ArticlePLoS pathogens2016
The Two-Component System ArlRS and Alterations in Metabolism Enable Staphylococcus aureus to Resist Calprotectin-Induced Manganese Starvation.
Article in PLoS pathogens, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 77 citations in OpenAlex.
- Formation of the intradimer disulfide bond in human calprotectin maintains metal-withholding function and tunes proteolytic susceptibility.Chemical science · 2026Article
- Overcoming methicillin resistance in Staphylococcus aureus via metal ion disruption of bacterial metabolism.npj antimicrobials and resistance · 2026Article
- ArlR regulates environmental stress tolerance and biofilm formation in foodborneCurrent research in food science · 2026Article
- Microbial metal physiology: ions to ecosystems.Nature reviews. Microbiology · 2025Review
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- The nucleobase analog 4-thiouracil hijacks the pyrimidine salvage pathway to inhibitMicrobiology spectrum · 2025Article
- Calprotectin-mediated survival ofmBio · 2025Article
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- The role of cGAS in epithelial dysregulation in inflammatory bowel disease and gastrointestinal malignancies.Frontiers in pharmacology · 2024Review
- Identification and validation of diagnostic biomarkers and immune cell abundance characteristics inFrontiers in immunology · 2024Article
- TheMicrobiology spectrum · 2023Article
- A structure activity relationship study of 3,4'-dimethoxyflavone for ArlRS inhibition inOrganic & biomolecular chemistry · 2023Article
- HowInternational journal of molecular sciences · 2023Review
- Article
- Diagnostic Accuracy of Fecal Calprotectin for Predicting Relapse in Inflammatory Bowel Disease: A Meta-Analysis.Journal of clinical medicine · 2023Review
- Key players in the regulation of iron homeostasis at the host-pathogen interface.Frontiers in immunology · 2023Review
- Article
- Novel Insights into Understanding the Molecular Dialogues between Bipolaroxin and the Gα and Gβ Subunits of the Wheat Heterotrimeric G-Protein during Host-Pathogen Interaction.Antioxidants (Basel, Switzerland) · 2022Article
- Therapeutic Inhibition of Staphylococcus aureus ArlRS Two-Component Regulatory System Blocks Virulence.Antimicrobial agents and chemotherapy · 2022Article
- Expression, Purification, and Characterization of the Recombinant, Two-Component, Response Regulator ArlR from Fusobacterium nucleatum.Applied biochemistry and biotechnology · 2022Article
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
During infection the host imposes manganese and zinc starvation on invading pathogens. Despite this, Staphylococcus aureus and other successful pathogens remain capable of causing devastating disease. However, how these invaders adapt to host-imposed metal starvation and overcome nutritional immunity remains unknown. We report that ArlRS, a global staphylococcal virulence regulator, enhances the ability of S. aureus to grow in the presence of the manganese-and zinc-binding innate immune effector calprotectin. Utilization of calprotectin variants with altered metal binding properties revealed that strains lacking ArlRS are specifically more sensitive to manganese starvation. Loss of ArlRS did not alter the expression of manganese importers or prevent S. aureus from acquiring metals. It did, however, alter staphylococcal metabolism and impair the ability of S. aureus to grow on amino acids. Further studies suggested that relative to consuming glucose, the preferred carbon source of S. aureus, utilizing amino acids reduced the cellular demand for manganese. When forced to use glucose as the sole carbon source S. aureus became more sensitive to calprotectin compared to when amino acids are provided. Infection experiments utilizing wild type and calprotectin-deficient mice, which have defects in manganese sequestration, revealed that ArlRS is important for disease when manganese availability is restricted but not when this essential nutrient is freely available. In total, these results indicate that altering cellular metabolism contributes to the ability of pathogens to resist manganese starvation and that ArlRS enables S. aureus to overcome nutritional immunity by facilitating this adaptation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.