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

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          Abstract

          Staphylococcus aureus causes acute and chronic infections resulting in significant morbidity. Urease, an enzyme that generates NH 3 and CO 2 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.

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          Most cited references69

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          Methicillin-resistant Staphylococcus aureus disease in three communities.

          Methicillin-resistant Staphylococcus aureus (MRSA) infection has emerged in patients who do not have the established risk factors. The national burden and clinical effect of this novel presentation of MRSA disease are unclear. We evaluated MRSA infections in patients identified from population-based surveillance in Baltimore and Atlanta and from hospital-laboratory-based sentinel surveillance of 12 hospitals in Minnesota. Information was obtained by interviewing patients and by reviewing their medical records. Infections were classified as community-associated [correction] MRSA disease if no established risk factors were identified. From 2001 through 2002, 1647 cases of community-associated [correction] MRSA infection were reported, representing between 8 and 20 percent of all MRSA isolates. The annual disease incidence varied according to site (25.7 cases per 100,000 population in Atlanta vs. 18.0 per 100,000 in Baltimore) and was significantly higher among persons less than two years old than among those who were two years of age or older (relative risk, 1.51; 95 percent confidence interval, 1.19 to 1.92) and among blacks than among whites in Atlanta (age-adjusted relative risk, 2.74; 95 percent confidence interval, 2.44 to 3.07). Six percent of cases were invasive, and 77 percent involved skin and soft tissue. The infecting strain of MRSA was often (73 percent) resistant to prescribed antimicrobial agents. Among patients with skin or soft-tissue infections, therapy to which the infecting strain was resistant did not appear to be associated with adverse patient-reported outcomes. Overall, 23 percent of patients were hospitalized for the MRSA infection. Community-associated MRSA infections are now a common and serious problem. These infections usually involve the skin, especially among children, and hospitalization is common. Copyright 2005 Massachusetts Medical Society.
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            Surviving the Acid Test: Responses of Gram-Positive Bacteria to Low pH

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              Ureases I. Functional, catalytic and kinetic properties: A review

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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draft
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                4 January 2019
                January 2019
                : 15
                : 1
                : e1007538
                Affiliations
                [1 ] Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
                [2 ] Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America
                [3 ] Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America
                University of Tubingen, GERMANY
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-1278-5901
                http://orcid.org/0000-0002-3033-8438
                http://orcid.org/0000-0002-3335-5284
                http://orcid.org/0000-0002-7886-0727
                http://orcid.org/0000-0002-9609-152X
                http://orcid.org/0000-0001-9948-6837
                http://orcid.org/0000-0001-7624-670X
                http://orcid.org/0000-0003-0939-6884
                Article
                PPATHOGENS-D-18-01616
                10.1371/journal.ppat.1007538
                6343930
                30608981
                7cd7a4cf-f6ec-45a7-b76e-23ffa6eaa819
                © 2019 Zhou et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 August 2018
                : 18 December 2018
                Page count
                Figures: 5, Tables: 0, Pages: 23
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: P01 AIAI083211
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: P01 AIAI083211
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: P01 AIAI083211
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R01 AI125588
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R01 AI125588
                Award Recipient :
                This study was funded by a grant from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Disease (NIAID; https://www.niaid.nih.gov) P01AI083211 to RP, TK and PDF. VCT and SSC were funded by NIH/NIAID R01AI125588. CZ was funded by the University of Nebraska Medical Center Graduate Studies Research Assistantship/Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Ureases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Ureases
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Urea
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Urea
                Biology and Life Sciences
                Organisms
                Bacteria
                Staphylococcus
                Staphylococcus Aureus
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Staphylococcus
                Staphylococcus Aureus
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Bacterial Pathogens
                Staphylococcus
                Staphylococcus Aureus
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Amino Acids
                Basic Amino Acids
                Arginine
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Amino Acids
                Basic Amino Acids
                Arginine
                Biology and Life Sciences
                Biochemistry
                Proteins
                Amino Acids
                Basic Amino Acids
                Arginine
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Physical Sciences
                Chemistry
                Chemical Compounds
                Ammonia
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Catabolism
                Custom metadata
                vor-update-to-uncorrected-proof
                2019-01-23
                All relevant data are within the manuscript and its supporting information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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