The C-Type Lectin Mincle Serves as a Pattern Recognition Receptor for the Lipid Envelope of Human Cytomegalovirus

Enveloped viruses possess a membrane composed of a complex mixture of host-derived lipids, glycolipids, and viral glycoproteins, which play a critical role in host-virus interactions. Viral glycoproteins can be detected by a range of immune lectins, thereby modulating and sometimes subverting the host immune responses to promote immune evasion. Whether viral lipids can directly interact with pattern recognition receptors to modulate antiviral immune responses remains unclear. In this study, we report recognition of the human cytomegalovirus (HCMV) viral envelope by the C-type lectin Mincle. Unlike previously described interactions between human lectins and viruses, Mincle recognition of HCMV and the concomitant activation of the prototypical downstream signaling pathway are mediated by host cell-derived lipids and glycolipids incorporated into the viral envelope. Using mass spectrometry, we identify multiple previously described ligands of Mincle in the HCMV viral envelope, including cholesterol and globosides. We show that Mincle recognition of HCMV viral particles, as well as pure cholesterol, induces proinflammatory cytokine production in primary human macrophages. Collectively, these findings demonstrate that Mincle recognition of the HCMV lipid envelope constitutes a novel pattern recognition mechanism that may apply to other enveloped viruses.