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ausgem 2014-2016 report

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2014-2016 report

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Reprinted April 2018


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Executive summary 4

Introduction 8

Ausgem and disease prediction, diagnosis and prevention 10

Ausgem and antimicrobial resistance 12

The value of Ausgem 13

Achievements Ausgem phase 1 (2013-2016) 15

Funding success 15

Operational achievements 15

Technical achievements - genomics, bioinformatics & enabling technologies 15

PhD programs 17

Collaborations 17

Research outcomes 17

Publications and presentations 19

Ausgem Phase 2 20

Phase 2, 2016-2019 20

Phase 2, 2017-2019 20

Investment value to DPI and UTS 20

Cost benefit 21

The future of Ausgem 21

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ExecutiveSummary


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The Australian Centre for Genomic Epidemiological Microbiology (Ausgem) was established as a collaborative partnership between the New South Wales Department of Primary Industries’ (NSW DPI) Elizabeth Macarthur Agricultural Institute (EMAI) and ithree institute at the University of Technology Sydney (UTS) with the aim of strengthening the state’s capacity to identify and respond to biosecurity threats1.

Ausgem research focuses on current and emerging pests and infectious and parasitic diseases of animals and plants as well as on the problem of antimicrobial resistance (AMR) — also a high priority global issue. The research program aims to help safeguard the state’s agriculture, horticulture, livestock and equine industries, which underpin the $15 billion primary industries sector in NSW, and to support the biosecurity system that protects the economy, environment and community from the impacts of pests, diseases and invasive species.

Increasingly, solutions to disease prediction, detection, spread, control and eradication will be based on information derived from scientific and technological innovation with economic and policy reform informed by this intelligence. Ausgem’s approach to managing the risks posed by

pests and pathogens is based on the latest DNA and RNA sequencing technologies and bioinformatics, proteomics and state-of-the-art microscopy. Moreover, the use of genetic technologies and corresponding data analysis is a core skill set for the next generation of epidemiologists, and the Ausgem partnership has enabled training and career development of numerous students and early-mid career researchers.

Ausgem’s research remit is based on the need for Australia to maintain its agricultural productivity and strong biosecurity record, to effectively manage issues of food safety, and to continue to demonstrate its human, animal and plant health status for the purposes of national and international trade. To that end, Ausgem scientists have established links with hospitals and primary producers incorporating crops, meat, poultry and aquaculture, to link the epidemiological and disease management skills that can be used to mitigate the impact of transboundary diseases and the costs associated with disease outbreaks. This big-picture perspective, which recognises that the health of people is connected to the health of

animals and the environment (One Health concept), informs the development of biosecurity measures through research projects that focus on disease detection and surveillance, diagnostics, and vaccine development.

Ausgem’s DNA-based approaches provide a baseline measurement for the antibiotic resistance genetic elements that are circulating between humans, pigs, and poultry. These include drug-resistant Escherichia coli, which cause urogenital and extraintestinal infections, Pseudomonas aeruginosa, Clostridium difficile, and emerging pathogens such as Kingella kingae. Knowing that virulence and resistance genes are often co-localised will also assist with detection of emerging diseases. In addition, the program has supported DNA sequencing of the largest cohort of Xanthomonas species, which were isolated from crops in geographically diverse regions of Australia. These bacteria are responsible for a wide variety of plant diseases and it is expected that this research will lead to significant improvements in how plant bacterial diseases are diagnosed.

Ausgem’s research remit is based on the need for Australia to maintain its agricultural productivity and strong biosecurity record.

1A memorandum of understanding was signed between UTS and the NSW DPI in November 2012 and Ausgem was formally launched Ausgem on December 4, 2014. From 2013 to 2015, DPI’s annual contribution of $300K was matched by UTS. This support helped to secure Australian Research Council (ARC) linkage funding and access to technology within the Ramaciotti Centre for Genomics (RCG) consortium. The MOU came to an end on October 31, 2016.

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The 1500+ DNA sequences generated by Ausgem scientists will soon be uploaded to public repositories so that investigators around the world can draw on the wealth of sequence data to help predict likelihood and source of major disease incidents.

In October 2015, a project entitled ‘Improved biosecurity through the engineering of microbial ecosystems’ was awarded $520,000 through the ARC Linkage program. This grant

reflects the strength of the collaboration between UTS and NSW DPI scientists: In total, Ausgem researchers attracted $937,000 of external grant funding.

