Human NOD2 Recognizes Structurally Unique Muramyl Dipeptides from Mycobacterium leprae.
The innate immune system recognizes microbial pathogens via pattern recognition receptors. One such receptor, NOD2, via recognition of muramyl dipeptide (MDP), triggers a distinct network of innate immune responses, including the production of interleukin-32 (IL-32), which leads to the differentiation of monocytes into dendritic cells (DC). NOD2 has been implicated in the pathogenesis of human leprosy, yet it is not clear whether Mycobacterium leprae, which has a distinct MDP structure, can activate this pathway. We investigated the effect of MDP structure on the innate immune response, finding that infection of monocytes with M. leprae induces IL-32 and DC differentiation in a NOD2-dependent manner. The presence of the proximal l-Ala instead of Gly in the common configuration of the peptide side chain of M. leprae did not affect recognition by NOD2 or cytokine production. Furthermore, amidation of the d-Glu residue did not alter NOD2 activation. These data provide experimental evidence that NOD2 recognizes naturally occurring structural variants of MDP.
Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA.
Mirjam
M
Schenk
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
Sebabrata
S
Mahapatra
Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA.
Phuonganh
P
Le
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
Hee Jin
HJ
Kim
Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA.
Aaron W
AW
Choi
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
Patrick J
PJ
Brennan
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
John T
JT
Belisle
Division of Dermatology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, California, USA rmodlin@mednet.ucla.edu.
Robert L
RL
Modlin
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007378:Interleukins / Q000378:metabolism; D007918:Leprosy / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009166:Mycobacterium leprae / Q000276:immunology / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*
C496971:IL32 protein, human; D007378:Interleukins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine