Staphylococcus aureus toxins – Their functions and genetics

Highlights

• S. aureus is a frequent cause of infection and a common human commensal.

• The S. aureus pan-genome encodes numerous toxins.

• The endowment of clinical S. aureus isolates with toxin genes is highly variable.

• Toxin gene distribution is not random but coupled to the genetic background.

• This has important implications for epidemiological studies of pathogenesis.

Abstract

The outcome of encounters between Staphylococcus (S.) aureus and its human host ranges from life-threatening infection through allergic reactions to symptom-free colonization. The pan-genome of this bacterial species encodes numerous toxins, known or strongly suspected to cause specific diseases or symptoms. Three toxin families are in the focus of this review, namely (i) pore-forming toxins, (ii) exfoliative toxins and (iii) superantigens. The majority of toxin-encoding genes are located on mobile genetic elements (MGEs), resulting in a pronounced heterogeneity in the endowment with toxin genes of individual S. aureus strains. Recent population genomic analysis have provided a framework for an improved understanding of the temporal and spatial scales of the motility of MGEs and their associated toxin genes. The distribution of toxin genes among clonal lineages within the species S. aureus is not random, and phylogenetic (sub-)lineages within clonal complexes feature characteristic toxin signatures. When studying pathogenesis, this lineage association, which is caused by the clonal nature of S. aureus makes it difficult to discriminate effects of specific toxins from contributions of the genetic background and/or other associated genetic factors.

Introduction

Staphylococcus (S.) aureus is notorious as the most common causative agent of hospital-acquired infections, and the spread of antibiotic resistant strains, particularly methicillin-resistant S. aureus (MRSA), in hospitals challenges health care systems worldwide. Moreover, S. aureus strains of increased virulence, known as community-aquired MRSA (CA-MRSA), can threaten even healthy individuals in the community (Chambers and DeLeo, 2009, David and Daum, 2010, DeLeo et al., 2010). In addition, S. aureus is currently being discussed as the trigger and/or enhancer of allergies of the respiratory system and the skin (Bachert and Zhang, 2012, Gould et al., 2007). Nevertheless up to now, no anti-S. aureus vaccine has been approved for medical practice (Schaffer and Lee, 2008, Spellberg and Daum, 2012). In spite of the above, the most frequent encounter of S. aureus with its human host is peaceful colonization, and around 20% of adults are persistent carriers of the micro-organisms, while another 60% are intermittently colonized (van Belkum et al., 2009, Wertheim et al., 2005). What makes the species S. aureus so immensely successful?

A salient feature of S. aureus is its variability. By indexing nucleotide sequence diversity at seven universally present genetic loci, multilocus-sequence typing (MLST) to date has revealed about 2,400 ‘sequence types’ (ST) for S. aureus (see <www.mlst.net>). The vast majority of these diverse STs, however, are clustered in a remarkably limited number of clonal complexes (CC) or lineages, each of which appears to be distributed worldwide (reviewed in (Nübel et al., 2011)). The predominant S. aureus lineages are CC1, 5, 8, 15, 22, 30, 45, 59, 80, 97 and 121 (Nübel et al., 2011).

About 75% of the S. aureus genes are shared by more than 95% of strains and hence may be considered the ‘core genome’ of the species. In addition, two kinds of variably present genes can be distinguished: (i) the core variable genes (∼10% of genes), which are largely conserved within each of the S. aureus clonal complexes and constitute their respective “make up”, and (ii) mobile genetic elements (MGEs, ∼15% of genes). The core variable genome includes most surface-associated genes (microbial surface components recognizing adhesive matrix molecules, MSCRAMMs) and regulator genes. Core variable genes are encoded on the bacterial chromosome and are, therefore, typically stable and transferred vertically (Lindsay et al., 2006). MGEs include bacteriophages, plasmids, S. aureus pathogenicity islands (SaPI), transposons, and staphylococcal chromosomal cassettes (SCC) (Feil et al., 2003, Lindsay, 2010, Lindsay and Holden, 2006, Lindsay et al., 2006). They mainly encode resistance (e.g. methicillin resistance genes) and virulence genes (e.g., Panton-Valentine leukocidin (PVL) genes, superantigen (SAg) genes). MGEs can be distributed either by vertical transmission to daughter cells or by horizontal transfer (Lindsay and Holden, 2006).

The full complement of all genes (also known as the pan-genome) of S. aureus encodes a wide array of secreted or cell-surface-associated virulence factors (Foster, 2005). These include proteins that

• mediate adherence to damaged tissue, extra-cellular matrix and the surface of host cells (Foster and Hook, 1998),

• facilitate tissue destruction and spreading,

• promote iron uptake (Skaar and Schneewind, 2004),

• bind to proteins in the bodily fluids to help evade antibody- and complement-mediated immune responses, including the action of phagocytes,

• lyse host cells and

• manipulate the innate and adaptive immune responses.

However, a clear association between virulence genes and disease symptoms has been established or is strongly suspected only for some potent S. aureus toxins causing, for example, toxic shock syndrome (TSS), staphylococcal scalded skin syndrome (SSSS), necrotizing pneumonia, or deep-seated skin infections (Dinges et al., 2000, Holtfreter and Bröker, 2005, Jarraud et al., 1999, Jarraud et al., 2002, Ladhani, 2003). This review focuses on such toxins, including pore-forming toxins, like PVL and hemolysin-α (Hla, α-toxin,), exfoliative toxins (ET) and the SAgs. They damage the membranes of host cells, degrade inter-cellular junctions, or modulate the immune response by aberrant activation of immune cells. Only a few S. aureus toxins, such as Hla and the phenol-soluble modulins (PSMs), are core genome-encoded, while most of the other toxin genes are localized on MGEs (Table 1). Hence, the species S. aureus is characterized by extraordinary heterogeneity regarding the toxin gene equipment of individual clinical isolates.