Although leprosy(Hansen's disease) is one ofthe oldestknown diseases, the pathogenicity of Mycobacterium leprae (M. leprae) remains enigmatic. Indeed, the cellwall components responsible for the... Show moreAlthough leprosy(Hansen's disease) is one ofthe oldestknown diseases, the pathogenicity of Mycobacterium leprae (M. leprae) remains enigmatic. Indeed, the cellwall components responsible for the immune response against M. leprae are as yet largely unidentified. We reveal herephenolic glycolipid-III (PGL-III) as an M. leprae-specific ligand for the immune receptor Mincle. PGL-III is a scarcelypresent trisaccharide intermediate in the biosynthetic pathway toPGL-I, an abundant and characteristic M. leprae glycolipid.Using activity-based purification, we identified PGL-III as a Mincleligand that is more potent than the well-known M. tuberculosis trehalose dimycolate. The cocrystal structure of Mincle and a syntheticPGL-III analogue revealed a unique recognition mode, implying thatit can engage multiple Mincle molecules. In Mincle-deficient miceinfected with M. leprae, increased bacterial burdenwith gross pathologies were observed. These results show that PGL-IIIis a noncanonical ligand recognized by Mincle, triggering protectiveimmunity.PGL-III, a potent immunostimulatory glycolipid,is limitedin M. leprae by the quick addition of a single methylgroup to convert it into immunosuppressive PGL-I, which confers immuneescape. Show less
