ORCID Profile
0000-0001-9620-8735
Current Organisation
University of Melbourne
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Publisher: Cold Spring Harbor Laboratory
Date: 26-03-2023
DOI: 10.1101/2023.03.25.534241
Abstract: Infections caused by metallo-beta-lactamase-producing organisms (MBLs) are a global health threat. Our understanding of transmission dynamics and how MBLs establish endemicity remains limited. We analysed two decades of bla IMP-4 evolution in a hospital using sequence data from 270 clinical and environmental isolates (including 169 completed genomes) and identified extreme gene promiscuity across 7 Gram-negative genera, 68 bacterial strains and 7 distinct plasmid types. An initial multi-species outbreak of conserved IncC plasmids (95 genomes across 37 strains) allowed endemicity to be established through the ability of bla IMP-4 to disseminate in successful strain-genetic setting pairs we termed ‘propagators’, in particular Serratia marcescens and Enterobacter hormaechei . From this reservoir, bla IMP-4 persisted through ersification of genetic settings that resulted from transfer of bla IMP-4 plasmids between bacterial hosts and of the integron carrying bla IMP-4 between plasmids. Our findings provide a framework for understanding endemicity and spread of MBLs and may have broader applicability to other carbapenemase-producing organisms.
Publisher: Springer Science and Business Media LLC
Date: 23-08-2022
DOI: 10.1186/S13073-022-01103-0
Abstract: Resistance to third-generation cephalosporins, often mediated by extended-spectrum beta-lactamases (ESBLs), is a considerable issue in hospital-associated infections as few drugs remain for treatment. ESBL genes are often located on large plasmids that transfer horizontally between strains and species of Enterobacteriaceae and frequently confer resistance to additional drug classes. Whilst plasmid transmission is recognised to occur in the hospital setting, the frequency and impact of plasmid transmission on infection burden, compared to ESBL + strain transmission, is not well understood. We sequenced the genomes of clinical and carriage isolates of Klebsiella pneumoniae species complex from a year-long hospital surveillance study to investigate ESBL burden and plasmid transmission in an Australian hospital. Long-term persistence of a key transmitted ESBL + plasmid was investigated via sequencing of ceftriaxone-resistant isolates during 4 years of follow-up, beginning 3 years after the initial study. We found 25 distinct ESBL plasmids. We identified one plasmid, which we called Plasmid A, that carried bla CTX-M-15 in an IncF backbone similar to pKPN-307. Plasmid A was transmitted at least four times into different Klebsiella species/lineages and was responsible for half of all ESBL episodes during the initial 1-year study period. Three of the Plasmid A-positive strains persisted locally 3–6 years later, and Plasmid A was detected in two additional strain backgrounds. Overall Plasmid A accounted for 21% of ESBL + infections in the follow-up period. Here, we systematically surveyed ESBL strain and plasmid transmission over 1 year in a single hospital network. Whilst ESBL plasmid transmission events were rare in this setting, they had a significant and sustained impact on the burden of ceftriaxone-resistant and multidrug-resistant infections. If onward transmission of Plasmid A-carrying strains could have been prevented, this may have reduced the number of opportunities for Plasmid A to transmit and create novel ESBL + strains, as well as reducing overall ESBL infection burden.
Publisher: Cold Spring Harbor Laboratory
Date: 16-09-2022
DOI: 10.1101/2022.09.16.508259
Abstract: RNAseq data can be used to infer genetic variants, yet its use for estimating genetic population structure remains underexplored. Here, we construct a freely available computational tool (RGStraP) to estimate RNAseq-based genetic principal components (RG-PCs) and assess whether RG-PCs can be used to control for population structure in gene expression analyses. Using whole blood s les from understudied Nepalese populations and the Geuvadis study, we show that RG-PCs had comparable results to paired array-based genotypes, with high genotype concordance and high correlations of genetic principal components, capturing subpopulations within the dataset. In differential gene expression analysis, we found that inclusion of RG-PCs as covariates reduced test statistic inflation. Our paper demonstrates that genetic population structure can be directly inferred and controlled for using RNAseq data, thus facilitating improved retrospective and future analyses of transcriptomic data.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 08-08-2023
DOI: 10.1038/S41467-023-39915-2