This report details the outcomes from Ausgem 1. Initially a three-year program ending in 2016, Ausgem has been extended for a further three years (Ausgem 2) due to the strong productive relationships that have formed and the value of its contribution

to changing agricultural practice through risk evaluation, mitigation and improved evidence-informed treatment. A $4M 50:50 matched funding research collaboration agreement has now been signed.

In the Ausgem 2 program, researchers will study the effectiveness of interventions such as prebiotics, probiotics and vaccines in disease management and as alternatives to antibiotics.

“Through the Ausgem partnership, UTS research will have a greater impact on tackling plant, animal and human disease by changing agricultural practice and informing the development of solutions to improve the health of our community and our environment.”

Professor Attila Brungs, Vice-Chancellor and President of the University of Technology Sydney

“UTS and NSW DPI have effectively combined their core strengths and unique capabilities to build a research program around the use of DNA technologies which will strengthen the State’s capacity to identify and respond to biosecurity threats, manage food safety, and increase agricultural productivity.”

Bruce M. Christie, Deputy Director General Biosecurity and Food Safety, NSW DPI

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Increasingly, we are seeing disease host specificity breakdown and an increasing ability of pathogens to spread rapidly between species in a way that has not taken place previously

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Introduction


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Globally, the risks associated with biosecurity and food safety are undeniably increasing. Australia has a strong need to maintain its enviable biosecurity record, to manage issues of food safety, and to continue to demonstrate its human, animal and plant health status for the purposes of national and international trade.

Furthermore, Australia has an opportunity to support the rapidly increasing global demand for livestock products brought about by improved living standards and urbanisation in many parts of the world. Along with these increased demands on food safety and biosecurity is an increasing awareness, within governments, industry and the public, of the risks associated with transboundary diseases and the costs associated with disease outbreaks. Nowhere is this clearer than in the field of AMR that threatens human health and livestock production due to the extensive global translocation of resistance factors.

Rapid advances in genomics are providing an exciting platform for a new generation of whole genome-based sequencing approaches to understanding and improving human and animal health management. Two key elements are critically needed to ensure the effective use of gene-based technologies and their ability to have a significant impact in health management. First, there needs to be a source of the basic pathological material that is causing the disease outbreak — whether this be a virus, a bacteria, a resistant gene or even defective host material. This must be accompanied by sound epidemiological information to place the material in context. Secondly, there is a need for rapid and high-throughput sequencing

capabilities with the associated bioinformatics to analyse the material and place this acquired genetic information within the context of disease events.

The problem has a further complexity. Increasingly, we are seeing disease host specificity breakdown and an increasing ability of pathogens to spread rapidly between species in a way that has not taken place previously, or has been occurring, but at a much slower rate. Whether this is the ability of an influenza virus to cross the species barrier, or the increased ability of Zika virus to affect a foetus or for antibiotic resistance to evolve en masse and spread across species, there is an increasing ‘blurring’ of species-specific health risks. The new term, One Health, has emerged

which recognises that the health of people is connected to the health of animals and the environment.

Ausgem’s One Health focus is underpinned by the creation of a new collection of skills and knowledge that include human medicine, veterinary science, wildlife ecology, environmental factors and the growing area of social science.

Ausgem takes the concept of molecular epidemiology and the One Health approach to a new level by linking the epidemiological and disease management skills and pathogen collections at EMAI with the high-throughput sequencing and related skills at ithree/UTS. This has created a unique blend of capabilities and knowledge to generate significant impact in this burgeoning science area.

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Action


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UTS• High-throughput genome sequencing

• Microbial imaging facility with super-resolution instruments

• Genomics, proteomics and transcriptomics expertise

• Mass spectrometry facility with proficiency in biological applications

• Bioinformatics specialists

• Internationally recognised experts and knowledge in infectious disease and resistance processes

• Eligible for research council funding

EMAI• High bio-containment laboratory and

animal and plant facilities

• ISO and NATA accredited diagnostic laboratories

• Archived collections of significant pests and pathogens

• Emergency response and surge capacity

Ausgem and disease prediction, diagnosis and prevention

Using the innovative capabilities within the Ausgem partnership, a number of projects were established to cover the development of disease prediction tools and diagnostic tests, to investigate the efficacy of probiotics and to develop new generation vaccines to prevent disease and reduce the use of antibiotics in food animals. These projects include:

• developing diagnostic assays that target unique molecular signatures critical for the rapid identification and tracking of complex antibiotic resistance and virulence gene loci to facilitate the global and local tracking of plasmids, genomic islands and the bacteria that carry them. These assays could be amended to field-based assays during an outbreak scenario

• computer automation and data science to pair genome sequencing with traditional epidemiology and characterise the origins, transmission, dynamics and evolution of infectious disease agents, thus providing enhanced scientific knowledge to inform policy and improve biosecurity

• using genomics to identify the emergence of new pathogen variants and/or of known zoonotic pathogens in new host species

• undertaking computational prediction studies of disease outbreaks in aquaculture systems using network analysis of microbial, environmental and host parameters.

