Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry into evolutionarily divergent host cells can be accomplished by recognition of different cellular receptors in different species, or by binding to receptors that are highly conserved across species. Although multiple
alphavirus receptors have been described1-3, most are not shared among vertebrate and invertebrate hosts. Here we identify the
very low-density lipoprotein receptor (VLDLR) as a receptor for the prototypic alphavirus Semliki forest virus. We show that the E2 and E1
glycoproteins (E2-E1) of Semliki forest virus, eastern equine encephalitis virus and Sindbis virus interact with the
ligand-binding domains (LBDs) of VLDLR and
apolipoprotein E receptor 2 (ApoER2), two closely related receptors. Ectopic expression of either
protein facilitates cellular attachment, and internalization of virus-like particles, a VLDLR LBD-Fc fusion
protein or a
ligand-binding antagonist block Semliki forest virus E2-E1-mediated
infection of human and mouse neurons in culture. The administration of a VLDLR LBD-Fc fusion
protein has protective activity against rapidly fatal
Semliki forest virus infection in mouse neonates. We further show that invertebrate receptor orthologues from mosquitoes and worms can serve as functional
alphavirus receptors. We propose that the ability of some alphaviruses to infect a wide range of hosts is a result of their engagement of evolutionarily conserved
lipoprotein receptors and contributes to their pathogenesis.