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

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

doi:10.3389/fmicb.2020.00561

Madison M Collins, Kyler B Pallister + Show 11 more

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https://doi.org/10.3389/fmicb.2020.00561

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Staphylococcus aureus (S. aureus) causes a range of diseases ranging from superficial skin and soft-tissue infections to invasive and life-threatening conditions (Klevens et al., 2007; Kobayashi et al., 2015). S. aureus 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 (USA300ΔsaeP and USA300ΔsaeQ). S. aureus survival was increased following phagocytosis of USA300ΔsaeP compared to USA300 by neutrophils. Additionally, secreted extracellular proteins produced by USA300ΔsaeP cells caused significantly more plasma membrane damage to human neutrophils than extracellular proteins produced by USA300 cells. Deletion of saeQ resulted in a similar phenotype, but effects did not reach significance during neutrophil interaction. The enhanced cytotoxicity of USA300ΔsaeP cells toward human neutrophils correlated with an increased expression of bi-component leukocidins known to target these immune cells. A saeP and saeQ double mutant (USA300ΔsaePQ) showed a significant increase in survival following neutrophil phagocytosis that was comparable to the USA300ΔsaeP single mutant and increased the virulence of USA300 during murine bacteremia. These data provide evidence that SaeP modulates the Sae-mediated response of S. aureus against human neutrophils and suggest that saeP and saeQ together impact pathogenesis in vivo.

Highlights

Staphylococcus aureus (S. aureus) is a highly-adaptable pathogen able to infect various tissues
SaeS and saeR, encoding the sensory kinase and response regulator respectively, have been demonstrated to be essential in S. aureus virulence and pathogenesis (Voyich et al, 2009; Nygaard et al, 2010, 2018; Flack et al, 2014; Liu et al, 2015, 2016; Zurek et al, 2015; Guerra et al, 2016), surprisingly little research has been performed on the two accessory genes of the Sae system, saeP and saeQ
The Sae two-component systems (TCSs) of S. aureus contributes to the expression and production of virulence and immunomodulatory factors that are essential for S. aureus neutrophil evasion and pathogenesis (Voyich et al, 2009; Nygaard et al, 2010; Sun et al, 2010; Flack et al, 2014; Zurek et al, 2014)

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Staphylococcus aureus (S. aureus) is a highly-adaptable pathogen able to infect various tissues. The response regulator, SaeR, is activated following phosphorylation by SaeS and subsequently alters gene transcription by directly binding to a specific recognition sequence in the promoter region of numerous virulence genes including nuc and the bi-component leukotoxins lukF (PVL), lukGH (lukAB), and hlgBC that target human neutrophils (Nygaard et al, 2010; Olson et al, 2013; Liu et al, 2016). The upregulation of these genes facilitates S. aureus survival following neutrophil phagocytosis (Voyich et al, 2009; Flack et al, 2014).

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