The role of virulence determinants in community-associated MRSA pathogenesis

Abstract

The recent emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) marked a quantum change in the biology and epidemiology of a major human pathogen. Various virulence determinants unique to CA-MRSA have been uncovered recently, which shed light on how these strains spread easily and sustainably among humans and frequently cause severe disease. The role of the Panton Valentine leukocidin (PVL) in CA-MRSA pathogenesis is a matter of much debate. Although epidemiological data have indicated a role for PVL in the CA-MRSA disease process, recent data from relevant animal models indicate that PVL does not impact virulence of prevalent CA-MRSA strains. Identifying specialized pathogenic traits of CA-MRSA remains a challenge that will yield new diagnostic tools and therapeutic targets for drug and vaccine development. Here, we discuss the roles of PVL, the arginine catabolic mobile element and phenol-soluble modulins in the pathogenesis of prevalent CA-MRSA strains.

Figure 1

Genetic diversity among S. aureus strains that have independently acquired type IV SCCmec (blue). The five predominant CA-MRSA clones (red) all have the lukPV gene operon encoding Panton Valentine leukocidin. The graph was constructed with Splitstree (version 4.8) using concatenated sequences of seven housekeeping gene fragments used in MLST for S aureus. The scale bar represents the evolutionary distance (number of substitutions per nucleotide position).

Figure 2

Interstrain differences in gene content among methicillin resistant Staphylococcus aureus. Concentric circles represent the circular chromosomes of USA300, COL, N315, MW2, and MRSA252. The core chromosome, consisting of genes shared by all strains of S. aureus, is shown in gray. The accessory chromosome, consisting of genes acquired through horizontal acquisition of mobile genetic elements, includes the different allotypes of SCCmec (blue), ACME (light blue), pathogenicity islands (red or green), and prophages (black).

Figure 3

The α-type phenol-soluble modulins (PSMs). (a), arrangement of the α-type PSM genes in the S. aureus genome (shown for strain USA300). (b), amino acid sequences of α-type PSMs. (c), α-type PSMs cause neutrophil lysis. Representative images of neutrophils incubated with PSMα3 (10 μg) or buffer after 60 min of incubation. (d), α-type PSMs are crucial for CA-MRSA skin and soft tissue infection. Representative images of dermonecrosis formed by USA300 wild-type and isogenic PSMα operon deletion strains.

Figure 4

Molecular basis of CA-MRSA infection. The exceptional success of CA-MRSA strains in the community is likely due to enhanced virulence and colonization. In addition to an enhanced capacity for nasal carriage [11], CA-MRSA strains are also commonly carried on the skin, thereby facilitating skin-to-skin spread and even sexual transmission [71-75]. Using isogenic mutant strains in CA-MRSA, 3 factors have a proven impact on CA-MRSA pathogenesis, as determined in animal models. PSMs (α-type) are crucial for abscess formation and bacteremia, the most widely found manifestations of CA-MRSA disease. α-toxin has a dramatic impact on the development of necrotizing pneumonia, one of the rarer and more dramatic diseases CA-MRSA may cause. Whether PSMs have a role in necrotizing pneumonia, or α-hemolysin in abscess formation and bacteremia of CA-MRSA, has not been tested yet. Both factors are widely found in S. aureus strains. However, CA-MRSA strains may differ from HA-MRSA strains in the expression of these factors, as shown for PSMs. The mobile genetic element ACME is thought to enhance colonization and survival on the skin and is only found in the USA300 background. USA300 CA-MRSA strains with ACME outcompete isogenic strains without ACME in a rabbit infection model.