• development of diagnostic assays for exotic high-priority plant pathogens through genome informed diagnostics

• using genomics to identify plant bacterial pathogens from the NSW DPI collection. This information will be used to determine pathogen presence initially within NSW and can be further used for universal diagnostic assay development

• using the mass spectrometry facilities at UTS and the pathogen libraries at EMAI to identify new vaccine antigens for pathogens affecting humans and agriculturally important animals (zoonotic pathogens)

• using the cutting-edge microscopy facilities at UTS, and the pathogen libraries at

Australia-wide collaborations and international research networks

Internationally recognised experts and knowledge in infectious disease and resistance processes and pathways

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EMAI to identify novel attributes of pathogens and their behaviour that can be targeted for vaccine and therapeutic development

Ausgem recognises that multiple antibiotic resistant pathogens represent a major clinical challenge in human and veterinary medicine, aquaculture, and in food production more broadly. Genes that encode resistance are context independent, that is, the same gene can be found in extremely disparate genetic environments. Resistance genes also accumulate on mobile genetic scaffolds also known as (complex antibiotic resistance gene loci (CRL)) and a selection pressure exerted by one antimicrobial agent is sufficient to maintain the entire locus in a commensal or pathogenic bacterial host cell. As such, CRL can be spread rapidly to diverse bacterial populations in the gastro-intestinal tract of humans and food animals, and in environments where there is constant antimicrobial selection pressure.

Multidrug resistant (MDR) bacterial populations are transported globally by air travel and trade practices. Scavenging animals (rodents), insects (flies) and assorted wildlife, and migratory bird species also pick up and spread these bacteria. These multiple mechanisms ensure that MDR bacteria are spread globally and often rapidly. With the decreasing effectiveness of current antibiotics and the pedestrian

Ausgem and antimicrobial resistance

• providing a critical alternative to antibiotic use in agriculture by developing new and improved vaccines for major disease-causing pathogens that affect agriculturally important food animals

• using genomic data for in silico vaccine discovery (reverse vaccinology) and untargeted proteomic approaches to antigen discovery

pace of the development of new antimicrobial agents, our ability to treat even common infections will weaken to levels that existed more than a century ago and death rates are projected to increase dramatically (from 700,000 to an estimated 10 million per annum by 2050).

The failure of urban and rural communities to adequately treat effluent waste exacerbates the problem of antibiotic resistance. In China alone, the world’s largest producer and consumer of pork, it is estimated that between 0.6 – 1.3 billion metric tonnes of porcine faecal waste is generated each year. That material is heavily contaminated with MDR bacteria, as well as a diverse selection of antimicrobial residues, and heavy metals that are used in feed

formulations as growth promoters and from therapeutic treatment for disease. These environmental pollutants contaminate prime agricultural land and the fresh produce that grows on it, water tables and estuaries, and provides a constant and relentless selection pressure that drives resistance gene capture and resistance gene spread to diverse microbial populations in natural ecosystems. In China in 2013, it has been estimated that 54,000 tons of antibiotic was excreted by humans and animals and entered into the environment following wastewater treatment. These practices are occurring globally in all industrialised and emerging economies and are poorly understood drivers of AMR.

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Ausgem is using a ground-breaking One Health, genomic epidemiological approach by combining the unique and complementary skills and resources of the founding partners. Specifically, it is harnessing the high-throughput genomic, proteomic, microscopy, and bioinformatics skills available through the ithree institute and UTS, and the extensive pathogen libraries, scientific expertise, biosecure facilities and containment laboratory and epidemiological skills at EMAI and through NSW DPI.

