PGL-III, a Rare Intermediate of Mycobacterium leprae Phenolic Glycolipid Biosynthesis, Is a Potent Mincle Ligand

Shigenari Ishizuka; J Hessel M van Dijk; Tomomi Kawakita; Yuji Miyamoto; Yumi Maeda; Masamichi Goto; Guillaume Le Calvez; L Melanie Groot; Martin D Witte; Adriaan J Minnaard; Gijsbert A van der Marel; Manabu Ato; Masamichi Nagae; Jeroen D C Codée; Sho Yamasaki

doi:10.1021/acscentsci.3c00040

PGL-III, a Rare Intermediate of Mycobacterium leprae Phenolic Glycolipid Biosynthesis, Is a Potent Mincle Ligand

ACS Cent Sci. 2023 Jul 12;9(7):1388-1399. doi: 10.1021/acscentsci.3c00040. eCollection 2023 Jul 26.

Authors

Shigenari Ishizuka^{1

2}, J Hessel M van Dijk³, Tomomi Kawakita⁴, Yuji Miyamoto⁴, Yumi Maeda⁴, Masamichi Goto⁵, Guillaume Le Calvez⁶, L Melanie Groot³, Martin D Witte⁶, Adriaan J Minnaard⁶, Gijsbert A van der Marel³, Manabu Ato⁴, Masamichi Nagae^{1

2}, Jeroen D C Codée³, Sho Yamasaki^{1

2

7}

Affiliations

¹ Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
² Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
³ Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
⁴ Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, 4-2-1 Aobacho, Higashimurayama, Tokyo 189-0002, Japan.
⁵ Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
⁶ Stratingh Institute for Chemistry, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
⁷ Center for Infectious Disease Education and Research, Osaka University (CiDER), 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.