Evolution of hypervirulence by a MRSA clone through acquisition of a transposable element

Abstract

SUMMARY Staphylococcus aureus has evolved as a pathogen that causes a range of diseases in humans. There are two dominant modes of evolution thought to explain most of the virulence differences between strains. First, virulence genes may be acquired from other organisms. Second, mutations may cause changes in the regulation and expression of genes. Here we describe an evolutionary event in which transposition of an IS element has a direct impact on virulence gene regulation resulting in hypervirulence. Whole genome analysis of a methicillin-resistant S. aureus (MRSA) strain USA500 revealed acquisition of a transposable element (IS256) that is absent from close relatives of this strain. Of the multiple copies of IS256 found in the USA500 genome, one was inserted in the promoter sequence of repressor of toxins (Rot), a master transcriptional regulator responsible for the expression of virulence factors in S. aureus. We show that insertion into the rot promoter by IS256 results in the derepression of cytotoxin expression and increased virulence. Taken together, this work provides new insight into evolutionary strategies by which S. aureus is able to modify its virulence properties and demonstrates a novel mechanism by which horizontal gene transfer directly impacts virulence through altering toxin regulation.

Influence of IS 256 on Genome Variability and Formation of Small-Colony Variants in Staphylococcus aureus

“…Strains SA137/93A and SA137/93G carried 21 common IS256 insertions, among others in the promoter of rot and in the open reading frame (ORF) of comGB. The insertion in the promoter of rot was at nearly the same place as the insertion described previously for S. aureus USA500 (14). However, IS256 is inserted in the opposite direction from that in S. aureus USA500; i.e., in strain SA137/93 the strong C-terminal Ϫ35 promoter sequence of IS256 is located in the vicinity of the promoter of rot, which might alleviate any negative effects of this insertion on transcription.…”

Diversity and Evolution of the Tn 5801-tet (M)-Like Integrative and Conjugative Elements among Enterococcus, Streptococcus, and Staphylococcus

“…Among type B variants, only the mutator family IS256 was consistently detected upstream of orf13 (types B20, B18, and B19), and this stability persisted even when some particular variants (e.g., B20) were disseminated across genera. Some ISs from the IS256 family have been implicated as modulators of gene expression, suggesting that future studies might reveal the role of this IS in the function of type B Tn5801-like elements (50)(51)(52)(53).…”

Complete Genome Sequence of the MRSA Isolate HC1335 from ST239 Lineage Displaying a Truncated AgrC Histidine Kinase Receptor

“…The presence of multiple copies of the IS 256 is a common feature in MRSA genomes (McEvoy et al 2013; Benson et al 2014). In addition to the IS 256 -derived element inserted in the agrC , 20 intact copies of the IS 256 element were detected in the chromosome of HC1335.…”