The adaptor molecule CARD9 is essential for tuberculosis control.
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(-/-) granulocytes failed to produce IL-10 after Mycobacterium 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.
Dorhoi
Anca
A
Max Planck Institute for Infection Biology, Department of Immunology, 10117 Berlin, Germany.
Desel
Christiane
C
Yeremeev
Vladimir
V
Pradl
Lydia
L
Brinkmann
Volker
V
Mollenkopf
Hans-Joachim
HJ
Hanke
Karin
K
Gross
Olaf
O
Ruland
Jürgen
J
Kaufmann
Stefan H E
SH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D000995:Antitubercular Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D037181:Lectins, C-Type; D047589:Leukocyte Reduction Procedures; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000473:pathology / Q000628:therapy; D011135:Polysaccharides, Bacterial / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011828:Radiation Chimera / Q000276:immunology / Q000382:microbiology; D016019:Survival Analysis; D000072377:Syk Kinase; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D000099181:Dectin-1
D048868:Adaptor Proteins, Signal Transducing; D000995:Antitubercular Agents; D053468:CARD Signaling Adaptor Proteins; D018925:Chemokines; D016207:Cytokines; D016179:Granulocyte Colony-Stimulating Factor; D016753:Interleukin-10; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011135:Polysaccharides, Bacterial; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D000099181:Dectin-1; C513280:Card9 protein, mouse; C000606897:Syk protein, mouse