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      Aspergillus fumigatus Triggers Inflammatory Responses by Stage-Specific β-Glucan Display

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          Abstract

          Inhalation of fungal spores (conidia) occurs commonly and, in specific circumstances, can result in invasive disease. We investigated the murine inflammatory response to conidia of Aspergillus fumigatus, the most common invasive mold in immunocompromised hosts. In contrast to dormant spores, germinating conidia induce neutrophil recruitment to the airways and TNF-α/MIP-2 secretion by alveolar macrophages. Fungal β-glucans act as a trigger for the induction of these inflammatory responses through their time-dependent exposure on the surface of germinating conidia. Dectin-1, an innate immune receptor that recognizes fungal β-glucans, is recruited in vivo to alveolar macrophage phagosomes that have internalized conidia with exposed β-glucans. Antibody-mediated blockade of Dectin-1 partially inhibits TNF-α/MIP-2 induction by metabolically active conidia. TLR-2- and MyD88-mediated signals provide an additive contribution to macrophage activation by germinating conidia. Selective responsiveness to germinating conidia provides the innate immune system with a mechanism to restrict inflammatory responses to metabolically active, potentially invasive fungal spores.

          Synopsis

          Aspergillus fumigatus is a mold that forms spores that are often inhaled by mammals. Humans with normal immune systems inhale several hundred A. fumigatus spores per day without developing detectable disease. Immunocompromised hosts, on the other hand, can develop invasive A. fumigatus infections. In these cases, inhaled spores germinate and form tissue-invasive hyphae that invade blood vessels and disseminate to remote tissues. The aim of this study was to investigate the normal inflammatory response to inhaled spores in mouse lungs. The researchers found that the earliest stage of spore germination, referred to as “swelling,” triggered the recruitment of inflammatory cells into the lung airways. Consistent with this finding, lung-derived cells stimulated with swollen spores secreted copious amounts of proteins that attract inflammatory cells. Analysis of spores revealed that swelling is accompanied by surface expression of β-glucan polymers. These carbohydrates, which are not present on the surface of mammalian cells, induce signaling by the mammalian Dectin-1 receptor and activate the expression of genes that promote the inflammatory response. The results suggest that mammalian lungs have evolved a mechanism to distinguish swollen and potentially threatening spores from innocuous, dormant spores.

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          Most cited references40

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          Aspergillus fumigatus and aspergillosis.

          J P Latgé (1999)
          Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.
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            Macrophage receptors and immune recognition.

            Macrophages express a broad range of plasma membrane receptors that mediate their interactions with natural and altered-self components of the host as well as a range of microorganisms. Recognition is followed by surface changes, uptake, signaling, and altered gene expression, contributing to homeostasis, host defense, innate effector mechanisms, and the induction of acquired immunity. This review covers recent studies of selected families of structurally defined molecules, studies that have improved understanding of ligand discrimination in the absence of opsonins and differential responses by macrophages and related myeloid cells.
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              Dectin-1 Is A Major β-Glucan Receptor On Macrophages

              Zymosan is a β-glucan– and mannan-rich particle that is widely used as a cellular activator for examining the numerous responses effected by phagocytes. The macrophage mannose receptor (MR) and complement receptor 3 (CR3) have historically been considered the major macrophage lectins involved in the nonopsonic recognition of these yeast-derived particles. Using specific carbohydrate inhibitors, we show that a β-glucan receptor, but not the MR, is a predominant receptor involved in this process. Furthermore, nonopsonic zymosan binding was unaffected by genetic CD11b deficiency or a blocking monoclonal antibody (mAb) against CR3, demonstrating that CR3 was not the β-glucan receptor mediating this activity. To address the role of the recently described β-glucan receptor, Dectin-1, we generated a novel anti–Dectin-1 mAb, 2A11. Using this mAb, we show here that Dectin-1 was almost exclusively responsible for the β-glucan–dependent, nonopsonic recognition of zymosan by primary macro-phages. These findings define Dectin-1 as the leukocyte β-glucan receptor, first described over 50 years ago, and resolves the long-standing controversy regarding the identity of this important molecule. Furthermore, these results identify Dectin-1 as a new target for examining the immunomodulatory properties of β-glucans for therapeutic drug design.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                ppat
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                November 2005
                18 November 2005
                : 1
                : 3
                : e30
                Affiliations
                [1 ] Infectious Diseases Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
                [2 ] Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
                [3 ] Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, New York, United States of America
                Johns Hopkins University, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: pamere@ 123456mskcc.org
                Article
                05-PLPA-RA-0114R2 plpa-01-03-06
                10.1371/journal.ppat.0010030
                1287910
                16304610
                25d0e9c2-8ac3-4816-99f4-bf74a9415fd8
                Copyright: © 2005 Hohl 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
                : 4 August 2005
                : 13 October 2005
                Page count
                Pages: 9
                Categories
                Research Article
                Immunology
                Infectious Diseases
                Yeast and Fungi
                Mus (Mouse)
                Custom metadata
                Hohl TM, Van Epps HL, Rivera A, Morgan LA, Chen PL, et al. (2005) Aspergillus fumigatus triggers inflammatory responses by stage-specific β-glucan display. PLoS Pathog 1(3): e30.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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