Antifungal defense of probiotic Lactobacillus rhamnosus GG is mediated by blocking adhesion and nutrient depletion (pdf)

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Antifungal defense of probiotic Lactobacillus rhamnosus GG is mediated by blocking adhesion and nutrient depletion

RESEARCH ARTICLE Antifungal defense of probiotic Lactobacillus rhamnosus GG is mediated by blocking adhesion and nutrient depletion Daniela Mailänder-Sánchez1¤a, Christina Braunsdorf1¤b, Christian Grumaz2, Christoph Müller3, Stefan Lorenz2, Philip Stevens4,5¤c, Jeanette Wagener1¤d, Betty Hebecker6,7¤d, Bernhard Hube6,7,8, Franz Bracher3, Kai Sohn2, Martin Schaller1* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Mailänder-Sánchez D, Braunsdorf C, Grumaz C, Müller C, Lorenz S, Stevens P, et al. (2017) Antifungal defense of probiotic Lactobacillus rhamnosus GG is mediated by blocking adhesion and nutrient depletion. PLoS ONE 12(10): e0184438. https://doi.org/10.1371/ journal.pone.0184438 Editor: Julian R. Naglik, King’s College London Dental Institute, UNITED KINGDOM Received: June 5, 2017 Accepted: August 23, 2017 Published: October 12, 2017 Copyright: © 2017 Mailänder-Sánchez 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. Data Availability Statement: All relevant data are available from the Gene Expression Omnibus at the following accession number: GSE97755. Funding: This work was funded by the German Research Council (DFG) Graduation College 685, Dr. Jekyll and Mr. Hyde: A systems approach to the therapy of nosocomial infections caused by Candida albicans: a commensal organism switches to a deadly pathogen/ PTJ (FKZ: 0315409BBMBF), the Dr. Manfred Plempel-foundation, the Dr. 1 Department of Dermatology, University Hospital Tübingen, Germany, 2 Fraunhofer IGB, Stuttgart, Germany, 3 Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Munich, Germany, 4 Center for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, University of Vienna, Medical University of Vienna, Vienna, Austria, 5 IGVP, University of Stuttgart, Stuttgart, Germany, 6 Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology–Hans Knoell Institute Jena (HKI), Jena, Germany, 7 Center for Sepsis Control and Care (CSCC), Jena, Germany, 8 Friedrich Schiller University, Jena, Germany ¤a Current address: Department of Internal Medicine I, University Hospital Tübingen, Tübingen ¤b Current address: Vetsuisse Faculty, Section of Immunology, University of Zürich, Zürich, Switzerland ¤c Current address: Noscendo GmbH, Stuttgart, Germany ¤d Current address: Aberdeen Fungal Group, MRC Centre for Medical Mycology, University of Aberdeen, Aberdeen, United Kingdom * Abstract Candida albicans is an inhabitant of mucosal surfaces in healthy individuals but also the most common cause of fungal nosocomial blood stream infections, associated with high morbidity and mortality. As such life-threatening infections often disseminate from superficial mucosal infections we aimed to study the use of probiotic Lactobacillus rhamnosus GG (LGG) in prevention of mucosal C. albicans infections. Here, we demonstrate that LGG protects oral epithelial tissue from damage caused by C. albicans in our in vitro model of oral candidiasis. Furthermore, we provide insights into the mechanisms behind this protection and dissect direct and indirect effects of LGG on C. albicans pathogenicity. C. albicans viability was not affected by LGG. Instead, transcriptional profiling using RNA-Seq indicated dramatic metabolic reprogramming of C. albicans. Additionally, LGG had a significant impact on major virulence attributes, including adhesion, invasion, and hyphal extension, whose reduction, consequently, prevented epithelial damage. This was accompanied by glucose depletion and repression of ergosterol synthesis, caused by LGG, but also due to blocked adhesion sites. Therefore, LGG protects oral epithelia against C. albicans infection by preventing fungal adhesion, invasion and damage, driven, at least in parts, by metabolic reprogramming due to nutrient limitation caused by LGG. PLOS ONE | https://doi.org/10.1371/journal.pone.0184438 October 12, 2017 1 / 19 Antifungal defense of probiotic Lactobacillus rhamnosus GG Siegried Stettendorf-Foundation, the InfectERA Program (FunComPath; BMBF FKZ 031L0001A), the Integrated Research and Treatment Center for Sepsis Control and Care (CSCC) project CanBac (BMBF, FKZ: 01EO1002), and the German Research Council (DFG) GZ:HE7565/1-1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Introduction As commensal microbe, the yeast Candida albicans is a common inhabitant of various mucosal surfaces of the human body. However, under opportune conditions, C. albicans can transform from an innocuous commensal to an aggressive pathogen, causing relatively harmless superficial infections but also life threatening sepsis. Predisposing factors for the development of localized Candida infections are mainly immunosuppression [1] and an imbalance of the autochthonous microflora after antibiotic treatment [2], while epithelial barrier breach and neutropenia are the most common predisposing conditions for systemic infections [3]. In recent years, the human microflora has gained increased scientific interest, as its importance for maintaining human health has become more and more evident, reviewed recently by Lin et al. [4]. One concept evolved from the ongoing research in this field includes the use of probiotic microorganisms to influence the resident microbiota and/or the host immune system to prevent or cure diseases. A number of trials show a positive effect of probiotics in the treatment of various diseases and disorders, e.g. atopic dermatitis [5], irritable bowel syndrome [6, 7], ulcerative colitis [8] and antibiotic-associated diarrhea[9]. Even preterm neonates are medicated with probiotics to prevent infections [10–12]. The use of probiotic microorganisms to protect mucosal surfaces from C. albicans infections was recently reviewed by our group [13]. Several clinical trials indicate a protective role for probiotics in the prevention of superficial C. albicans infections, and diverse strains of the genus Lactobacillus have been found to be useful for the prevention and treatment of vulvovaginal candidiasis [14, 15], while combinations of different genera improved the outcome of oral candidiasis [16, 17]. Previous studies addressing the mechanisms behind probiotic action on C. albicans explored the ability of probiotic bacteria to inhibit fungal growth [18–21], to prevent adhesion [22, 23] or to influence anti-fungal immune responses [23, 24], respectively. Despite the numerous studies on probiotics, the mechanisms behind the beneficial effects of probiotics on human health and well-being are still unclear. A better und (...truncated)