<i>Staphylococcus aureus</i> induces a muted host response in human blood that blunts the recruitment of neutrophils.

Abstract

<i>Staphylococcus aureus</i> is an opportunistic pathogen and chief among bloodstream-infecting bacteria. <i>S. aureus</i> produces an array of human-specific virulence factors that may contribute to immune suppression. Here, we defined the response of primary human phagocytes following infection with <i>S. aureus</i> using RNA-sequencing (RNA-Seq). We found that the overall transcriptional response to <i>S. aureus</i> was weak both in the number of genes and in the magnitude of response. Using an ex vivo bacteremia model with fresh human blood, we uncovered that infection with <i>S. aureus</i> resulted in the down-regulation of genes related to innate immune response and cytokine and chemokine signaling. This muted transcriptional response was conserved across diverse <i>S. aureus</i> clones but absent in blood exposed to heat-killed <i>S. aureus</i> or blood infected with the less virulent staphylococcal species <i>Staphylococcus epidermidis</i>. Notably, this signature was also present in patients with <i>S. aureus</i> bacteremia. We identified the master regulator <i>S. aureus</i> exoprotein expression (SaeRS) and the SaeRS-regulated pore-forming toxins as key mediators of the transcriptional suppression. The <i>S. aureus</i>-mediated suppression of chemokine and cytokine transcription was reflected by circulating protein levels in the plasma. Wild-type <i>S. aureus</i> elicited a soluble milieu that was restrictive in the recruitment of human neutrophils compared with strains lacking <i>saeRS</i>. Thus, <i>S. aureus</i> blunts the inflammatory response resulting in impaired neutrophil recruitment, which could promote the survival of the pathogen during invasive infection.