Molecular and structural basis of Echovirus 11 infection by using the dual-receptor system of CD55 and FcRn

Abstract

Echovirus 11 (Echo 11) is a serotype of Enterovirus B (EV-B) belonging to the genus Enterovirus in the family Picornaviridae . Echo 11 infections are associated with viral encephalitis (VE), viral meningitis (VM), and viral meningo-encephalitis (VME). Echo 11 was reported to cause severe illnesses in neonates or infants, with high morbidity and mortality. In addition, Echo 11 has frequently been identified as the causative agent of outbreaks, greatly threatens public health. For example, in early 2019, an Echo 11 outbreak occurred in a hospital of Guangdong Province in China, leading to nineteen infections of newborns and five of them died. CD55 has been designated an attaching receptor of several echoviruses in the 1990s. But CD55 alone is unable to help the virus to complete its whole entry process. In our earlier work, we found that the human neonatal Fc receptor (FcRn) is the cellular uncoating receptor for Enterovirus B and illustrated the entry mechanism taking Echo 6 as an example. We proposed the coordination of attaching and uncoating “dual-receptor system” in the entry pathways. Here, we analyzed 10 cryo-electron microscopy (Cryo-EM) structures of Echo 11 viral particles in three different forms (free, “A-particle” and empty particle), and Echo 11 in complex with receptor CD55 or FcRn, under both neutral (pH 7.4) and acidic (pH 5.5) conditions. With atomic or near-atomic resolutions (2.32−3.4 A), we obtained detailed characterization of the molecular events during Echo 11 entry. The structures revealed that CD55 is the attaching receptor of Echo 11, which facilitates the viral attachment to cell surface. Similar to Echo 12 and Echo 7, Echo 11 uses its VP2 and VP3 domain to bind short consensus repeat (SCR) module SCR 3 and SCR4 domains of CD55. FcRn is the uncoating receptor, which uses the α2 domain of its heavy chain FCGRT to insert into and bind the “canyon” of Echo 11 VP1 domain. The binding induced the extrusion of “pocket factor” and resulted in virus uncoating and genome release. FcRn induced Echo 11 viral particle conformational change and “pocket factor” release started at neutral pH, which is different from Echo 6, there the “pocket factor” release occurs at low pH. This hints us that acidic treatment might not be an essential requirement for the uncoating of all Enterovirus B which uses FcRn as their uncoating receptor. The uncoating process is able to start in early endosomes. SPR (Surface plasmon resonance) analysis certified that, Echo 11 can bind to both receptors, but has a higher affinity with FcRn than to CD55. FcRn-mediated Echo 11 uncoating was further confirmed with an FcRn-decorated liposome model, which induced the structural transitions of Echo 11 into empty particles. This work provided a molecular and structural basis for our understanding of the mechanisms of Echo 11 entry. And it is an important progress in dissecting the mechanism of the “dual-receptor system” in non-enveloped virus entry.