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          Institute: MPI für Infektionsbiologie     Collection: Department of Immunology     Display Documents

ID: 533092.0, MPI für Infektionsbiologie / Department of Immunology
The adaptor molecule CARD9 is essential for tuberculosis control
Authors:Dorhoi, Anca; Desel, Christiane; Yeremeev, Vladimir; Pradl, Lydia; Brinkmann, Volker; Mollenkopf, Hans J.; Hanke, Karin; Gross, Olaf; Ruland, Jürgen; Kaufmann, Stefan H. E.
Date of Publication (YYYY-MM-DD):2010-04-12
Title of Journal:Journal of Experimental Medicine
Journal Abbrev.:J. Exp. Med.
Issue / Number:4
Start Page:777
End Page:792
Copyright:© 2010 Dorhoi et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
Review Status:Peer-review
Audience:Experts Only
Abstract / Description:The cross talk between host and pathogen starts with recognition of bacterial signatures through pattern recognition receptors (PRRs), which mobilize downstream signaling cascades. We investigated the role of the cytosolic adaptor caspase recruitment domain family, member 9 (CARD9) in tuberculosis. This adaptor was critical for full activation of innate immunity by converging signals downstream of multiple PRRs. Card9(-/-) mice succumbed early after aerosol infection, with higher mycobacterial burden, pyogranulomatous pneumonia, accelerated granulocyte recruitment, and higher abundance of proinflammatory cytokines and granulocyte colony-stimulating factor (G-CSF) in serum and lung. Neutralization of G-CSF and neutrophil depletion significantly prolonged survival, indicating that an exacerbated systemic inflammatory disease triggered lethality of Card9(-/-) mice. CARD9 deficiency had no apparent effect on T cell responses, but a marked impact on the hematopoietic compartment. Card9(-/-) ranulocytes failed to produce IL-10 after Mycobaterium tuberculosis infection, suggesting that an absent antiinflammatory feedback loop accounted for granulocyte-dominated pathology, uncontrolled bacterial replication, and, ultimately, death of infected Card9(-/-) mice. Our data provide evidence that deregulated innate responses trigger excessive lung inflammation and demonstrate a pivotal role of CARD9 signaling in autonomous innate host defense against tuberculosis.
Comment of the Author/Creator:This work received financial support from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung) Kompetenznetzwerk “PathoGenoMikPlus” to S.H.E. Kaufmann.
External Publication Status:published
Document Type:Article
Communicated by:Hilmar Fünning
Affiliations:MPI für Infektionsbiologie/Department of Immunology
External Affiliations:Tech Univ Munich, Med Klin 2, Klinikum Rechts Isar, D-81675 Munich, Germany.
Identifiers:ISI:000276552700011 [ID No:1]
ISSN:0022-1007 [ID No:2]
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