Virulence attributes of successful methicillin-resistant Staphylococcus aureus lineages

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of severe and often fatal infections. MRSA epidemics have occurred in waves, whereby a previously successful lineage has been replaced by a more fit and better adapted lineage. Selection pressures in both hospital and community settings are not uniform across the globe, which has resulted in geographically distinct epidemiology. This review focuses on the mechanisms that trigger the establishment and maintenance of current, dominant MRSA lineages across the globe. While the important role of antibiotic resistance will be mentioned throughout, factors which influence the capacity of S. aureus to colonize and cause disease within a host will be the primary focus of this review. We show that while MRSA possesses a diverse arsenal of toxins including alpha-toxin, the success of a lineage involves more than just producing toxins that damage the host. Success is often attributed to the acquisition or loss of genetic elements involved in colonization and niche adaptation such as the arginine catabolic mobile element, as well as the activity of regulatory systems, and shift metabolism accordingly (e.g., the accessory genome regulator, agr). Understanding exactly how specific MRSA clones cause prolonged epidemics may reveal targets for therapies, whereby both core (e.g., the alpha toxin) and acquired virulence factors (e.g., the Panton-Valentine leukocidin) may be nullified using anti-virulence strategies.

Keywords: gene regulation; metabolism; methicillin-resistant Staphylococcus aureus; mobile genetic elements; superantigens; toxins; virulence.

Fig 1

Defining MRSA lineages. (A) Pulsed-field gel electrophoresis (PFGE) was previously the standard method to discriminate S. aureus lineages and is based on comparing DNA patterns following restriction enzyme digestion [adapted from reference (88)]. (B) Characterization of the relatedness between S. aureus strains was advanced by comparing the sequence of seven housekeeping genes, which is known as multi-locus sequence typing (MLST). (C) As all MRSA strains carry the staphylococcal cassette chromosome mec (SCCmec), identifying sequence and structural similarities of SCCmec between the isolates provides another dimension for lineage definition [based on reference (34)]. (D) Sequence types of MRSA strains defined by MLST can be grouped into clonal complexes (CCs) to infer evolutionary descent across MRSA lineages [adapted from reference (89) with permission of the publisher). (E) Whole-genome sequencing is increasingly being used for phylogenetic analysis to trace the evolution and transmission of successful MRSA clones at high resolution. In the example shown, phylogenetic analysis of 348 genomes illustrates the relationship structure of clinically important CC8 groups. These groups include (A) CC8a Archaic/Iberian, (B) CC8b MSSA clade, (C) CC8c USA500, (D) CC8d CMRSA-9, (E) CC8e (USA500, EB-USA300, USA300-SAE), and (F) CC8f USA300-NAE. Throughout the figure, red boxes indicate how these technologies can be integrated to define a lineage. Here, we have highlighted MRSA-ST8-IVa (USA300-NAE) [adapted from reference (90)].

Fig 2

Virulence factors in Staphylococcus aureus. The factors are encoded in the genome or acquired via horizontal gene transfer and can be grouped into two categories: establishing niches and responding to stress. Control of these factors is intertwined via two-component regulatory systems (TCS) and the accessory genome regulator (agr). ACME, arginine catabolic mobile element; ClfA/B, clumping factor A/B; Cna, collagen adhesin; FnBPA/B, fibronectin-binding protein A/B; HK, histidine kinase; IsdB, iron-regulated surface determinant B; MGEs, mobile genetic elements; PIA, polysaccharide intercellular adhesin; PSMs, phenol soluble modulins; PVL, Panton-Valentine leucocidin; RR, response regulator; SasG, S. aureus surface protein G; SCCmec, staphylococcal cassette chromosome mec; Sbi, immunoglobulin-binding protein; Spa, staphylococcal protein A.

Fig 3

Distribution of current dominant MRSA lineages. The major lineages of HA-MRSA, CA-MRSA, and LA-MRSA reported in each continent or region are shown. (a) Data on LA-MRSA from Africa, Latina America, and Australia were retrieved from single reports due the paucity of available data and, therefore, should not be considered as predominant LA-MRSA lineages in these regions. (b) Although there is no clear distinction between HA- and CA-MRSA clones reported from the African continent, the results should be interpreted with caution since they may reflect the lack of epidemiological data.