The Use of Genomics in Microbiology: From Vaccines to Drug Resistance

  • Grant A. Hill-Cawthorne

Student thesis: Doctoral Thesis

Abstract

Since 2004 sequencing has undergone a revolutionary change with the advent of first the 454 sequencer, followed by the introduction of the Solexa/Illumina chemistries. This has led to the ability to sequence the whole genomes of a large number of microorganisms in a short space of time. Microbiology’s last revolution was in the introduction of PCR, which allowed for faster detection of pathogens, particularly viruses. With whole genome sequencing (WGS) many of the time-consuming steps carried out by a reference laboratory can be skipped. These include organism detection, speciation, antimicrobial susceptibility testing, typing and molecular epidemiology – all carried out in a single sequencing run followed by bioinformatics analysis. So far the merits of WGS in microbiology have only been demonstrated in highly specialised scientific laboratories in high-income countries. However, with continuingly decreasing costs and increasing throughput, many public health laboratories are now acquiring sequencers and their use will inevitably spread to middle-income countries. In this thesis I explore the use of WGS in three specific areas and include details on how to develop and assess bioinformatics pipelines. First, I shall demonstrate that WGS can be used to assess highly divergent regions within microorganisms by using the example of the weaknesses in current approaches to the molecular detection of methicillin-resistant Staphylococcus aureus isolates. In particular, I shall highlight how current molecular tests have limitations in detecting drug resistance when the regions of the genome conferring resistance have significant mutations. Second, I will examine how WGS can provide insights into the biology of the current vaccine against tuberculosis, Bacillus Calmette Guerin (BCG), particularly how the continued passage of the seedlot for this vaccine has led to very different versions being used around the globe. Finally, I will demonstrate how WGS can be used to develop a more targeted public health approach to tuberculosis, in particular how antimycobacterial drug resistance evolves within a population and how not all clades of Mycobacterium tuberculosis should be treated the same. Whole genome sequencing clearly has a lot to offer the fields of microbiology and communicable disease control. The next step is in translating its use into public health policy and ensuring that global approaches are unified to best benefit the populations served.
Date of AwardMay 2015
Original languageEnglish (US)
Awarding Institution
  • Biological, Environmental Science and Engineering
SupervisorArnab Pain (Supervisor)

Keywords

  • Genomics
  • Public Health
  • Microbiology
  • Tuberculosis
  • MRSA
  • BCG

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