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PMID: 16365150 Published · ppublish English Comparative Study Journal Article

TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis.

The Journal of experimental medicine ·Vol. 202 ·No. 12 ·2005-12-19 ·Pages 1715-24

Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A

Abstract

To investigate the role of Toll-like receptor (TLR)9 in the immune response to mycobacteria as well as its cooperation with TLR2, a receptor known to be triggered by several major mycobacterial ligands, we analyzed the resistance of TLR9(-/-) as well as TLR2/9 double knockout mice to aerosol infection with Mycobacterium tuberculosis. Infected TLR9(-/-) but not TLR2(-/-) mice displayed defective mycobacteria-induced interleukin (IL)-12p40 and interferon (IFN)-gamma responses in vivo, but in common with TLR2(-/-) animals, the TLR9(-/-) mice exhibited only minor reductions in acute resistance to low dose pathogen challenge. When compared with either of the single TLR-deficient animals, TLR2/9(-/-) mice displayed markedly enhanced susceptibility to infection in association with combined defects in proinflammatory cytokine production in vitro, IFN-gamma recall responses ex vivo, and altered pulmonary pathology. Cooperation between TLR9 and TLR2 was also evident at the level of the in vitro response to live M. tuberculosis, where dendritic cells and macrophages from TLR2/9(-/-) mice exhibited a greater defect in IL-12 response than the equivalent cell populations from single TLR9-deficient animals. These findings reveal a previously unappreciated role for TLR9 in the host response to M. tuberculosis and illustrate TLR collaboration in host resistance to a major human pathogen.

MeSH Terms
Animals Antigen-Presenting Cells/immunology Cytokines/metabolism DNA Primers Flow Cytometry Immunity, Innate/immunology Lung/metabolism Mice Mice, Knockout Mycobacterium tuberculosis/immunology Reverse Transcriptase Polymerase Chain Reaction Th1 Cells/immunology Toll-Like Receptor 9/genetics,immunology Tuberculosis/immunology
Chemicals
Cytokines DNA Primers Tlr9 protein, mouse Toll-Like Receptor 9
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Bafica Andre
Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, MD 20892, USA. abafica@niaid.nih.gov
Scanga Charles A
Feng Carl G
Leifer Cynthia
Cheever Allen
Sher Alan
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20051782
Email
abafica@niaid.nih.gov
Published
2005-12-19
Pages
1715-24
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2212963
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20051782 PMC Full Text View journal details
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