobial resistance (AMR) and lack of novel alternative treatments have been declared a global public health emergency by WHO. The greatest impact of AMR is experienced in resource-poor settings, because of lack of access to alternative antibiotics and because the prevalence of multidrug-resistant bacterial strains may be higher in low-income and middle-income countries (LMICs). Intelligent surveillance of AMR infections is key to informed policy decisions and public health interventions to counter AMR. Molecular surveillance using whole-genome sequencing (WGS) can be a valuable addition to phenotypic surveillance of AMR. WGS provides insights into the genetic basis of resistance mechanisms, as well as pathogen evolution and population dynamics at different spatial and temporal scales. Due to its high cost and complexity, WGS is currently mainly carried out in high-income countries. However, given its potential to inform national and international action pl...
Journal of Clinical Microbiology, 2015
Treatment of drug resistant tuberculosis cases is challenging: drug options are limited and existing diagnostics are inadequate. Whole genome sequencing (WGS) has been used in a clinical setting to investigate six cases of suspected Extensively Drug Resistant Mycobacterium tuberculosis (XDR-TB) encountered at a London teaching hospital between 2008 and 2014. 16 isolates from six suspected XDR-TB cases were sequenced; five cases were analysed in a clinically relevant timeframe with one case sequenced retrospectively. WGS identified mutations in M. tuberculosis genes associated with antibiotic resistance likely to be responsible for the phenotypic resistance. Thus an evidence base was developed to inform clinical decisions around antibiotic treatment over prolonged periods. All strains belonged to the East Asian (Beijing) lineage, and strain relatedness was consistent with expectations from case histories, confirming one contact transmission event. We demonstrate that WGS data can be produced in a clinically relevant timescale some weeks before drug sensitivity testing (DST) data is available, and actively help clinical decision making through the assessment of whether an isolate (1) has a particular resistance mutation and DST is absent or contradictory, (2) has no further resistance markers and therefore unlikely to be XDR, or (3) is identical to an isolate of known resistance (i.e. a likely transmission event). A small number of discrepancies between genotypic predictions and phenotypic DST are discussed in the wider context of interpretation and reporting of WGS results.
Scientific Reports, 2019
Whole genome sequencing (WGS) can elucidate Mycobacterium tuberculosis (Mtb) transmission patterns but more data is needed to guide its use in high-burden settings. In a household-based TB transmissibility study in Peru, we identified a large MIRU-VNTR Mtb cluster (148 isolates) with a range of resistance phenotypes, and studied host and bacterial factors contributing to its spread. WGS was performed on 61 of the 148 isolates. We compared transmission link inference using epidemiological or genomic data and estimated the dates of emergence of the cluster and antimicrobial drug resistance (DR) acquisition events by generating a time-calibrated phylogeny. Using a set of 12,032 public Mtb genomes, we determined bacterial factors characterizing this cluster and under positive selection in other Mtb lineages. Four of the 61 isolates were distantly related and the remaining 57 isolates diverged ca. 1968 (95%HPD: 1945-1985). Isoniazid resistance arose once and rifampin resistance emerged subsequently at least three times. Emergence of other DR types occurred as recently as within the last year of sampling. We identified five cluster-defining SNPs potentially contributing to transmissibility. In conclusion, clusters (as defined by MIRU-VNTR typing) may be circulating for decades in a high-burden setting. WGS allows for an enhanced understanding of transmission, drug resistance, and bacterial fitness factors. Tuberculosis (TB) remains among the top ten causes of deaths globally, with 10.4 million new cases in 2016 alone 1. Peru remains a high burden country for multidrug-resistant (MDR) TB with 117 TB cases reported per 100,000 population in 2016 and approximately 9% being MDR or rifampicin-resistant (RR) 1. Molecular methods have been instrumental in identifying outbreaks, and single nucleotide polymorphism (SNPs) identified using whole genome sequencing (WGS) have a higher resolution in identifying transmission links compared to traditional genotyping methods such as spoligotyping or Mycobacterium interspersed repetitive unit-variable number tandem repeats (MIRU-VNTR) 2-12. Yet we don't yet fully understand how to use all the genetic information generated by WGS. By convention, as much as 10% of the genome is excluded 2,3 and in some instances too little remaining variation is found to enable the resolution of transmission chains 13. Resolving transmission events accurately is particularly challenging in high-burden settings where multiple source case suspects are common. In addition to guiding public health interventions including appropriate contact tracing, identifying the source case can inform patient care in some cases, such as in pediatric TB where the source case microbiological data can inform treatment 14,15. Furthermore, in high-burden countries the term 'outbreak' may not apply as TB has been