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PGL-III, a Rare Intermediate of Mycobacterium leprae Phenolic Glycolipid Biosynthesis, Is a Potent Mincle Ligand
Shigenari Ishizuka1,2, J Hessel M van Dijk3, Tomomi Kawakita4
1Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Abstract:
Although leprosy (Hansen's disease) is one of the oldest known diseases, the pathogenicity of Mycobacterium leprae (M. leprae) remains enigmatic. Indeed, the cell wall components responsible for the immune response against M. leprae are as yet largely unidentified. We reveal here phenolic glycolipid-III (PGL-III) as an M. leprae-specific ligand for the immune receptor Mincle. PGL-III is a scarcely present trisaccharide intermediate in the biosynthetic pathway to PGL-I, an abundant and characteristic M. leprae glycolipid. Using activity-based purification, we identified PGL-III as a Mincle ligand that is more potent than the well-known M. tuberculosis trehalose dimycolate. The cocrystal structure of Mincle and a synthetic PGL-III analogue revealed a unique recognition mode, implying that it can engage multiple Mincle molecules. In Mincle-deficient mice infected with M. leprae, increased bacterial burden with gross pathologies were observed. These results show that PGL-III is a noncanonical ligand recognized by Mincle, triggering protective immunity.
Insights
Phenolic glycolipid-III (PGL-III) from Mycobacterium leprae is identified as a potent immune activator. This discovery reveals how PGL-III triggers protective immunity against leprosy, a significant advancement in understanding the disease.
Area of Science:
- Immunology
- Microbiology
- Structural Biology
Background:
- Leprosy (Hansen's disease) pathogenesis by Mycobacterium leprae (M. leprae) is poorly understood.
- Key M. leprae cell wall components eliciting immune responses remain largely unidentified.
Purpose of the Study:
- To identify novel M. leprae-specific ligands for immune receptors.
- To elucidate the role of identified ligands in the host immune response to M. leprae.
Main Methods:
- Activity-based purification to identify Mincle ligands.
- Cocrystallography to determine the Mincle-PGL-III interaction structure.
- Infection studies using Mincle-deficient mice.
Main Results:
- Phenolic glycolipid-III (PGL-III), a M. leprae trisaccharide intermediate, was identified as a potent Mincle ligand.
- PGL-III demonstrated higher Mincle binding potency than Mycobacterium tuberculosis trehalose dimycolate.
- Structural analysis revealed a unique Mincle recognition mode for PGL-III.
- Mincle-deficient mice exhibited increased M. leprae burden and pathology.
Conclusions:
- PGL-III is a noncanonical Mincle ligand that triggers protective immunity against M. leprae.
- Mincle-mediated recognition of PGL-III is crucial for controlling leprosy infection.
- This finding offers new insights into host-pathogen interactions in leprosy.
