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      Differential Behavior of Non- albicans Candida Species in the Central Nervous System of Immunocompetent and Immunosuppressed Mice

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          Abstract

          The genus Candida includes commensal fungi that can cause local and systemic infections, frequently involving vital organs as the central nervous system (CNS). Candida spp. occupy the fourth place among infections that affect the CNS. Although the incidence of Candida albicans is decreasing among patients under immunosuppressive therapies, the incidence of non- albicans Candida is increasing. In this context, the objective of this work was to evaluate the ability of non- albicans Candida species to spread to the CNS of immunocompetent and immunosuppressed mice. Adult female C57BL/6 mice were treated with prednisolone, intravenously infected with Candida glabrata, Candida krusei and Candida parapsilosis yeasts and then evaluated at the 3rd and 14th days after infection. All Candida species disseminated to the brain from immunocompetent animals and induced local inflammation at the third day post-infection. The immunosuppression resulted in body weight loss, leukopenia and reduced IL-2 production by spleen cell cultures. Higher fungal loads were recovered from the CNS of immunosuppressed mice. Inflammatory infiltration associated to a Th1 subset profile was higher in brain samples from C. krusei immunosuppressed mice compared with immunocompetent ones. Additionally, C. krusei was able to transform into pseudohypha inside microglia in vitro infected cells and also to induce elevated nitric oxide production. Altogether, these results indicate that C. glabrata, C. krusei and C. parapsilosis are able to disseminate to the CNS and promote local inflammation in both immunocompetent and immunosuppressed mice. C. krusei displayed a distinct behavior at the CNS triggering a local Th1 profile. The possible contribution of these non- albicans Candida species to other CNS pathologies as multiple sclerosis, Parkinson’s and Alzheimer’s diseases deserves further attention.

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          Most cited references57

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          Neutrophil-Derived Cytokines: Facts Beyond Expression

          Polymorphonuclear neutrophils, besides their involvement in primary defense against infections – mainly through phagocytosis, generation of toxic molecules, release of enzymes, and formation of extracellular traps – are also becoming increasingly important for their contribution to the fine regulation in development of inflammatory and immune responses. These latter functions of neutrophils occur, in part, via their de novo production and release of a large variety of cytokines, including chemotactic cytokines (chemokines). Accordingly, the improvement in technologies for molecular and functional cell analysis, along with concomitant advances in cell purification techniques, have allowed the identification of a continuously growing list of neutrophil-derived cytokines, as well as the characterization of their biological implications in vitro and/or in vivo. This short review summarizes crucial concepts regarding the modalities of expression, release, and regulation of neutrophil-derived cytokines. It also highlights examples illustrating the potential implications of neutrophil-derived cytokines according to recent observations made in humans and/or in experimental animal models.
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            Epidemiology and risk factors for invasive candidiasis

            Nur Yapar (2014)
            The number of immunosuppressive patients has increased significantly in recent years. These patients are at risk for opportunistic infections, especially fungal infections. Candidiasis is one of the most frequent fungal infections determined in these immunosuppressive patients and its epidemiology has changed over the last two decades. Recently, new antifungal agents and new therapy strategies such as antifungal prophylaxis, secondary prophylaxis, and preemptive therapy have come into use. These changes resulted in the alteration of Candida species causing invasive infections. The incidence of Candida albicans was decreased in many countries, especially among patients with immunosuppressive disorders, while the incidence of species other than C. albicans was increased. In this review, incidence, risk factors, and species distribution of invasive candidiasis are discussed.
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              Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments.

              The ability of Candida albicans to rapidly and reversibly switch between yeast and filamentous morphologies is crucial to pathogenicity, and it is thought that the filamentous morphology provides some advantage during interaction with the mammalian immune system. Dectin-1 is a receptor that binds beta-glucans and is important for macrophage phagocytosis of fungi. The receptor also collaborates with Toll-like receptors for inflammatory activation of phagocytes by fungi. We show that yeast cell wall beta-glucan is largely shielded from Dectin-1 by outer wall components. However, the normal mechanisms of yeast budding and cell separation create permanent scars which expose sufficient beta-glucan to trigger antimicrobial responses through Dectin-1, including phagocytosis and activation of reactive oxygen production. During filamentous growth, no cell separation or subsequent beta-glucan exposure occurs, and the pathogen fails to activate Dectin-1. The data demonstrate a mechanism by which C. albicans shape alone directly contributes to the method by which phagocytes recognize the fungus.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                08 January 2019
                2018
                : 9
                : 2968
                Affiliations
                [1] 1Botucatu Medical School, São Paulo State University (UNESP) , Botucatu, Brazil
                [2] 2Institute of Biosciences, São Paulo State University (UNESP) , Botucatu, Brazil
                Author notes

                Edited by: Miriam Postan, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina

                Reviewed by: Sharvan Sehrawat, Indian Institute of Science Education and Research, Mohali, India; Rodnei Dennis Rossoni, São Paulo State University, Brazil

                *Correspondence: Thais F. C. Fraga-Silva, thaisfragasilva@ 123456gmail.com

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2018.02968
                6332706
                0f46cd8b-3633-4545-8094-23699364734b
                Copyright © 2019 Sanches, Mimura, Oliveira, Ishikawa, Garces, Bagagli, Sartori, Kurokawa and Fraga-Silva.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 June 2018
                : 18 November 2018
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 67, Pages: 12, Words: 0
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                candida spp.,fungal infections,prednisolone,neuroinflammation,microglia
                Microbiology & Virology
                candida spp., fungal infections, prednisolone, neuroinflammation, microglia

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