Ausgem also provides a fertile training ground for the next generation of scientists seeking to apply genomics and big data analysis to their research and elevating skill levels of early and mid-career scientists within NSW

DPI and UTS more broadly. This is an important element of the Ausgem approach, as the fast pace of change in the biological, chemical and physical sciences is such that it is necessary to continually seek to upgrade platform skill bases. In addition, major items of technology infrastructure have a limited window of productivity before they are superseded by next- generation technology. Technology hubs located within research environments like UTS offer a cost-effective model to ensure access to a larger stakeholder base and to the broader research community. The ithree/NSW DPI Ausgem collaboration promotes this strategy.

Investments so far have resulted in improved capabilities (human

and infrastructure) to utilise modern genomics, proteomics and microscopy with tangible outcomes being delivered. The entity itself has demonstrated viability in operation and delivery.

Access to high-end research infrastructure The Ramaciotti Centre for Genomics (RCG) at the UNSW installed a PacBio sequencer, awarded as part of an ARC Large Infrastructure Endowment Fund (LIEF) grant in 2015. The Australian Government provided $630,000 for the purchase of this instrument, with the remaining monies (~$1.2 million) provided by the consortium members on the grant application including UTS. Ausgem researchers rely on and use this facility extensively. Furthermore, the RCG is

In order to address this severe and continually increasing problem, key areas of research were established that include:

• identifying baseline carriage rates of antimicrobial resistance genes in commensal bacterial populations in the gastrointestinal tract of food producing animals and humans

• identification of the genetic basis of antibiotic resistance in key bacteria from food animals

• identification of the basis of antibiotic resistance in major human pathogens

• identification of bacterial pathogens that flux between humans and food animals

• identification of the mechanism for transfer of antibiotic resistance between key bacteria that colonise humans and agriculturally-important animal and plant species and develop mitigation strategies

• characterisation of mobile genetic elements carrying antibiotic resistance genes that move between bacterial populations that colonise humans, food animals, agriculturally important plant species and the environment more broadly

• identification of pathogenic bacteria that harbour resistance to multiple antibiotics

• identification of mobile elements that carry combinations of virulence and antimicrobial resistance genes - known as superbug monitoring

• development of bacterial ‘fingerprinting’ methods using genome sequencing to track antibiotic resistant clonal groups in endemic agents and disease outbreaks.

• development and evaluation of metagenomic methods to more rapidly and accurately track changes to complex microbial populations.

• development of tools that use metagenomic approaches to monitor reservoirs of antibiotic resistance genes in uncultivable bacteria

The value of Ausgem

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upgrading its high-throughput genome sequencing facilities. Researchers within Ausgem will have access to this cutting-edge technology and lead scientists from UTS are able to contribute to decision-making and long-term infrastructure planning as members of the RCG steering committee. They also contribute to ARC Linkage LIEF scheme, typically on an annual basis.

Collaborations and partnershipsGenomic epidemiology is an important national asset providing essential baseline data on the prevalence of MDR gene carriage and identifying mobile elements that play a key role in disseminating drug resistance. This information can only be assembled using whole-genome sequencing approaches and

cannot be cost effectively generated using PCR and microarray technologies. Ausgem seeks to show leadership by progressing the field of genomic epidemiology by providing and sharing new data that will indicate the depth and scale of the problem of AMR in Australia. Ausgem aims to facilitate preparedness for detecting and monitoring emerging pathogens and outbreaks globally, and to develop products and strategies to control enduring endemic pathogens.

Ausgem data sets will be critically important for:

• developing diagnostic tools to track MDR in pathogens and commensals that affect the health of humans, food animals, aquaculture, plants and wildlife

• monitoring the success of potential intervention strategies, such as lowering antimicrobial use, and promoting the use of probiotics, vaccination and phage therapies in food production systems

• identifying emerging pathogens

• identifying reservoirs for AMR genes and the elements that carry these genes

• identifying industries and practices that are at risk

• providing guidance to improve livestock health and reduce risks of passage of AMR between species and through the food chain

• advising policy-makers

Bovine theileriosis is an emerging disease of cattle in Australia and the Asia-Pacific region and is caused by a microscopic parasite carried by ticks

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Funding successIn 2016, ‘The improved biosecurity through the engineering of microbial ecosystems’ project was funded by a $520,000 ARC linkage program grant together with $450,000 from NSW DPI. Ausgem 1 received a total of $937,000 through external grants. The ability to secure monies via a competitive funding grant scheme not usually directly available to NSW DPI demonstrates one of many advantages of the relationship.

