The Journal of Experimental Medicine
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Published 19 December 2005. doi:10.1084/jem.20051782
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 12, 1715-1724
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ARTICLE

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

Andre Bafica1,3, Charles A. Scanga1, Carl G. Feng1, Cynthia Leifer2, Allen Cheever4, and Alan Sher1

1 Immunobiology Section, Laboratory of Parasitic Diseases
2 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
3 Laboratorio de Imunorregulacao e Microbiologia, Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, Bahia 40296-710, Brazil
4 Biomedical Research Institute, Rockville, MD 20852

CORRESPONDENCE Andre Bafica: abafica{at}niaid.nih.gov OR Alan Sher: asher{at}niaid.nih.gov

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.

Abbreviations used: BCG, bacillus of Calmette and Guerin; BMDCs, BM-derived DCs; BMM, BM-derived macrophages; DKO, double KO; MOI, multiplicity of infection; TLR, Toll-like receptor.

A. Bafica and C.A. Scanga contributed equally to this work.


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