Genome-wide association studies reveal candidate genes associated to bacteraemia caused by ST93-IV CA-MRSA

- Genome-wide association studies reveal candidate genes associated to bacteraemia caused by ST93-IV CA-MRSA.
- Background: The global emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has seen the dominance of specific clones in different regions around the world with the PVL-positive ST93-IV as the predominant CA-MRSA clone in Australia.
- In this study we applied a genome-wide association study (GWAS) approach on a collection of Australian ST93-IV MRSA genomes to screen for genetic traits that might have assisted the ongoing transmission of ST93-IV in Australia.
- We also compared the genomes of ST93-IV bacteraemia and non- bacteraemia isolates to search for potential virulence genes associated with bacteraemia..
- Results: Based on single nucleotide polymorphism phylogenetics we revealed two distinct ST93-IV clades.
- One of the clades contained isolates primarily isolated in the northern regions of Australia whilst isolates in the second clade were distributed across the country.
- Analyses of the ST93-IV genome plasticity over a 15-year period revealed an observed gain in accessory genes amongst the clone ’ s population.
- Conclusions: Although this hypothesis was not tested here, it is possible that the emergence of a ST93-IV clade containing additional virulence genes might be related to the high prevalence of ST93-IV infections amongst the indigenous population living in the northern regions of Australia.
- Over the last three decades, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged globally.
- Although polyclonal, a small num- ber of CA-MRSA clones are dominant in different re- gions of the world such as multilocus sequence type.
- Transmission of the dom- inant clones in other regions has occurred, and charac- teristically they harbour the lukS/F-PV genes that encode the Panton-Valentine leukocidin (PVL) toxin [2]..
- In Australia, the dominant CA-MRSA clone is PVL- positive ST93-IV[3].
- Colloquially known as the “Queens- land CA-MRSA clone”, ST93-IV was first described in the early 2000 s.
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- infections including necrotizing pneumonia, ST93-IV is typically associated with skin and soft tissue infections [4].
- Reported across Australia, the clone is frequently isolated in the indigenous Australian population where its dominance is believed to be linked to overcrowding [5], poor hygiene and healthcare [6].
- aureus lineage that emerged in the 1970 s in the North Western region of Australia [5].
- Although earlier studies into the genetic diversity of ST93 showed multiple rearrangements of the spa sequence, the core regions of the genome were very stable [2].
- However in 2014, Stinear et al.
- To screen for potential association between gene con- tent and disease, genome-wide association studies (GWAS) can be performed by analysing single nucleo- tide polymorphisms (SNPs), and the accessory genes provided by WGS data.
- aureus bacteraemia isolates, no obvious associations in the number of virulence genes present in isolates from patients with and without S.
- For example recent GWAS performed on livestock-associated CC398 MRSA, showed the clone frequently lost antimicrobial resistance genes and ac- quired human specific virulence genes in relation to the origin of the host [10]..
- Phylogenetic analysis of the genomes was performed by examining SNPs in the core genome and investigating the absence/presence of accessory genes.
- To screen for potential genetic traits that may have assisted the on- going transmission of ST93-IV in Australia we corre- lated the absence and presence of accessory genes in the ST93-IV genomes to time, location and whether they originated from a bloodstream infection..
- The 423 ST93-IV were isolated across Australia from the following states and mainland territories: Northern Territory (n = 141), Queensland (n = 98), New South.
- Iso- lates in the two PCA clusters correlated with isolates in the two SNP derived phylogenetic clades..
- Overall, of the 302 bacter- aemia isolates, 76 % (n = 230) carried both genes.
- Only 43 and 45 % of the non-bacteraemia isolates carried the clfA and hsdM genes respectively..
- The seven clade 1 specific accessory genes were ohrR (organic hydroperoxide resistance transcriptional regula- tor), acul (putative acrylyl-Coa reductase), ypuA (hypo- thetical protein), hutl_2 (hypothetical protein), entE (enterotoxin E), soj (chromosome-partitioning ATPase) and entA_2 (enterotoxin A) (Fig.
