AUTHOR=Collins Madison M. , Behera Ranjan K. , Pallister Kyler B. , Evans Tyler J. , Burroughs Owen , Flack Caralyn , Guerra Fermin E. , Pullman Willis , Cone Brock , Dankoff Jennifer G. , Nygaard Tyler K. , Brinsmade Shaun R. , Voyich Jovanka M. 

TITLE=The Accessory Gene saeP of the SaeR/S Two-Component Gene Regulatory System Impacts Staphylococcus aureus Virulence During Neutrophil Interaction

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.00561

DOI=10.3389/fmicb.2020.00561

ISSN=1664-302X

ABSTRACT=<p><italic>Staphylococcus aureus</italic> (<italic>S. aureus</italic>) causes a range of diseases ranging from superficial skin and soft-tissue infections to invasive and life-threatening conditions (<xref ref-type="bibr" rid="B20">Klevens et al., 2007</xref>; <xref ref-type="bibr" rid="B21">Kobayashi et al., 2015</xref>). <italic>S. aureus</italic> utilizes the Sae sensory system to adapt to neutrophil challenge. Although the roles of the SaeR response regulator and its cognate sensor kinase SaeS have been demonstrated to be critical for surviving neutrophil interaction and for causing infection, the roles for the accessory proteins SaeP and SaeQ remain incompletely defined. To characterize the functional role of these proteins during innate immune interaction, we generated isogenic deletion mutants lacking these accessory genes in USA300 (USA300Δ<italic>saeP</italic> and USA300Δ<italic>saeQ</italic>). <italic>S. aureus</italic> survival was increased following phagocytosis of USA300Δ<italic>saeP</italic> compared to USA300 by neutrophils. Additionally, secreted extracellular proteins produced by USA300Δ<italic>saeP</italic> cells caused significantly more plasma membrane damage to human neutrophils than extracellular proteins produced by USA300 cells. Deletion of <italic>saeQ</italic> resulted in a similar phenotype, but effects did not reach significance during neutrophil interaction. The enhanced cytotoxicity of USA300Δ<italic>saeP</italic> cells toward human neutrophils correlated with an increased expression of bi-component leukocidins known to target these immune cells. A <italic>saeP</italic> and <italic>saeQ</italic> double mutant (USA300Δ<italic>saePQ</italic>) showed a significant increase in survival following neutrophil phagocytosis that was comparable to the USA300Δ<italic>saeP</italic> single mutant and increased the virulence of USA300 during murine bacteremia. These data provide evidence that SaeP modulates the Sae-mediated response of <italic>S. aureus</italic> against human neutrophils and suggest that <italic>saeP</italic> and <italic>saeQ</italic> together impact pathogenesis <italic>in vivo</italic>.</p>