Holt laboratory: Pathogen genomics and bioinformatics

  • Head of Laboratory

    Dr Kathryn Holt
    T: +61 03 9035 3155
    E: kholt@unimelb.edu.au
    Location: Centre for Systems Genomics, Building 184 (Old Microbiology), Royal Pde, Parkville
    W: Personal web page

Research Overview

We focus on two main areas of bacterial genomics:

  1. Genomic epidemiology, or the study of bacterial pathogen populations
  2. Metagenomics, or the study of bacterial communities

A detailed introduction to these concepts and the differences between them is available on my blog.

Pathogen genomic epidemiology

We use whole genome sequencing to study populations of bacteria that contribute to disease in Australia and developing countries. This includes in-depth studies of microevolution in specific pathogen populations (e.g. Salmonella Typhi - typhoid; Shigella sonnei - dysentery; Klebsiella pneumoniae - pneumonia, UTI and other infections), using next-generation sequencing technologies to sequence and compare the genomes of hundreds of closely related isolates of the same pathogen.

In these studies, the minor differences between isolates (e.g. between Salmonella Typhi isolated from different typhoid fever patients in a particular location) are of most interest as they reveal how the pathogen is evolving in response to selective pressures (e.g. exposure to antibiotics, vaccine-induced immunity, or natural host immunity).

Focus areas:

  • antibiotic resistance
  • transmission, infection control and public health
  • novel bioinformatics methods to interrogate genome data
  • developing bioinformatics tools suitable for use in public health laboratories

Specific pathogens under study:

  • Salmonella Typhi and Paratyphi A (typhoid fever)
  • other Salmonella (food poisoning)
  • Shigella (dysentery)
  • Listeria (food poisoning)
  • Klebsiella pneumoniae (hospital acquired infections)
  • Acinetobacter baumannii (hospital acquired infections)

scheme showing E. coli genome

Whole genome comparisons of pathogenic E. coli strains including the 2011 German outbreak strain, compared to an enterohaemorrhagic (EHEC) strain.

Bacterial communities

While some bacteria are pathogenic, meaning they make us sick, most of the bacteria we encounter are not pathogenic and live inside our bodies as commensal microorganisms. In fact, for every human cell in our bodies, there are about 10 bacterial cells. These communities of bacteria are a part of healthy human physiology and are referred to as the 'human microbiome'.

We use high-throughput sequencing to profile the microbiome of the nasopharynx in cohorts of children, to see how their bacterial communities change during childhood and how the communities are related to the development of non-bacterial disease, including the severity of viral infections of the lung and the development of asthma and allergy.

About the lab

We are a computational lab based in the Bio21 Institute, but work closely with collaborators in other research, public health and hospital labs to develop projects and generate data. We then use a combination of phylogenetics, sequence analysis, comparative genomics, spatiotemporal analysis and epidemiological methods to analyse and interpret the data. Much of this is done using high performance computing, including the Victorian Life Sciences Computation Initiative (VLSCI) at the University of Melbourne.

We publish open access wherever we can, deposit all data in public databases and release open source code.

Beginner's guide - Comparative bacterial genome analysis

We have recently written a beginner's guide to comparative bacterial genome analysis, which walks readers through the process of assembly and three different approaches to genome comparison. It is open access and comes with an accompanying tutorial, with step-by-step instructions using public data. Details here.

Software - Sequence typing for bacteria

We have recently released SRST2: Short read sequence typing for bacterial pathogens. The code is open source and performs highly sensitive and accurate MLST (multi-locus sequence typing) and typing of resistance genes, virulence genes, etc direct from Illumina reads in a matter of minutes.

Code & documentation in GitHub; our manuscript in Genome Medicine.

Staff

Postdoctoral researchers

Research assistants

Graduate students

  • Jane Hawkey (PhD student) - Mobile elements and resistance; Salmonella phylogenomics, ISMapper developer
    co-supervisor: Helen Billman-Jacobe, Veterinary and Agricultural Sciences
  • Claire Gorrie (PhD student) - K. pneumoniae genomic epidemiology
    co-supervisors: Adam Jenney, Alfred Hospital and Dick Strugnell, Dept Microbiology & Immunology
  • Danielle Ingle (PhD student) - E. coli genomics
    co-supervisor: Roy Robins-Browne, Dept Microbiology & Immunology
  • Yu Wan (PhD student) - Bacterial gene networks
    co-supervisors: Mike Inouye, Dept Pathology and Justin Zobel, Dept Computing & Information Systems
  • Stephen Watts (PhD student) - Respiratory microbial communities
  • Harriet Dashnow (PhD student) - tandem repeat analysis
    primary supervisor: Alicia Oshlack, Murdoch Children's Research Institute
  • Nagaraj Moily (PhD student)
    primary supervisors: Danny Hatters, Dept Biochemistry & Molecular Biology and Anthony Hannan, Florey Institute

Visiting researchers

  • Helen Crabb (PhD student, School of Vet & Ag Sciences) - Salmonella transmission genomics

Previous staff & students

  • Dr Paul McAdam (PhD) - TB phylogenomics
  • Harriet Dashnow (MSc Bioinformatics/VLSCI intern) - SRST2 development
  • Morgan Cerqueira Alves (3rd-year Biochemistry research project) – ESBL in K. pneumoniae
  • Partha Sarathi Gope (MPhil student) - Plasmid bioinformatics
  • Damien Zammit (MSc Bioinformatics student) – Recombination analysis

Funding

Bacterial population genomics and human disease – $404,884 (2014-2017)
NHMRC Career Development Fellowship #1061409 – KE Holt

How are Klebsiella pneumoniae infections acquired in hospital? – $478,770 (2013-2015)
NHMRC Project Grant #1043822 – KE Holt & AJ Jenney

Identifying key players in the spread of antimicrobial resistance – $789,320 (2013-2015)
NHMRC Project Grant #1043830 – KE Holt, RM Hall, M Inouye, J Zobel

The interaction between the host and pathogen genetics in susceptibility to pulmonary tuberculosis – $379,277 (2013-2015)
NHMRC/A*STAR Targeted Research Grant #1056689 – S Dunstan, YY Teo, CC Khor, M Hibberd M, M Caws, M Inouye, KE Holt

Unravelling enteropathogenic E. coli – $693,820 (2014-2016)
NHMRC Project Grant #1067428 – R Robins-Browne, KE Holt, M Tauschek

A strategic vision to drive the control of enteric fever through vaccination – (2015-2019)
Wellcome Trust Strategic Award – A Pollard, S Baker, G Dougan, V Pitzer, KE Holt, B Grenfell, J Clemens, M Gordon, F Powrie, R Heyderman

Systems biology of asthma development in early childhood – $742,750 (2013-2015)
NHMRC Project Grant #1049539 – M Inouye, KE Holt

Stop asthma with immunostimulation – $651,059 (2013-2016)
NHMRC Project Grant #1041983 – P Sly P, PG Holt, KE Holt

A multidisciplinary DNA analysis of modern and ancient Antarctic ice cores – $60,000 (2014-2015)
Joyce Lambert Antarctic Research Seed Funding – M Schultz, KE Holt, J Moreau, A Johnson

Research Publications

Click here for the results of a PubMed search of Kathryn's publications.

Click here for the results of a Google Scholar analysis of Kathryn's publications.