Operational achievementsSince its inception Ausgem has:

• established a governance and operating structure that includes a governing board with independent expert advisers and a management committee with specific scientific expertise and peer review capabilities

• developed enabling technologies and software packages to secure the success of Ausgem

• developed a strategic plan for ongoing activities

• launched www.ausgem.net

Technical achievements - genomics, bioinformatics & enabling technologiesSurveillance and biosecurity measures benefit from technological solutions that provide rapid identification of pathogens and deliver detailed insights around emerging and existing threats.

Ausgem 1 has placed a premium on the development of enabling

technologies, including genomics and bioinformatics, as part of their value proposition. This enables the program scientists to access major federally-funded projects in areas such as AMR.

Sequencing technologies• refinement of Illumina (short

read) sequencing technologies that ensure the cost of sequencing remains low. This is needed to develop comprehensive databanks of sequence information essential for establishing baseline levels of resistance gene carriage in commensal and potentially zoonotic E. coli and to identify reservoirs of CRL

• development and quality control of sequence analysis pipelines that enable rapid and effective analysis of large data sets. This is an ongoing task

• development and assessment of long-read sequencing technologies (PacBio and Oxford Nanopore) and their application to Ausgem projects. These technologies enable complete genome assemblies and the identification and analysis of CRL

• The analysis of CRL is essential to understanding the ecology and epidemiology of MDR and co-evolution of MDR and virulence on mobile genetic elements. Complete genome assembly technology also provides essential information that supports molecular diagnostic assays for detecting and tracking MDR bacteria

• development of 3C sequencing and analysis protocols. These sequencing technologies seek

to make it feasible to use metagenomic strategies to link mobile elements with the chromosome of the bacterial host. These methodologies have been road-tested in Ausgem 1 and will underpin efforts to better understand the ecology of AMR within complex microbial communities in the GI tract of humans and food animals during Ausgem 2

• development and assessment of metagenomics analysis pipelines. This is a major milestone in the ARC Linkage proposal that is closely aligned with Ausgem and an excellent example of how the Ausgem consortium has been able to successfully leverage funding provided to Ausgem from NSW DPI from the ARC

• development of high-resolution ‘fingerprinting’ pipelines for identification and epidemiological analysis of both endemic bacterial pathogens and outbreaks. These pipelines are currently being used to facilitate study of antibiotic-resistant ExPEC and zoonotic outbreaks of Chlamydia psittici

• development of a similar pipeline for the molecular epidemiological analysis of microbial parasites, such as Theileria orientalis

Genomes sequenced• 1,000 Xanthomonas

• 550 E. coli

• 10 MDR E. coli

• 80 Vibrio species

• Clostridium difficile

Achievements Ausgem phase 1 (2013-2016)

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• Clostridium chauvoei

• MDR Pseudomonas aeruginosa

• Shewanella algae

InformaticsAusgem scientists have developed a suite of informatics tools that can process and analyse DNA sequence data. This includes software packages such as Mauve, Phylosift and new algorithms to analyse 3-C and HiC data. This toolkit is necessary to manage the assembly of DNA sequences into chromosomes and plasmids, identify antibiotic resistance and important virulence genes, and

perform phylogenetic analyses (a measure of strain relatedness). All these tools have been packaged into a suite of software that can be used by the cohort of students and post-doctoral scientists in the Ausgem team as well as global scientists, a large number of whom have adopted these tools, putting us in a global technology leadership position. The team also provided the opportunity to quality control these algorithms, further adding to the utility and accuracy of the informatics pipeline with a number of key publications demonstrating the ability to

sequence microbial genes and perform phylogenetic analyses.

Methods developed in Ausgem 1 also assisted NSW DPI researchers with analyses of the fruit fly microbiome. This work is part of a major government research program aimed at developing new ways to combat fruit fly infestations that annually cost the agricultural industry $300 million in control measures and lost productivity.

ProteomicsResearchers in the Ausgem network are also contributing to developments in the field of mass

Sequenced more than 1500 bacterial genomes including 1,000 Xanthomonas species solated from geographically-diverse diseased crops

Developed and refined bioinformatics tools and sequencing technologies that can be used in a range of biosecurity and pathogen surveillance projects

Approximately $1m external grant income that includes an ARC

linkage grant

Seven new Australian collaborations, including four with hospitals

Five new international collaborations

23 peer-reviewed scientific publications and five invited review articles

More than 40 research presentations

Novel Mycoplasma hyopneumoniae pig vaccine in development

Identification of avian Chlamydia species as an emerging cause of equine abortion

Discovered a new means by which bacteria transfer multi-drug resistance in a clinical setting

Increased knowledge of diversity and epidemiology of Theileria orientalis, a tick-borne parasite that infects cattle

Topics generated for 11 PhD research programs with 6 PhD completions anticipated in 2017/2018


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spectrometry and sample preparation for protein analysis.

