Prophages and adaptation of Staphylococcus aureus ST398 to the human clinic

Abstract

Background: It has been suggested that prophages in the ST398 S. aureus clone are responsible for expanding ST398's spectrum of action and increasing its ability to cause human infections. We carried out the first characterization of the various prophages carried by 76 ST398 bloodstream infection (BSI) isolates obtained over 9 years of observation.

Results: Whole-genome sequencing of 22 representative isolates showed (1) the presence of the φ3-prophage and diverse genetic features typical of animal-associated isolates (i.e., SCCmec XI element, Tn916 transposon and non φ3-prophages) in a majority of BSI isolates, (2) one BSI isolate devoid of the φ3-prophage but otherwise similar to an animal-infecting isolate, (3) 35 prophages carrying numerous genes previously associated with virulence or immune evasion in animal models of staphylococcal infections. The analysis of prophage content in all 76 BSI isolates showed an increasing prevalence of polylysogeny over time. Overall, over the course of the last 10 years, the BSI isolates appear to have acquired increasing numbers of genetic features previously shown to contribute to bacterial adaptation and virulence in animal models of staphylococcal infections.

Conclusions: We hypothesize that lysogeny has played a significant role in increasing the ability of the ST398 clone to cause infections in humans. Our findings highlight the risk that the ST398 lineage will increase its threat to public health by continuing to acquire virulence and/or multiple antibiotic-resistance genes from hospital-associated clones of Staphylococcus aureus.

Keywords: Bloodstream infections; CC398 lineage; Evolution; Livestock-associated; Phage content; Prophage; Staphylococcus aureus; φ3-prophage.

Fig. 1

General results of the whole-genome sequence analysis. ¹ Single-nucleotide polymorphism between core genomes in the human and animal ST398 isolates. In this comparison, 14–265 is used as the reference genome; ²(Ac) colonizing animal-associated isolate, (Ai) infecting animal-associated isolate; all other isolates are from human BSI ³Oxa (methicillin), K (kanamycin), T (tobramycin), E (erythromycin), Te (tetracycline), Fu (fusidic acid); ⁴(+) Tn916-like element, with no tet gene; ⁵ + (2) two different prophages harboured into the bacterial genome

Fig. 2

Comparisons of the proteomes of animal-associated infecting (AI, in red), animal-associated colonizing (AC, in light red), and human BSI-associated (from dark to light blue) S. aureus ST398 isolates. This figure was created with the “CGView Comparison Tool” [21]. From the outside to the inside: ring 1, COG classification (see COG definitions in Additional file 4: Table S1) of ORFs shown in ring 2; rings 2 and 3, ORFs; ring 4, COG classification of ORFs shown in ring 3; rings 5 to 10 (in red and light red), the AI and AC genomes; rings 11 and 12 (in dark yellow), the reference genome (HI SA10-17 isolate) and the unusual HI SA14_265 genome; rings 13 to 26 (in blue), all other HI genomes; rings 27 and 28, the %GC content and GC skew, respectively, of the reference genome. Arrows indicate the locations of the φ3-like and MR11-like prophages, the transposon Tn916, and the SCCmec IV type in the SA10-17 genome

Fig. 3

Proteome-based clustering of the prophages harbored by BSI isolates. The tree was inferred using the online web-server “CVTree3” program (http://tlife.fudan.edu.cn/cvtree3/). Branch lengths referring to the sequence variations are shown on the tree