NOD2 and Toll-Like Receptors Are Nonredundant Recognition Systems of Mycobacterium tuberculosis

PLoS Pathogens

Reinout van Crevel¹  Gosse J Adema²  Lionel Le Bourhis³  Tom H. M Ottenhoff³  Gerben Ferwerda³  Mihai G Netea⁴  Stephen E Girardin⁵  Dirk J. de Jong⁵  Jos W. M. Van der Meer⁵  Bart-Jan Kullberg⁶  Dennis M. L Langenberg⁶ 

[1] Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands;Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;Department of Tumor Immunology, Radboud University Medical Center, Nijmegen, The Netherlands;Nijmegen University Center for Infectious Diseases, Nijmegen, The Netherlands;Unité de Pathogénie Microbienne Moléculaire, INSERM U389, Institut Pasteur, Paris Cedex, France

关键词: Mycobacterium tuberculosis;    Cytokines;    Pattern recognition receptors;    Toll-like receptors;    Macrophages;    Crohn's disease;    Peptidoglycans;    Lipoproteins;   

DOI  :  10.1371/journal.ppat.0010034

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Infection with Mycobacterium tuberculosis is one of the leading causes of death worldwide. Recognition of M. tuberculosis by pattern recognition receptors is crucial for activation of both innate and adaptive immune responses. In the present study, we demonstrate that nucleotide-binding oligomerization domain 2 (NOD2) and Toll-like receptors (TLRs) are two nonredundant recognition mechanisms of M. tuberculosis. CHO cell lines transfected with human TLR2 or TLR4 were responsive to M. tuberculosis. TLR2 knock-out mice displayed more than 50% defective cytokine production after stimulation with mycobacteria, whereas TLR4-defective mice also released 30% less cytokines compared to controls. Similarly, HEK293T cells transfected with NOD2 responded to stimulation with M. tuberculosis. The important role of NOD2 for the recognition of M. tuberculosis was demonstrated in mononuclear cells of individuals homozygous for the 3020insC NOD2 mutation, who showed an 80% defective cytokine response after stimulation with M. tuberculosis. Finally, the mycobacterial TLR2 ligand 19-kDa lipoprotein and the NOD2 ligand muramyl dipeptide synergized for the induction of cytokines, and this synergism was lost in cells defective in either TLR2 or NOD2. Together, these results demonstrate that NOD2 and TLR pathways are nonredundant recognition mechanisms of M. tuberculosis that synergize for the induction of proinflammatory cytokines.

【 授权许可】

CC BY