Date Published: February 2, 2017
Publisher: Public Library of Science
Author(s): Li Qin, Fei Da, Emilie L. Fisher, Daniel C. S. Tan, Thuan H. Nguyen, Chih-Lung Fu, Vee Y. Tan, Joshua W. McCausland, Daniel E. Sturdevant, Hwang-Soo Joo, Shu Y. Queck, Gordon Y. C. Cheung, Michael Otto, Angelika Grundling.
Bacterial sepsis is a major killer in hospitalized patients. Coagulase-negative staphylococci (CNS) with the leading species Staphylococcus epidermidis are the most frequent causes of nosocomial sepsis, with most infectious isolates being methicillin-resistant. However, which bacterial factors underlie the pathogenesis of CNS sepsis is unknown. While it has been commonly believed that invariant structures on the surface of CNS trigger sepsis by causing an over-reaction of the immune system, we show here that sepsis caused by methicillin-resistant S. epidermidis is to a large extent mediated by the methicillin resistance island-encoded peptide toxin, PSM-mec. PSM-mec contributed to bacterial survival in whole human blood and resistance to neutrophil-mediated killing, and caused significantly increased mortality and cytokine expression in a mouse sepsis model. Furthermore, we show that the PSM-mec peptide itself, rather than the regulatory RNA in which its gene is embedded, is responsible for the observed virulence phenotype. This finding is of particular importance given the contrasting roles of the psm-mec locus that have been reported in S. aureus strains, inasmuch as our findings suggest that the psm-mec locus may exert effects in the background of S. aureus strains that differ from its original role in the CNS environment due to originally “unintended” interferences. Notably, while toxins have never been clearly implied in CNS infections, our tissue culture and mouse infection model data indicate that an important type of infection caused by the predominant CNS species is mediated to a large extent by a toxin. These findings suggest that CNS infections may be amenable to virulence-targeted drug development approaches.
Bacterial sepsis is a frequent cause of death in hospitalized patients. Coagulase-negative staphylococci (CNS) are the leading cause of nosocomial sepsis, especially in neonates [1–3]. CNS sepsis most often originates from the infection of indwelling medical devices, such as in catheter-related bloodstream infections (CRBSIs) or central line-associated blood stream infections (CLABSIs) . Most prominent among CNS infections are those due to the skin commensal Staphylococcus epidermidis . However, the bacterial factors contributing to the development of sepsis, in particular in CNS, are poorly understood.
To analyze the impact of the psm-mec locus on S. epidermidis sepsis, we produced isogenic psm-mec deletion mutants (Δpsm-mec) in two MRSE strains, a clinical isolate (SE620) and the genome-sequenced strain RP62A. PSM-mec production in these strains is representative of clinical PSM-mec-positive MRSE (S1 Fig), which we determined in a clinical S. epidermidis strain collection from Norway to occur in ~ 2/3 (59/91) of the ~ 50% (91/180) methicillin-resistant S. epidermidis. We also introduced a point mutation in the start codon of the psm-mec gene in the genome of strain SE620 to differentiate between effects mediated by the PSM-mec peptide versus those due to the psm-mec srRNA (psm-mec*). Notably, the stability of the psm-mec RNA was not significantly altered by introduction of the 1-basepair start codon mutation (S2 Fig).