Structural basis of Semliki Forest virus entry using the very-low-density lipoprotein receptor

Alphaviruses are a group of important viruses that cause significant diseases in humans. Among them, Semliki Forest virus (SFV) not only causes symptoms such as joint pain but also infects neuron cells and induces encephalitis in rodents. Recently, the very-low-density lipoprotein receptor (VLDLR) was identified as the cellular receptor for SFV entry. In this study, we present the cryo-electron microscopy structure of SFV bound to human VLDLR. VLDLR targets E1-DIII region of SFV using its membrane-distal LDLR class A (LA) repeats. Structural and functional analyses emphasize the synergistic role of multiple VLDLR repeats in the SFV entry. Remarkably, VLDLR's binding mode to SFV closely mirrors that of minor group human rhinoviruses but differs significantly from other alphaviruses' interactions with receptors in the canyon region of the E protein. We also assessed SFV binding to VLDLR or apolipoprotein E receptor 2 (ApoER2) proteins in horses and mosquitoes and revealed their use of multiple but different LA repeats for binding. Our findings illuminate SFV's cross-species infectivity, offering insights into potential antiviral strategies against alphavirus infections.