Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMα3 peptide. We found that this variant, PSMα3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMα3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms.
Highlights
Staphylococcus aureus is a dangerous human pathogen that is responsible for thousands of deaths annually in the U
We found the mass corresponding to the PSMa3N22Y peptide in all CC30 strains that we analyzed, containing contemporary and historic strains (Fig. 1C) [9], but never in any of the large number of S. aureus strains of different genetic backgrounds that we had analyzed over the last,5 years
We report an allelic variant in a psm gene that is characteristic for a specific S. aureus lineage, namely CC30, and shows reduced immune-stimulatory and cytolytic activities
Summary
Staphylococcus aureus is a dangerous human pathogen that is responsible for thousands of deaths annually in the U. Virulence of S. aureus is due to a large repertoire of virulence factors, including immune evasion factors and aggressive cytolytic toxins [2]. S. aureus infections become dangerous when they are caused by strains that are resistant to commonly used antibiotics. Methicillin-resistant S. aureus (MRSA) is of especially great concern, as identification of MRSA eliminates the therapeutic use of most beta-lactam antibiotics, which are antibiotics of first choice against pathogenic staphylococci. Many countries report high rates of methicillin resistance among hospital-associated infections caused by S. aureus [3]. Community-associated strains of MRSA (CA-MRSA) have emerged over the last two decades that have the capacity to infect healthy individuals outside of hospital settings [4]
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