Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry in evolutionarily divergent host cells could 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 described, 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 (SFV). We show that the E2/E1 glycoproteins of SFV, eastern equine encephalitis (EEEV), and S... More
Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry in evolutionarily divergent host cells could 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 described, 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 (SFV). We show that the E2/E1 glycoproteins of SFV, eastern equine encephalitis (EEEV), and Sindbis (SINV) viruses interact with the ligand binding domains (LBDs) of VLDLR and apolipoprotein E receptor 2 (ApoER2), a closely related receptor. Ectopic expression of either protein facilitates cellular attachment and internalization of virus-like particles (VLPs), a VLDLR LBD-Fc fusion protein or a ligand binding antagonist block SFV E2/E1-mediated infection of human and mouse neurons in culture, and administration of a VLDLR LBD-Fc fusion protein has protective activity against rapidly fatal SFV infection in mouse neonates. We further show that invertebrate receptor orthologues as evolutionary distant from vertebrates as 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.
