Journal article
Staphylococcus aureus adhesion in endovascular infections is controlled by the ArlRS-MgrA signaling cascade
PLoS pathogens, Vol.15(5), pp.e1007800-e1007800
05/01/2019
DOI: 10.1371/journal.ppat.1007800
PMCID: PMC6548404
PMID: 31116795
Abstract
Staphylococcus aureus is a leading cause of endovascular infections. This bacterial pathogen uses a diverse array of surface adhesins to clump in blood and adhere to vessel walls, leading to endothelial damage, development of intravascular vegetations and secondary infectious foci, and overall disease progression. In this work, we describe a novel strategy used by S. aureus to control adhesion and clumping through activity of the ArlRS two-component regulatory system, and its downstream effector MgrA. Utilizing a combination of in vitro cellular assays, and single-cell atomic force microscopy, we demonstrated that inactivation of this ArlRS-MgrA cascade inhibits S. aureus adhesion to a vast array of relevant host molecules (fibrinogen, fibronectin, von Willebrand factor, collagen), its clumping with fibrinogen, and its attachment to human endothelial cells and vascular structures. This impact on S. aureus adhesion was apparent in low shear environments, and in physiological levels of shear stress, as well as in vivo in mouse models. These effects were likely mediated by the de-repression of giant surface proteins Ebh, SraP, and SasG, caused by inactivation of the ArlRS-MgrA cascade. In our in vitro assays, these giant proteins collectively shielded the function of other surface adhesins and impaired their binding to cognate ligands. Finally, we demonstrated that the ArlRS-MgrA regulatory cascade is a druggable target through the identification of a small-molecule inhibitor of ArlRS signaling. Our findings suggest a novel approach for the pharmacological treatment and prevention of S. aureus endovascular infections through targeting the ArlRS-MgrA regulatory system.
Details
- Title: Subtitle
- Staphylococcus aureus adhesion in endovascular infections is controlled by the ArlRS-MgrA signaling cascade
- Creators
- Jakub M. Kwiecinski - University of Colorado DenverHeidi A. Crosby - University of Colorado DenverClaire Valotteau - UCLouvainJoseph A. Hippensteel - University of Colorado DenverManasa K. Nayak - University of IowaAnil K. Chauhan - University of IowaEric P. Schmidt - University of Colorado HealthYves F. Dufrene - UCLouvainAlexander R. Horswill - University of Colorado Denver
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.15(5), pp.e1007800-e1007800
- DOI
- 10.1371/journal.ppat.1007800
- PMID
- 31116795
- PMCID
- PMC6548404
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Publisher
- Public Library Science
- Number of pages
- 35
- Grant note
- T32AI007511 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) T32 AI007511; AI083211 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Swedish Society for Medical Research I01 BX002711 / Department of Veteran Affairs; US Department of Veterans Affairs R01HL125371; R35HL139926; R01NS109910 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 693630 / European Research Council under the European Union's Horizon 2020 research and innovation programme; European Research Council (ERC) R35HL139926 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) National Fund for Scientific Research (FNRS); Fonds de la Recherche Scientifique - FNRS P30DK054759 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) 18EIA33900009; 17POST33670580; 15POST25720016 / American Heart Association WELBIO-CR-2015A-05 / FNRS-WELBIO; Fonds de la Recherche Scientifique - FNRS; WELBIO R01NS109910 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Language
- English
- Date published
- 05/01/2019
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359868602771
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