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      Coxiella burnetii Induces Inflammatory Interferon-Like Signature in Plasmacytoid Dendritic Cells: A New Feature of Immune Response in Q Fever

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          Abstract

          Plasmacytoid dendritic cells (pDCs) play a major role in antiviral immunity via the production of type I interferons (IFNs). There is some evidence that pDCs interact with bacteria but it is not yet clear whether they are protective or contribute to bacterial pathogenicity. We wished to investigate whether Coxiella burnetii, the agent of Q fever, interacts with pDCs. The stimulation of pDCs with C. burnetii increased the expression of activation and migratory markers (CD86 and CCR7) as determined by flow cytometry and modulated gene expression program as revealed by a microarray approach. Indeed, genes encoding for pro-inflammatory cytokines, chemokines, and type I INF were up-regulated. The up-regulation of type I IFN was correlated with an increase in IFN-α release by C. burnetii-stimulated pDCs. We also investigated pDCs in patients with Q fever endocarditis. Using flow cytometry and a specific gating strategy, we found that the number of circulating pDCs was significantly lower in patients with Q fever endocarditis as compared to healthy donors. In addition, the remaining circulating pDCs expressed activation and migratory markers. As a whole, our study identified non-previously reported activation of pDCs by C. burnetii and their modulation during Q fever.

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          Most cited references38

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          The nature of the principal type 1 interferon-producing cells in human blood.

          Interferons (IFNs) are the most important cytokines in antiviral immune responses. "Natural IFN-producing cells" (IPCs) in human blood express CD4 and major histocompatibility complex class II proteins, but have not been isolated and further characterized because of their rarity, rapid apoptosis, and lack of lineage markers. Purified IPCs are here shown to be the CD4(+)CD11c- type 2 dendritic cell precursors (pDC2s), which produce 200 to 1000 times more IFN than other blood cells after microbial challenge. pDC2s are thus an effector cell type of the immune system, critical for antiviral and antitumor immune responses.
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            Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon.

            We have identified two cell subsets in human blood based on the lack of lineage markers (lin-) and the differential expression of immunoglobulin-like transcript receptor 1 (ILT1) and ILT3. One subset (lin-/ILT3+/ILT1+) is related to myeloid dendritic cells. The other subset (lin-/ILT3+/ILT1+) corresponds to 'plasmacytoid monocytes'. These cells are found in inflamed lymph nodes in and around the high endothelial venules. They express CD62L and CXCR3, and produce extremely large amounts of type I interferon after stimulation with influenza virus or CD40L. These results, with the distinct cell phenotype, indicate that plasmacytoid monocytes represent a specialized cell lineage that enters inflamed lymph nodes at high endothelial venules, where it produces type I interferon. Plasmacytoid monocytes may protect other cells from viral infections and promote survival of antigen-activated T cells.
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              Natural history and pathophysiology of Q fever.

              Q fever is a zoonosis caused by Coxiella burnetii. Infection with C burnetii can be acute or chronic, and exhibits a wide spectrum of clinical manifestations. The extreme infectivity of the bacterium results in large outbreaks and makes it a potential bioweapon. In the past decade, the complete genome sequencing of C burnetii, the exploration of bacterial interactions with the host, and the description of the natural history of the disease in human beings and in experimental models have all added to our knowledge about this fascinating disease. Advances in understanding the pathophysiology and natural history of Q fever are reviewed.
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                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                27 June 2016
                2016
                : 6
                : 70
                Affiliations
                [1] 1Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, UMR 63, Centre National de la Recherche Scientifique 7278, INSERM U1095, IRD 198, Aix-Marseille Université Marseille, France
                [2] 2INSERM UMR 1068, Centre de Recherche en Cancérologie de Marseille Marseille, France
                Author notes

                Edited by: Damien F. Meyer, CIRAD, France

                Reviewed by: Janakiram Seshu, The University of Texas at San Antonio, USA; Matteo Bonazzi, Centre National de la Recherche Scientifique, France

                *Correspondence: Jean-Louis Mege jean-louis.mege@ 123456univ-amu.fr
                Article
                10.3389/fcimb.2016.00070
                4921463
                27446817
                ebf84497-039e-4b3c-9383-89bd09f9aee8
                Copyright © 2016 Ka, Mezouar, Ben Amara, Raoult, Ghigo, Olive and Mege.

                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) or licensor 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
                : 30 March 2016
                : 11 June 2016
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 44, Pages: 9, Words: 5824
                Categories
                Microbiology
                Original Research

                Infectious disease & Microbiology
                plasmacytoid dendritic cells,coxiella burnetii,q fever,interferon,infection

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