The receptors and cellular factors used by phleboviruses (Bunyaviridae) to enter host cells remain largely unidentified. In addition to the C-type lectin DC-SIGN (Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin), we report here that several phleboviruses subvert the closely related protein L-SIGN for infection. Together, our results establish that L-SIGN is an attachment factor not required for virus internalization whereas DC-SIGN is an authentic entry receptor required for both binding and endocytosis. Our study underlines the importance of the subsequent entry processes in virus–receptor interactions beyond attachment.
Bunyaviruses represent a growing threat to humans and livestock globally. The receptors, cellular factors and endocytic pathways used by these emerging pathogens to infect cells remain largely unidentified and poorly characterized. DC-SIGN is a C-type lectin highly expressed on dermal dendritic cells that has been found to act as an authentic entry receptor for many phleboviruses (Bunyaviridae), including Rift Valley fever virus (RVFV), Toscana virus (TOSV) and Uukuniemi virus (UUKV). We found that these phleboviruses can exploit another C-type lectin, L-SIGN, for infection. L-SIGN shares 77% sequence homology with DC-SIGN and is expressed on liver sinusoidal endothelial cells. L-SIGN is required for UUKV binding but not for virus internalization. An endocytosis-defective mutant of L-SIGN was still able to mediate virus uptake and infection, indicating that L-SIGN acts as an attachment receptor for phleboviruses rather than an endocytic receptor. Our results point out a fundamental difference in the use of the C-type lectins L-SIGN and DC-SIGN by UUKV to enter cells, although both proteins are closely related in terms of molecular structure and biological function. This study sheds new light on the molecular mechanisms by which phleboviruses target the liver and also highlights the added complexity in virus–receptor interactions beyond attachment.