Staphylococcus aureus uses the ArlRS and MgrA cascade to regulate immune evasion during skin infection
Jakub M. Kwiecinski,
Rachel M. Kratofil,
Corey P. Parlet,
Bas G.J. Surewaard,
Paul Kubes,
Alexander R. Horswill
Affiliations
Jakub M. Kwiecinski
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow 30387, Poland
Rachel M. Kratofil
Department of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 4Z6, Canada; Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N 4Z6, Canada
Corey P. Parlet
Department of Veterans Affairs, Iowa City VA Medical Center, Iowa City, IA 52246, USA; Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA
Bas G.J. Surewaard
Department of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 4Z6, Canada; Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N 4Z6, Canada
Paul Kubes
Department of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 4Z6, Canada; Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N 4Z6, Canada
Alexander R. Horswill
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Veterans Affairs, Eastern Colorado Health Care System, Aurora, CO 80045, USA; Corresponding author
Summary: 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.
