The Virulence Regulator Agr Controls the Staphylococcal Capacity to Activate Human Neutrophils via the Formyl Peptide Receptor 2

Abstract

The Agr quorum-sensing system represents the master regulator for staphylococcal virulence factors and is known to have a strong impact on the release of pathogen-associated molecular pattern (PAMP) molecules. Among the various staphylococcal PAMPs, phenol-soluble modulin (PSM) peptides have attracted increasing interest because they are crucial for staphylococcal virulence and have neutrophil-recruiting properties. The latter depend on recognition of PSMs by the neutrophil formyl peptide receptor 2 (FPR2/ALX), for which PSMs are highly efficient agonists. We demonstrate that Agr inactivation in Staphylococcus aureus or S. epidermidis leads to strongly reduced neutrophil responses, which is in agreement with the previously reported strict control of PSM expression by Agr. Agr had a distinct and profound impact on activation of FPR2/ALX but not of the related FPR1 receptor that senses bacterial formylated peptides. S. epidermidis PSMs had similar FPR2/ALX-activating properties but differed in their dependence on N-terminal formylation compared to S. aureus PSMs. Moreover, S. aureus and S. epidermidis PSMs upregulated the neutrophil complement receptor CD11b via FPR2/ALX stimulation in an Agr-dependent fashion. Hence, Agr controls the capacity of staphylococcal pathogens to activate FPR2/ALX-dependent neutrophil responses, underscoring the crucial role of FPR2/ALX and PSMs in staphylococcus-host interaction.

The AgrD N-Terminal Leader Peptide of Staphylococcus aureus Has Cytolytic and Amyloidogenic Properties

“…PSMs can induce proinflammatory responses by neutrophils, such as neutrophil chemotaxis and IL-8 cytokine release (12)(13)(14). Since N-AgrD displayed cytolytic activity against host cells (Fig.…”

“…PSMs are of particular interest because they perform multiple roles in pathogenesis. These short peptides compound pathogenicity by activating host receptor-mediated inflammatory responses (12)(13)(14)(15)(16)(17), lysing red and white blood cells (16,18,19), altering biofilm development (20)(21)(22)(23), and acting as antimicrobial agents against nicheoccupying organisms in the host (24)(25)(26)(27).…”

“…Agr directly regulates the expression of all three PSM types characterized (PSM␣1-4, PSM␤1-2, and delta-toxin) (13,33). The agrBDCA operon encodes the core components of the quorum-sensing system, while the divergently transcribed RNAIII is a regulatory RNA and the primary effector of the agr regulon.…”

Phenol Soluble Modulin (PSM) Variants of Community-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) Captured Using Mass Spectrometry-Based Molecular Networking

“…Associated with biofilm formation and possessing bioactivity toward host cells, PSMs are produced more abundantly by CA-MRSA compared with HA-MRSA strains (13,14). PSMs are biosynthesized and released with formylated initiator methionine, allowing binding and activation of host neutrophils via the formyl peptide receptor 2 (FPR2) (15). A number of PSMs show cytolytic properties toward host cell lines, and supporting this, isogenic PSMknockout mutants have decreased virulence in murine models of invasive infection (13).…”

Characterization of coagulase-negative staphylococci isolated from hospital indoor air and a comparative analysis between airborne and inpatient isolates of Staphylococcus epidermidis

“…It was reported that S. epidermidis PSMs upregulate the neutrophil complement receptor CD11b via stimulation of the neutrophil formyl peptide receptor 2 (FPR2/ALX) in an agr-dependent manner, underlining the important role of FPR2/ALX and PSMs in bacteria-host interactions (Kretschmer et al, 2012). Six types of PSMs have been described thus far in S. epidermidis (Wang et al, 2011).…”