A Strain-Specific Clumping Mechanism Enables <i>Staphylococcus aureus</i> ST88 to Circumvent the Host Neutrophil Response

Community-associated methicillin-resistant <i>Staphylococcus aureus</i> strains often demonstrate enhanced virulence, with different strains eliciting varied immune responses in humans. The factors that enable some <i>S. aureus</i> strains to evade killing by immune cells remain unclear. Here, we describe studies designed to understand <i>ex vivo</i> intracellular survival assays that revealed that while a well-characterized MRSA ST8 strain (USA300) was susceptible to phagocytic clearance, a genotypically similar MRSA ST88 strain (LVP-7) effectively evaded neutrophil killing. A pronounced enhancement in neutrophil lysis upon ST88 infection suggests that ST88 can infect polymorphonuclear human neutrophils yet circumvent phagocytosis-associated killing. Both ST8 and ST88 strains show a similar response to extracellular stress elicited by H₂O₂, HOCl, or NO. Host bactericidal mechanisms, such as the release of reactive oxygen species, myeloperoxidases, and elastases, were similar when infected with either strain. The transcriptome profile of ST88 upon phagocytosis at different stages of infection alongside a comparison of the phenotypic traits of ST8 and ST88 revealed factors that could potentially rationalize ST88's evasion of killing by neutrophils. Upon phagocytosis, the ST88 transcriptome showed distinct changes in the levels of the quorum sensing accessory gene regulator (Agr). Confocal imaging revealed that the ST88 strain clusters more with higher bacteria per infected neutrophil than the ST8 strain. A pronounced reduction in ST88 clumping was seen upon the addition of the cognate autoinducing peptide AIP-III, consistent with the premise that the Agr mechanism plays a role in the evasion of neutrophil-mediated killing by the ST88 strain. It thus appears likely that clumping, modulated by quorum sensing, provides a route for this <i>S. aureus</i> strain to evade the human innate immune response.