Staphylococcus aureus uses the ArlRS and MgrA cascade to regulate immune evasion during skin infection

Skin is one of the most common sites of host immune response against Staphylococcus aureus infection. Here, through a combination of in vitro assays, mouse models, and intravital imaging, we find that S. aureus immune evasion in skin is controlled by a cascade composed of the ArlRS two-component regulatory system and its downstream effector, MgrA. S. aureus lacking either ArlRS or MgrA is less virulent and unable to form correct abscess structure due to de-repression of a giant surface protein, Ebh. These S. aureus mutants also have decreased expression of immune evasion factors (leukocidins, chemotaxis-inhibitory protein of S. aureus [CHIPS], staphylococcal complement inhibitor [SCIN], and nuclease) and are unable to kill neutrophils, block their chemotaxis, degrade neutrophil extracellular traps, and survive direct neutrophil attack. The combination of disrupted abscess structure and reduced immune evasion factors makes S. aureus susceptible to host defenses. ArlRS and MgrA are therefore the main regulators of S. aureus immune evasion and promising treatment targets. [Display omitted] •S. aureus requires the ArlRS-MgrA regulatory cascade for virulence in skin infection•Inactivation of ArlRS or MgrA blocks S. aureus adhesion and abscess structuring•The ArlRS-MgrA cascade is essential for S. aureus immune evasion Kwiecinski et al. show that Staphylococcus aureus uses the ArlRS-MgrA regulatory system to coordinate gene expression during skin infection. This cascade is required for proper abscess structuring and evasion of the host innate immune system, which together are essential for full S. aureus virulence.