Affiliation:
1. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
Abstract
ABSTRACT
A hallmark of
Proteus mirabilis
infection of the urinary tract is the formation of stones. The ability to induce urinary stone formation requires urease, a nickel metalloenzyme that hydrolyzes urea. This reaction produces ammonia as a byproduct, which can serve as a nitrogen source and weak base that raises the local pH. The resulting alkalinity induces the precipitation of ions to form stones. Transcriptional regulator UreR activates expression of urease genes in a urea-dependent manner. Thus, urease genes are highly expressed in the urinary tract where urea is abundant. Production of mature urease also requires the import of nickel into the cytoplasm and its incorporation into the urease apoenzyme. Urease accessory proteins primarily acquire nickel from one of two nickel transporters and facilitate incorporation of nickel to form mature urease. In this study, we performed a comprehensive RNA-seq to define the
P. mirabilis
urea-induced transcriptome as well as the UreR regulon. We identified UreR as the first defined regulator of nickel transport in
P. mirabilis
. We also offer evidence for the direct regulation of the Ynt nickel transporter by UreR. Using bioinformatics, we identified UreR-regulated urease loci in 15
Morganellaceae
family species across three genera. Additionally, we located two mobilized UreR-regulated urease loci that also encode the
ynt
transporter, implying that UreR regulation of nickel transport is a conserved regulatory relationship. Our study demonstrates that UreR specifically regulates genes required to produce mature urease, an essential virulence factor for
P. mirabilis
uropathogenesis.
IMPORTANCE
Catheter-associated urinary tract infections (CAUTIs) account for over 40% of acute nosocomial infections in the USA and generate $340 million in healthcare costs annually. A major causative agent of CAUTIs is
Proteus mirabilis
, an understudied Gram-negative pathogen noted for its ability to form urinary stones via the activity of urease. Urease mutants cannot induce stones and are attenuated in a murine UTI model, indicating this enzyme is essential to
P. mirabilis
pathogenesis. Transcriptional regulation of urease genes by UreR is well established; here, we expand the UreR regulon to include regulation of nickel import, a function required to produce mature urease. Furthermore, we reflect on the role of urea catalysis in
P. mirabilis
metabolism and provide evidence for its importance.
Funder
HHS | NIH | National Institute of General Medical Sciences
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
HHS | NIH | National Institute of Allergy and Infectious Diseases
Publisher
American Society for Microbiology