PhD programs Ausgem1 funded three PhD programs with others being aligned to the research program and funded through UTS and external grants.

Details in Appendix D.

1. Genomic sequencing of extra intestinal pathogenic Escherichia coli from urinary tract and blood sepsis hospital infections

2. Genomic surveillance of porcine commensal multidrug resistant Escherichia coli and phylogenetically related pathogens from humans

3. Developing vaccine antigens for Mycoplasma hyopneumoniae

4. Presentation of Mycoplasma hyopneumoniae antigens to its porcine host

5. Identification and characterisation of novel Mycoplasma hyopneumoniae antigens

6. Genomic surveillance of porcine multidrug resistant Escherichia coli

7. Genomic epidemiology of bacterial pathogens causing human blood borne

8. Characterization of the exotic plant pest Verticillium dahliae

9. Unravelling the pathogenicity and diversity of Theilleria orientalis in Australia

10. Metagenome analyses of microbial populations in the pig gut

11. Characterisation of avian pathogenic E. coli in Australia

Six UTS PhD completions are expected in 2017/2018

CollaborationsDetails in Appendix E.

AustraliaUniversity of Melbourne

Royal North Shore Hospital

Concord Hospital

Orange Base Hospital

Sydney Adventist Hospital

University of the Sunshine Coast

Tick Fever Centre (QLD Department of Agriculture and Fisheries)

InternationalAusgem has recognised that the impact of its research programs will be amplified through local and global collaboration. To date, these have focussed on combined efforts to build phylogenetic tools for epidemiology research and to establish best practise for metagenomic analyses. For example, collaborations with Danish researchers include monitoring the impact that reducing antibiotic load has on the carriage of antibiotic resistance genes in pig and poultry production. Denmark banned the use of antibiotics for food animal growth promotion more than 20 years ago and remains a world leader in limiting antibiotic use. Large-scale genome analyses will help determine if antimicrobial load reduction is a viable strategy to reduce AMR gene carriage, or if resistance genes persist in the face of antibiotic concentrations used strictly to treat disease.

Ausgem 1 collaborations also include the University of Liverpool; University of Warwick, UK (Thames river samples); University of Bern, Switzerland.

Research outcomes Six projects have already benefited from the enabling technologies outlined above:

1. Genomic analysis of bacterial plant pathogens Xanthomonas sp. are bacterial pathogens that impact agriculturally important crop species. These organisms are poorly characterised by conventional bacteriological protocols and it is historically difficult to infer phylogeny. NSW DPI has comprehensive collections amassed over more than two decades. The project involves sequencing up to 1000 isolates. To date, 800-plus isolates have been completed and data analysis will commence when the last 200 are completed.

2. Genomic analysis of extra-intestinal pathogenic Escherichia coli (ExPEC) ExPEC are the most frequently isolated Gram-negative pathogen costing billions of dollars globally. ExPEC are responsible for most urinary tract infections including cystitis pyelonephritis, wound abscesses and life-threatening conditions such as sepsis and meningitis. ExPEC also cause serious morbidity and mortalities in poultry and disease in pigs. There is now mounting evidence to suggest that the ExPEC-related disease in humans has a foodborne origin. Ausgem is leading the way in Australia in conducting genomic surveillance of ExPEC in poultry and pigs. Several review articles and papers describing the genomics of E. coli pathogens have been published. Manuscripts describing the analyses of several hundred genomes are due to be published.

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3. Genomic analysis of Clostridium difficile isolates from humans and animalsC. difficile is an important emergent human gastrointestinal pathogen. Non-toxigenic isolates from pigs and horses supplied by NSW DPI as well as several human isolates have been sequenced and characterised. The aim of these studies is to examine their phylogeny with respect to published sequences of toxigenic variants as non-toxigenic varieties have been poorly characterised to date.

