A Systematic Evaluation of the Two-Component Systems Network Reveals That ArlRS Is a Key Regulator of Catheter Colonization by Staphylococcus aureus

Saioa Burgui, Carmen Gil, Cristina Solano, Iñigo Lasa, Jaione Valle

Two-component systems (TCS) are modular signal transduction pathways that allow cells to adapt to prevailing environmental conditions by modifying cellular physiology.Staphylococcus aureushas 16 TCSs to adapt to the diverse microenvironments encountered during its life cycle, including host tissues and implanted medical devices.S. aureusis particularly prone to cause infections associated to medical devices, whose surfaces coated by serum proteins constitute a particular environment. Identification of the TCSs involved in the adaptation ofS. aureusto colonize and survive on the surface of implanted devices remains largely unexplored. Here, using anin vivocatheter infection model and a collection of mutants in each non-essential TCS ofS. aureus, we investigated the requirement of each TCS for colonizing the implanted catheter. Among the 15 mutants in non-essential TCSs, thearlmutant exhibited the strongest deficiency in the capacity to colonize implanted catheters. Moreover, thearlmutant was the only one presenting a major deficit in PNAG production, the main exopolysaccharide of theS. aureusbiofilm matrix whose synthesis is mediated by theicaADBClocus. Regulation of PNAG synthesis by ArlRS occurred through repression of IcaR, a transcriptional repressor oficaADBCoperon expression. Deficiency in catheter colonization was restored when thearlmutant was complemented with theicaADBCoperon. MgrA, a global transcriptional regulator downstream ArlRS that accounts for a large part of thearlRSregulon, was unable to restore PNAG expression and catheter colonization deficiency of thearlRSmutant. These findings indicate that ArlRS is the key TCS to biofilm formation on the surface of implanted catheters and that activation of PNAG exopolysaccharide production is, among the many traits controlled by the ArlRS system, a major contributor to catheter colonization.