Alphaviruses are enveloped RNA viruses that cause disease in humans ranging from acute febrile illness with rash and arthritis to lethal encephalitis. Like many other mosquito-borne viruses, they infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Viral entry into 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. I will discuss our laboratory’s recent identification of the very low-density lipoprotein receptor (VLDLR) as a receptor for the alphaviruses Semliki Forest virus (SFV), eastern equine encephalitis (EEEV), and Sindbis (SINV). We showed that these viruses interact with the ligand binding domains (LBDs) of VLDLR and apolipoprotein E receptor 2 (ApoER2), a closely related receptor whose expression is mostly restricted to the central nervous system. We further demonstrated that ectopic expression of either VLDLR or ApoER2 facilitated cellular attachment and internalization of virus-like particles (VLPs), that a VLDLR LBD-Fc fusion protein or a ligand binding antagonist can block SFV E2/E1 envelope protein-mediated infection of human and mouse neurons in culture, and that administration of a VLDLR LBD-Fc fusion protein had protective activity against rapidly fatal SFV infection in mouse neonates. Overexpression studies further revealed that invertebrate receptor orthologs as evolutionary distant from vertebrates as mosquitoes and worms could 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.

Learning objectives:
1. Clarify the role of alphaviruses as agents that cause acute human febrile illnesses with either arthritis or encephalitis as the outcome of infection.
2. Explain the organization of the alphavirus envelope glycoproteins and their role in mediating viral entry.
3. Summarize the role of LDLR-related receptors as factors that facilitate the cell surface binding and internalization of some alphaviruses.