4. Genomic analysis of Clostridium chauvoei isolates from humans and animalsFull genome sequences of 20 strains of Clostridium chauvoei, the etiological agent of blackleg of cattle and sheep, isolated from four different continents, over a period of 64 years, were determined and analyzed. The study reveals that the genome of the species C. chauvoei is highly

homogeneous compared to the closely related species Clostridium perfringens, a widely spread pathogen that affects human and many animal species that shows more variation. However, the major virulence genes including the highly toxic CctA toxin, the sialidase and the two hyaluronidases are fully conserved as are the metabolic and structural genes of C. chauvoei indicating that C. chauvoei being a strict ruminant-associated pathogen has reached the end in its evolution.

5. Genomic analysis of MDR Pseudomonas aeruginosa genomesMDR, extrensively drug resistant (XDR) and pan-resistant P. aeruginosa cause life-threatening infections in patients with cystic fibrosis and people who are immunocompromised. We have characterised MDR and XDR isolates from a burns ward in a major Sydney hospital and demonstrated that the CRL is

located in chromosomal islands. This is unusual because plasmids were for a long time considered the primary vehicle for transmitting MDR in this species. Several papers have been published describing these observations during Ausgem 1.

6. Characterisation of virus and bacterial infections of oysters and the mitigation of their risks to both oyster and human health Microrganisms were cultured from disease-affected oysters. In total 80 complete Vibrio sp. genomes have been sequenced: publication is planned for 2018.

Pathogen discoveryAusgem scientists have identified an avian Chlamydia species as a new and emerging cause of equine abortion with the aid of genomic analyses. This has led to new collaborations that draw on expertise in the genomics, cellular biology and pathogenesis of Chlamydia.

Disease aetiologySignificant advances have been made in characterizing the causative agent of Theilerosis and understanding disease

transmission. This is a NSW DPI/Meat & Livestock Australia funded project with significant input from the Ausgem team.

VaccinesAusgem scientists have been developing novel vaccine antigens for prevention of Mycoplasma hyopneumoniae infections in pigs and are testing these ‘next-generation’ vaccines at NSW DPI EMAI laboratories. This has become an important focus heading into Ausgem 2.

Case studies: Pathogen discovery and characterisation These projects are ready for the next stage of development.


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Publications and presentationsPeer-reviewed international publications: 23. Invited review articles: five. These are listed in Appendix B.

The full article list is also available at: http://www.ausgem.net/news-events/publications-archive/

Ausgem scientists have given more than 40 research presentations many at global conferences. These are listed in Appendix F.

Ausgem has recognised that the impact of its research programs will be amplified through local and global collaboration.

Ausgem research is being supported through collaboration with hospitals in NSW and internationally

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Phase 2, 2016-2019The success of Ausgem 1 prompted UTS and DPI to consider the next steps for the Ausgem collaboration. A strategic plan was determined with funding requirements for the next three years estimated at around $4M. The financial commitments and resources from UTS and DPI will to be used to secure key personnel and attract further funding through ARC linkage grants and other funding bodies such as the McGarvie Smith Institute and the Rural Industries Research and Development Corporation.

Phase 2, 2017-2019 Further investment by DPI and UTS will ensure that the considerable achievements to date can be progressed and expanded upon and that the genuine potential for growth and sustainability through innovation, collaboration and partnership can be realised.

Ausgem will build on its established track record and expand its science base through seeking engagement with other research and development partners including national and international universities, agricultural industries and government organisations. These partnerships will seek to leverage grant funding by forming consortiums to submit joint funding proposals and present a united front to funding bodies demonstrating that the partnership will deliver more than isolated institutions competing with each other in the same space. Overseas funding will also be sought through partnerships

with international universities and industries.

Ausgem will continue to progress the development and utilisation of next-generation technologies and through the appointment of a business manager, concentrate efforts upon producing a business plan for industry engagement and improving business processes designed to maximise the potential of the Ausgem model. NSW DPI has also appointed a molecular epidemiologist.

The four primary funded projects proposed for Ausgem phase 2 are:

Project 1: Genomic surveillance program

Project 2: Development of novel vaccines for Mycoplasma hyopneumoniae in swine

Project 3: Software systems for real-time genomic surveillance of infectious disease outbreaks

Project 4: New tools to decipher, predict and manage Pacific oyster mortality episodes

Satellite projects relating to these four projects are being run by DPI scientists who have leveraged monies from alternate funding sources and which have benefitted from the genomic sciences developed at UTS as part of the Ausgem project.