Abstract: Infections caused by metallo-beta-lactamase-producing organisms (MBLs) are a global health threat. Our understanding of transmission dynamics and how MBLs establish endemicity remains limited. We analysed two decades of bla IMP-4 evolution in a hospital using sequence data from 270 clinical and environmental isolates (including 169 completed genomes) and identified the bla IMP-4 gene across 7 Gram-negative genera, 68 bacterial strains and 7 distinct plasmid types. We showed how an initial multi-species outbreak of conserved IncC plasmids (95 genomes across 37 strains) allowed endemicity to be established through the ability of bla IMP-4 to disseminate in successful strain-genetic setting pairs we termed propagators, in particular Serratia marcescens and Enterobacter hormaechei . From this reservoir, bla IMP-4 persisted through ersification of genetic settings that resulted from transfer of bla IMP-4 plasmids between bacterial hosts and of the integron carrying bla IMP-4 between plasmids. Our findings provide a framework for understanding endemicity and spread of MBLs and may have broader applicability to other carbapenemase-producing organisms.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2023
DOI: 10.1038/S42003-023-05171-9
Abstract: RNAseq data can be used to infer genetic variants, yet its use for estimating genetic population structure remains underexplored. Here, we construct a freely available computational tool (RGStraP) to estimate RNAseq-based genetic principal components (RG-PCs) and assess whether RG-PCs can be used to control for population structure in gene expression analyses. Using whole blood s les from understudied Nepalese populations and the Geuvadis study, we show that RG-PCs had comparable results to paired array-based genotypes, with high genotype concordance and high correlations of genetic principal components, capturing subpopulations within the dataset. In differential gene expression analysis, we found that inclusion of RG-PCs as covariates reduced test statistic inflation. Our paper demonstrates that genetic population structure can be directly inferred and controlled for using RNAseq data, thus facilitating improved retrospective and future analyses of transcriptomic data.
Publisher: Cold Spring Harbor Laboratory
Date: 11-10-2021
DOI: 10.1101/2021.10.10.463858
Abstract: The Klebsiella pneumoniae species complex (KpSC) is a set of seven Klebsiella taxa which are found in a variety of niches, and are an important cause of opportunistic healthcare-associated infections in humans. Due to increasing rates of multi-drug resistance within the KpSC, there is a growing interest in better understanding the biology and metabolism of these organisms to inform novel control strategies. We collated 37 sequenced KpSC isolates isolated from a variety of niches, representing all seven taxa. We generated strain-specific genome scale metabolic models (GEMs) for all 37 isolates and simulated growth phenotypes on 511 distinct carbon, nitrogen, sulphur and phosphorus substrates. Models were curated and their accuracy assessed using matched phenotypic growth data for 94 substrates (median accuracy of 96%). We explored species-specific growth capabilities and examined the impact of all possible single gene deletions on growth in 145 core carbon substrates. These analyses revealed multiple strain-specific differences, within and between species and highlight the importance of selecting a erse range of strains when exploring KpSC metabolism. This erse set of highly accurate GEMs could be used to inform novel drug design, enhance genomic analyses, and identify novel virulence and resistance determinants. We envisage that these 37 curated strain-specific GEMs, covering all seven taxa of the KpSC, provide a valuable resource to the Klebsiella research community.
Publisher: Cold Spring Harbor Laboratory
Date: 04-08-2023
DOI: 10.1101/2023.08.02.23293478
Abstract: New Delhi metallo-beta-lactamases (NDMs) are major contributors to the spread of carbapenem resistance globally. In Australia, NDMs were previously associated with international travel but from 2019 we noted increasing NDM episodes. We conducted an investigation to determine the clinical and genomic epidemiology of NDM-carriage at a tertiary Australian hospital from 2016-2021. We identified 49 patients with 84 NDM-carrying isolates in an institutional database and collected clinical data from electronic medical records. Short- and long-read whole genome sequencing was performed on all isolates. Completed genome assemblies were used to assess the genetic setting of bla NDM genes and compare NDM plasmids. Of 49 patients, 38 (78%) were identified in 2019-2021 and only 11/38 (29%) reported prior travel compared with 9/11 (82%) in 2016-2018 ( P= 0.037). In patients with NDM infection, crude 7-day mortality was 0% and 30-day mortality was 14% (2/14 patients). NDMs were noted in 41 bacterial strains (i.e. species/sequence type combinations). Four NDM variants ( bla NDM-1 , bla NDM-4 , bla NDM-5 , bla NDM-7 ) were detected across 13 plasmid groups. We noted a change from a erse NDM plasmid repertoire in 2016-2018 to the emergence of conserved bla NDM-1 IncN and bla NDM-7 IncX3 epidemic plasmids with inter-strain spread in 2019-2021. These plasmids were noted in 19/38 (50%) patients and 35/68 (51%) genomes in 2019-2021. Increased NDM case numbers were due to local circulation of two epidemic plasmids with extensive inter-strain transfer. Our study underscores the challenges of outbreak detection when horizontal transmission of plasmids is the primary mode of spread.
No related grants have been discovered for Taylor Harshegyi.