Urease is an essential component of the acid response network of Staphylococcus aureus and is required for a persistent murine kidney infection

Staphylococcus aureus causes acute and chronic infections resulting in significant morbidity. Urease, an enzyme that generates NH3 and CO2 from urea, is key to pH homeostasis in bacterial pathogens under acidic stress and nitrogen limitation. However, the function of urease in S. aureus niche colonization and nitrogen metabolism has not been extensively studied. We discovered that urease is essential for pH homeostasis and viability in urea-rich environments under weak acid stress. The regulation of urease transcription by CcpA, Agr, and CodY was identified in this study, implying a complex network that controls urease expression in response to changes in metabolic flux. In addition, it was determined that the endogenous urea derived from arginine is not a significant contributor to the intracellular nitrogen pool in non-acidic conditions. Furthermore, we found that during a murine chronic renal infection, urease facilitates S. aureus persistence by promoting bacterial fitness in the low-pH, urea-rich kidney. Overall, our study establishes that urease in S. aureus is not only a primary component of the acid response network but also an important factor required for persistent murine renal infections. Author summary Urease has been reported to be crucial to bacteria in environmental adaptation, virulence, and defense against host immunity. Although the function of urease in S. aureus is not clear, recent evidence suggests that urease is important for acid resistance in various niches. Our study deciphered a function of S. aureus urease both in laboratory conditions and during host colonization. Furthermore, we uncovered the major components of the regulatory system that fine-tunes the expression of urease. Collectively, this study established the dual function of urease which serves as a significant part of the S. aureus acid response while also serving as an enzyme required for persistent kidney infections and potential subsequent staphylococcal metastasis.