Investment value to DPI and UTS Ausgem seeks to maximise the value of genomics to enhance agricultural productivity of NSW farmers and to mitigate the biosecurity, food safety and health risks associated with pests and diseases of animals, plants and humans. If the advances made through Ausgem are to be

realised, further and increased investment is required.

Confidence in Ausgem has already been shown through the attraction of research funding, notably from the ARC but also from other research funding organisations. It is notable that early and mid-career scientists at NSW DPI and at UTS have benefitted extensively from the training they have received during the course of Ausgem 1 and the interaction with a large number of scientists from a variety of disciplines. This partnership has strengthened our staff knowledge base and enabled a two-way access to state of the art equipment, facilities, culture collections and skills that would not normally be available.

Ausgem scientists are leading current developments in whole- genome sequence technologies and the bioinformatics skills required in the big data sciences and are actively involved in generating novel outputs and solutions to complex problems. Prestigious universities around the globe are now seeking Ausgem scientists to assist with placement and training of PhD and postdoctoral scientists — evidence of our recognised knowledge reputation.

Both the strategic plan and the business plan (framework completed) provide a detailed account of the value of this investment in overall terms. In the immediate term (2016 – 2019) further investment will ensure the bedding down of Ausgem as an established long-term entity and the completion of much of the developmental science that is

Ausgem Phase 2


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essential for underpinning the outcomes to pest and disease risk mitigation. This will then lead to better health outcomes and agricultural production increases that using a genomic and other ‘omics’ approach.

Cost benefit The agricultural sector in NSW is exposed to biosecurity risks from pests and disease that have historically quarantined selected activities, restricted exports and caused financial losses. The Ausgem partnership seeks to mitigate these risks through intentional investment in scientific innovation, research and development in genomic sequencing technology, downstream genome analysis and the provision of management and control solutions.

There are both tangible and intangible benefits from the Ausgem partnership and the return on investment will be realised

through the securing and expansion of business opportunities for the NSW agricultural sector.

The future of Ausgem In Ausgem 2, we will now apply the tools and data resources from Ausgem 1 to deliver improved biosecurity and reduce foodborne illness and antibiotic pollution, while continuing to strengthen our core technology base that enables these outcomes. Ausgem 2 will leverage techniques and methods developed in phase 1, which will result in a significant expansion in the number of pathogen genomes sequenced and analysed. In addition, we have expanded the scope to include the development and evaluation of intervention strategies (probiotic trials in swine and porcine respiratory disease vaccine development) that will reduce the reliance on the use of antimicrobials in animal production. The strength of the collaboration between UTS and

NSW DPI has been recognised through a successful, highly competitive ARC Linkage grant (refer to Funding success section). This is an excellent example of how the collaborative relations between NSW DPI and UTS can generate opportunities for securing substantial external research support. Using this model, further ARC Linkage projects have been submitted as part of Ausgem 2.

As the risks from new and emerging pests and diseases and from antibiotic resistance continue to grow globally, Ausgem will play a lead role in highlighting the importance of next generation tools and capabilities that can be fully realised through the emerging genomics era. Ausgem has already demonstrated a clear ability to make a positive impact in the areas of human, animal and plant health and further investment in this One Health approach will ensure that this continues.

Ausgem’s work on a new vaccine could one day eliminate the swine pneumonia that wreaks havoc in the global pork industry

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APEC Avian pathogenic E. coli

ARC Australian Research Council

Ausgem Australian Centre for Genomic Epidemiological Microbiology

BATOG Bovine anemia and Theileriosis orientalis group

CRL Complex antibiotic resistance gene loci

EMAI Elizabeth Macarthur Agricultural Institute

ExPEC Extra-intestinal pathogenic Escherichia coli

NSW DPI New South Wales Department of Primary Industries

MAR Multiple antibiotic-resistance

MDR Multidrug-resistant

MLA Meat & Livestock Australia

USYD University of Sydney

UTI Urinary tract infections

UTS University of Technology Sydney

XDR Extrensively drug-resistant

Appendix A: Project contributions (2013-2016)

Appendix B: Ausgem associated peer-reviewed publications

Appendix C. Key linkages for Ausgem projects for Theileria

Appendix D. Ausgem 1 supported PhD programs

Appendix E. Ausgem collaborations

Appendix F. International and national conference presentations

Glossary

List of Appendices

Appendices are available on request.


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There are both tangible and intangible benefits from the Ausgem partnership and the return on investment will be realised through the securing and expansion of business opportunities for NSW

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