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

Abstract

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.

Comparative Genomics Reveals Broad Genetic Diversity, Extensive Recombination and Nascent Ecological Adaptation in Micrococcus luteus

“…Furthermore, extensive copy number variation of the VF genes was also found. For example, genes ureABG, which are involved in bacteria urea hydrolysis and have been reported to be crucial to pathogenic bacteria virulence and defense against host immunity [49,50], have shown an obvious gene expansion (three to six copies) in strain SK58 (isolated from human skin); and genes msrA/B(pilB), the protein of which can promote the successful infection of humans and also respond to adverse conditions [51], has also shown a gene expansion (n=3) in ve widely distributed strains (strains DE0459, UMB0038, UMB0189, DE0566 and J28).…”

Role of Nickel in Microbial Pathogenesis

“…Before its concentration in the kidneys, urea is present in the bloodstream, thus in blood-rich organs. It is abundant in the blood, with levels estimated to range between 2.5 and 7.1 mM; urea is also found in sweat, saliva, and gastric juices [38,119]. Saliva levels in healthy individuals vary from 3 to 10 mM, albeit they can reach up to 15 mM in patients with renal disease [120].…”

“…It colonizes approximately 30% of the population asymptomatically; however, it can also cause infections ranging from mild skin and soft tissue infections to invasive infections, including sepsis and pneumonia [132]. A recent study by Zhou and coworkers examined the S. aureus urease response and its roles in host persistence [38]. The authors note that S. aureus combats many different host environments, and urease may have very different roles in different pH conditions, in part due to the largely underappreciated differing mode of action of strong versus weak acids on the cells.…”

“…Therefore, the weak acids cause macromolecular damage via intracellular proton release. Using a mutant strain analysis approach, it was concluded that urease activity is important to cell viability under weak acid stress conditions [38]. Kidney colonization was compared in a mouse bacteremia model; kidneys infected with the S. aureus ure mutant strain had significantly lower bacterial burden in the longer term (12 and 19-day) infections than did the wild type strain.…”

Urease Expression in Pathogenic Yersinia enterocolitica Strains of Bio-Serotypes 2/O:9 and 1B/O:8 Is Differentially Regulated by the OmpR Regulator

“…Ureases are highly conserved enzymes widely distributed among bacterial species Konieczna et al, 2012;Kappaun et al, 2018). They play an important role in acid resistance and the virulence of several human pathogens, including Proteus mirabilis, Helicobacter pylori and Staphylococcus aureus (Stingl et al, 2002;Rutherford, 2014;Zhou et al, 2019). Bacterial ureases are multi-subunit nickel-dependent enzymes which catalyze the hydrolysis of urea into ammonia (urea amidohydrolase, EC 3.5.1.5).…”