Structural Insights into Entry and Antibody Neutralization of Eastern Equine Encephalitis Virus

Abstract

Alphaviruses are enveloped pathogens that cause arthritis and encephalitis. Host entry of alphaviruses involves binding to plasma and endosomal membranes followed by low pH-triggered membrane fusion. Here we present a 3.5-6.5Å resolution (average 4.4Å) cryo-electron microscopy (cryoEM) structure of Eastern Equine Encephalitis virus (EEEV), an alphavirus that often causes fatal encephalitis in humans. Motifs for potential binding of host membrane receptors were identified. The capsid protein structure showed an RNA genome-binding segment and an inherently unstable nucleocapsid core primed for disassembly. CryoEM structures of five different Fab-EEEV complexes derived from neutralizing antibodies showed how the icosahedral structure of alphaviruses poses steric restrictions on interactions with antibodies. These results also identified molecular mechanisms of host cell entry that likely are conserved among enveloped icosahedral viruses.