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Journal Article

The adaptor molecule CARD9 is essential for tuberculosis control

MPS-Authors
http://pubman.mpdl.mpg.de/cone/persons/resource/persons81854

Dorhoi,  Anca
Department of Immunology, Max Planck Institute for Infection Biology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons81847

Desel,  Christiane
Department of Immunology, Max Planck Institute for Infection Biology, Max Planck Society;

Yeremeev,  Vladimir
Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons82103

Pradl,  Lydia
Department of Immunology, Max Planck Institute for Infection Biology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons81827

Brinkmann,  Volker
Core Facilities / Microscopy, Max Planck Institute for Infection Biology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons82058

Mollenkopf,  Hans J.
Core Facilities / Microarray, Max Planck Institute for Infection Biology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons81923

Hanke,  Karin
Department of Immunology, Max Planck Institute for Infection Biology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons81969

Kaufmann,  Stefan H. E.
Department of Immunology, Max Planck Institute for Infection Biology, Max Planck Society;

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Fulltext (public)

J_Exp_Med_2010_207_777.pdf
(Publisher version), 4MB

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Citation

Dorhoi, A., Desel, C., Yeremeev, V., Pradl, L., Brinkmann, V., Mollenkopf, H. J., et al. (2010). The adaptor molecule CARD9 is essential for tuberculosis control. Journal of Experimental Medicine, 207(4), 777-792.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-BFFF-4
Abstract
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.