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. 2014 May 6;111(18):6738-43.
doi: 10.1073/pnas.1401006111. Epub 2014 Apr 21.

Molecular tracing of the emergence, diversification, and transmission of S. aureus sequence type 8 in a New York community

Anne-Catrin Uhlemann  1 , Janina Dordel, Justin R Knox, Kathy E Raven, Julian Parkhill, Matthew T G Holden, Sharon J Peacock, Franklin D Lowy
Affiliations

Molecular tracing of the emergence, diversification, and transmission of S. aureus sequence type 8 in a New York community

Anne-Catrin Uhlemann et al. Proc Natl Acad Sci U S A. .

Abstract

During the last 2 decades, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains have dramatically increased the global burden of S. aureus infections. The pandemic sequence type (ST)8/pulsed-field gel type USA300 is the dominant CA-MRSA clone in the United States, but its evolutionary history and basis for biological success are incompletely understood. Here, we use whole-genome sequencing of 387 ST8 isolates drawn from an epidemiological network of CA-MRSA infections and colonizations in northern Manhattan to explore short-term evolution and transmission patterns. Phylogenetic analysis predicted that USA300 diverged from a most common recent ancestor around 1993. We found evidence for multiple introductions of USA300 and reconstructed the phylogeographic spread of isolates across neighborhoods. Using pair-wise single-nucleotide polymorphism distances as a measure of genetic relatedness between isolates, we observed that most USA300 isolates had become endemic in households, indicating their critical role as reservoirs for transmission and diversification. Using the maximum single-nucleotide polymorphism variability of isolates from within households as a threshold, we identified several possible transmission networks beyond households. Our study also revealed the evolution of a fluoroquinolone-resistant subpopulation in the mid-1990s and its subsequent expansion at a time of high-frequency outpatient antibiotic use. This high-resolution phylogenetic analysis of ST8 has documented the genomic changes associated with USA300 evolution and how some of its recent evolution has been shaped by antibiotic use. By integrating whole-genome sequencing with detailed epidemiological analyses, our study provides an important framework for delineating the full diversity and spread of USA300 and other emerging pathogens in large urban community populations.

Keywords: CC8; drug resistance; genomics; phylogeny.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Phylogeny of ST8 and the emergence of USA300. (A) Maximum likelihood phylogenetic tree of ST8 isolates, rooted by using the distantly related S. aureus isolate named COL as an out-group. The USA300 clade is shaded in black, and the non-USA300 ST8 clades are in gray. Dots indicate the USA500 clade. Colors in the outer ring show the isolate type, and colors in the middle circle indicate the neighborhoods. Lines connect distantly related isolates with >23 SNPs from the same household (colored by neighborhood). (B) A unique subclade, defined by a nonsense mutation in wrbA, is shown in blue. Colors on the left indicate isolate type, and on the right they indicate neighborhood. Lines connect distantly related isolates from the same household.
Fig. 2.
Fig. 2.
Bayesian phylogenetic reconstruction of northern Manhattan USA300 isolates. The phylogeny is a maximum clade consensus tree, estimated from core genome SNPs. (A) Colors of internal and terminal branches indicate neighborhoods. Branches are scaled with time (months/years). (B) Map of New York City indicating the sampled neighborhoods (adapted from Wikimedia Commons M. Minderhound).
Fig. 3.
Fig. 3.
Pairwise SNP comparisons between (A) multiple body sites from one person (nose, throat, and skin sites axilla or groin) or (B) within households (red) or between isolates from different community households (blue).
Fig. 4.
Fig. 4.
Putative transmission of isolates within and between community households. Upright red triangles indicate transmission within households, which corresponds with the number of similar isolates. Downward blue triangles indicate multiple unrelated ST8 isolates, and green highlights single ST8 isolate households. Linkages between households are shown as black lines (identical sequences), red lines (sequence and epidemiological connection), or green lines (epidemiological but no sequence link).
Fig. 5.
Fig. 5.
Accessory genome diversity in ST8. (A) The presence of MGEs closely mirrors the phylogeny of the core genome. ACME is restricted to the USA300 clade (shaded in black). (B) Evidence for ACME remnants in isolates carrying SAPI5 and SCCmec IVa. Visualization of a BlastN pairwise comparison in ACT (48) of the ACME regions of FPR3757 reference sequence (*) and isolate USFL058 (#).
Fig. 6.
Fig. 6.
Clonal emergence of fluoroquinolone resistance-conferring mutations in gyrA and grlA. (A) Maximum likelihood tree of all isolates. (B) Bayesian phylogenetic reconstruction based on 112 clinical isolates. The phylogeny is a maximum clade consensus tree estimated from core genome SNPs. Branches are colored according to the fluoroquinolone genotype as susceptible (blue) and resistant (red). The tips of the tree are constrained by isolation date. PP, posterior probability. Gains of MGEs SAPI5, ACME, Sa2int, and the nonsense mutation in wrbA (*) have been mapped on the tree.
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