11
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Mucormycosis is a life-threatening respiratory fungal infection predominantly caused by Rhizopus species. Mucormycosis has incompletely understood pathogenesis, particularly how abnormalities in iron metabolism compromise immune responses. Here we show how, as opposed to other filamentous fungi, Rhizopus spp. establish intracellular persistence inside alveolar macrophages (AMs). Mechanistically, lack of intracellular swelling of Rhizopus conidia results in surface retention of melanin, which induces phagosome maturation arrest through inhibition of LC3-associated phagocytosis. Intracellular inhibition of Rhizopus is an important effector mechanism, as infection of immunocompetent mice with swollen conidia, which evade phagocytosis, results in acute lethality. Concordantly, AM depletion markedly increases susceptibility to mucormycosis. Host and pathogen transcriptomics, iron supplementation studies, and genetic manipulation of iron assimilation of fungal pathways demonstrate that iron restriction inside macrophages regulates immunity against Rhizopus. Our findings shed light on the pathogenetic mechanisms of mucormycosis and reveal the role of macrophage-mediated nutritional immunity against filamentous fungi.

          Abstract

          Mucormycosis is a life-threatening respiratory fungal infection that typically occurs in patients with abnormalities in iron metabolism. Here the authors show that iron restriction inside the phagosome of macrophages is an essential component of the host defense against Rhizopus, the main species causing mucormycosis.

          Related collections

          Most cited references 45

          • Record: found
          • Abstract: found
          • Article: not found

          Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).

          Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Novel perspectives on mucormycosis: pathophysiology, presentation, and management.

            Mucormycosis is a life-threatening fungal infection that occurs in immunocompromised patients. These infections are becoming increasingly common, yet survival remains very poor. A greater understanding of the pathogenesis of the disease may lead to future therapies. For example, it is now clear that iron metabolism plays a central role in regulating mucormycosis infections and that deferoxamine predisposes patients to mucormycosis by inappropriately supplying the fungus with iron. These findings raise the possibility that iron chelator therapy may be useful to treat the infection as long as the chelator does not inappropriately supply the fungus with iron. Recent data support the concept that high-dose liposomal amphotericin is the preferred monotherapy for mucormycosis. However, several novel therapeutic strategies are available. These options include combination therapy using lipid-based amphotericin with an echinocandin or with an azole (largely itraconazole or posaconazole) or with all three. The underlying principles of therapy for this disease remain rapid diagnosis, reversal of underlying predisposition, and urgent surgical debridement.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The cell wall: a carbohydrate armour for the fungal cell.

               Jean Latgé (2007)
              The cell wall is composed of a polysaccharide-based three-dimensional network. Considered for a long time as an inert exoskeleton, the cell wall is now seen as a dynamic structure that is continuously changing as a result of the modification of culture conditions and environmental stresses. Although the cell wall composition varies among fungal species, chemogenomic comparative analysis have led to a better understanding of the genes and mechanisms involved in the construction of the common central core composed of branched beta1,3 glucan-chitin. Because of its essential biological role, unique biochemistry and structural organization and the absence in mammalian cells of most of its constitutive components, the cell wall is an attractive target for the development of new antifungal agents. Genomic as well as drug studies have shown that the death of the fungus can result from inhibition of cell wall polysaccharide synthases. To date, only beta1,3 glucan synthase inhibitors have been launched clinically and many more targets remain to be explored.
                Bookmark

                Author and article information

                Contributors
                ibrahim@labiomed.org
                hamilos@imbb.forth.gr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                20 August 2018
                20 August 2018
                2018
                : 9
                Affiliations
                [1 ]Department of Medicine, University of Crete, Foundation for Research and Technology, 71300 Heraklion, Crete Greece
                [2 ]ISNI 0000 0004 0635 685X, GRID grid.4834.b, Institute of Molecular Biology and Biotechnology, , Foundation for Research and Technology, ; 71300 Heraklion, Crete Greece
                [3 ]ISNI 0000 0004 0620 8857, GRID grid.417975.9, Laboratory of Immunobiology, Center for Clinical, Experimental Surgery, and Translational Research, , Biomedical Research Foundation of the Academy of Athens, ; 11527 Athens, Greece
                [4 ]ISNI 0000 0001 0157 6501, GRID grid.239844.0, Division of Infectious Diseases, Los Angeles Biomedical Research Institute, , Harbor-University of California Los Angeles (UCLA) Medical Center, ; 1124 West Carson Street, St. John’s Cardiovascular Research Center, Torrance, CA 90502 USA
                [5 ]ISNI 0000 0004 4686 5317, GRID grid.412789.1, Sharjah Institute for Medical Research, College of Pharmacy, , University of Sharjah, ; PO Box 27272 Sharjah, UAE
                [6 ]ISNI 0000 0001 2175 4264, GRID grid.411024.2, Institute for Genome Sciences, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                [7 ]ISNI 0000 0001 2176 4817, GRID grid.5399.6, CNRS, BIP (UMR 7281), IMM (FR 3479), , Aix-Marseille Université, ; 31 chemin J. Aiguier, 13402 Marseille, France
                [8 ]ISNI 0000 0001 2353 6535, GRID grid.428999.7, Unité des Aspergillus, , Institut Pasteur, ; 75015 Paris, France
                [9 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Infectious Diseases, Infection Control, and Employee Health, , The University of Texas MD Anderson Cancer Center, ; Houston, TX 77030 USA
                [10 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, David Geffen School of Medicine at UCLA, ; Los Angeles, CA 90095 USA
                Article
                5820
                10.1038/s41467-018-05820-2
                6102248
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Categories
                Article
                Custom metadata
                © The Author(s) 2018

                Uncategorized

                Comments

                Comment on this article