Abstract
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.
Highlights
Worldwide, 2 billion people are currently believed to be infected with Mycobacterium tuberculosis, with an estimated death toll of 2 million patients each year [1]
A sonicate of M. tuberculosis strongly activated a Chinese hamster ovary fibroblast (CHO) cell line cotransfected with human TLR2 and CD14, whereas cells transfected with CD14 alone or a combination of CD14 and TLR4 displayed no signaling upon activation with the sonicated mycobacterial preparation (Figure 1A)
We investigated the role of Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD), the two most important classes of pattern recognition receptor (PRR) in the recognition by macrophages of M. tuberculosis
Summary
2 billion people are currently believed to be infected with Mycobacterium tuberculosis, with an estimated death toll of 2 million patients each year [1]. M. tuberculosis is an intracellular pathogen capable of infecting and surviving within the host’s mononuclear cells (MNCs), and a coordinated response of the innate and adaptive immune systems is required for an effective host defense. This involves sequestration of the microorganism in macrophages within organized granulomas, and elimination of the pathogen through a combination of killing mechanisms and apoptosis of host macrophages [2]. These responses are coordinated by T helper 1-type proinflammatory cytokines, which are synthesized by phagocytes upon recognition of pathogen-associated molecular patterns of mycobacteria by pattern recognition receptors (PRRs). TLR2À/À mice had a decreased clearance of the bacteria and developed chronic pneumonia when infected with a low dose of microorganisms [13], whereas in other studies only minor effects have been found
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