- Approximately 88 % (n = 98/111) of the clade 1 genomes harboured all seven genes, with seven isolates containing none of the seven genes.
- Genomic diversity of ST93 over Time and Location No significant differences in the presence or absence of accessory genes over time or location were identified..
- Recombination/rearrangement of the ST93 genome When we analysed conserved gene neighbourhoods, we observed two genes affected by re-arrangements correl- ating to bacteraemia, sdrF (serine-aspartate repeat- containing protein F) and pls (surface protein) (Supple- mentary Table 4).
- Analysis of the genes show that inver- sions occurred in regions containing sdrF and pls (Supplementary Figure 1)..
- In the current study we have identified two distinct ST93-IV clades circulating concurrently in Australia..
- The identification of the two clades by SNP analysis of the core region was supported by the PCA based on the absence and presence of genes matrix.
- The clade 1 iso- lates were primarily isolated in the northern regions of Australia spread over three states/territories (Western Australia, Northern Territory and Queensland) whilst.
- Based on genomic data of the van Hal et al.
- [5] historic ST93-IV isolates that were located at the root of the phylogenetic tree, we believe the two clades recently di- verged from a common ancestor..
- The known biological significance of these accessory genes varies.
- ST93-IV genomes.
- The roles of the three remaining accessory genes, acul (a putative protein), and ypuA and hutl (both hypo- thetical proteins) are not known.
- The acquisition of the seven accessory genes, which are likely to have origi- nated on mobile genetic elements, may explain the high.
- rates of ST93-IV skin infections amongst indigenous children living in the northern regions of Australia [17]..
- Further studies are required to determine if clade 1 has become the predominant ST93-IV strain in the region’s indigenous communities and the role of these additional genes in the expansion and fitness of this pathogen..
- Based on the variability of the ST93-IV accessory genes over time and location we attempted to identify clade 1 or 2 specific subclades.
- 2 Principal Component Analysis of pan-genome gene matrix of ST93-IV isolates.
- Non Bacteraemia Isolates N.
- (for example, four isolates contained qacA [antiseptic re- sistance protein], qacR [HTH-type transcriptional regu- lator] and tnsB [transposon] which were all located on the same contig), no important difference in the absence or presence of accessory genes related to specific sub- clades were observed..
- aureus bacteraemia and non-bacteraemia genomes [9].
- After accounting for a possible clade 1 selection bias GWAS identified two genes associ- ated with the ST93-IV bacteraemia isolates.
- The 23 bacteraemic genomes that did not harbor hsdM and clfA all carried rearrange- ments of the pls and sdrF, genes.
- aureus clones, the sdr gene in the ST93 strain JKD6159 is the most diverse suggesting sdr acquisition by horizontal gene transfer.
- In the Huping et al.
- study the sdr in the ST93 genome was classified as sdrC [26].
- epidermidis colonisation of the skin [27]..
- In the current study we selected accessory genes and gene rearrangements that show sig- nificant statistical associations with ST93-IV bacter- aemia.
- Finally, phylogenetic analysis has shown ST93-IV has recently gained accessory virulence genes which might be contributing to the clone’s persistence in the Australian indigenous communities..
- A total of 300 ST93 MRSA bacteraemia isolates were identified in the and 2017 [30] Aus- tralian Group on Antimicrobial Resistance (AGAR) Aus- tralian Staphylococcus aureus Sepsis Outcome Programs (ASSOPs).
- The MLST profiles of the remaining 269 genomes were determined using the mlst tool described by Seeman et al.
- In addition to the 269 ASSOP ST93 MRSA, whole genome sequences for 154 ST93 MRSA collected be- tween 2002 and 2012 from Van Hal et al.
- ASSOPs: Australian Staphylococcus aureus Sepsis Outcome Programs.
- CA-MRSA: Community- Associated Methicillin-Resistant Staphylococcus aureus.
- Additional file 1:Supplementary Table 1: ST93-IV isolates used in this study with bacteremia gene matrix.
- Collection of ST93 S.
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