Unraveling a Three-Step Spatiotemporal Mechanism of Triggering of Receptor-Induced Nipah Virus Fusion and Cell Entry

Qian Liu,Jacquelyn A Stone,Scott B Biering,Jeffrey Dabundo,Hector C Aguilar,Javier A Benavides Montano,Birgit Bradel-Tretheway,Anthony V Nicola,Jennifer Santos-Montanez,Xiaonan Lu,Ronald M Iorio,Sean Whelan

doi:10.1371/journal.ppat.1003770

Abstract

Membrane fusion is essential for entry of the biomedically-important paramyxoviruses into their host cells (viral-cell fusion), and for syncytia formation (cell-cell fusion), often induced by paramyxoviral infections [e.g. those of the deadly Nipah virus (NiV)]. For most paramyxoviruses, membrane fusion requires two viral glycoproteins. Upon receptor binding, the attachment glycoprotein (HN/H/G) triggers the fusion glycoprotein (F) to undergo conformational changes that merge viral and/or cell membranes. However, a significant knowledge gap remains on how HN/H/G couples cell receptor binding to F-triggering. Via interdisciplinary approaches we report the first comprehensive mechanism of NiV membrane fusion triggering, involving three spatiotemporally sequential cell receptor-induced conformational steps in NiV-G: two in the head and one in the stalk. Interestingly, a headless NiV-G mutant was able to trigger NiV-F, and the two head conformational steps were required for the exposure of the stalk domain. Moreover, the headless NiV-G prematurely triggered NiV-F on virions, indicating that the NiV-G head prevents premature triggering of NiV-F on virions by concealing a F-triggering stalk domain until the correct time and place: receptor-binding. Based on these and recent paramyxovirus findings, we present a comprehensive and fundamentally conserved mechanistic model of paramyxovirus membrane fusion triggering and cell entry.

Highlights

The Paramyxoviridae is a medically-important negative-sense single-stranded RNA enveloped virus family that includes measles (MeV), mumps (MuV), parainfluenza (PIV), respiratory syncytial (RSV), Newcastle disease (NDV), human metapneumo- (HMPV), and the henipa-viruses Nipah (NiV) and Hendra (HeV)
After paramyxoviruses attach to a receptor at a cell surface, fusion between viral and cellular membranes must occur before the virus genetic material can enter the cell and replication of the virus inside the cell can begin
Viral/ cell membrane fusion requires the concerted actions of two viral glycoproteins

Summary

Introduction

The Paramyxoviridae is a medically-important negative-sense single-stranded RNA enveloped virus family that includes measles (MeV), mumps (MuV), parainfluenza (PIV), respiratory syncytial (RSV), Newcastle disease (NDV), human metapneumo- (HMPV), and the henipa-viruses Nipah (NiV) and Hendra (HeV). NiV and HeV cause high mortality rates in humans, approaching 75% in recent NiV outbreaks [1]; death is associated with syncytium formation, vasculitis, pneumonia, and encephalitis. These biosafety level 4 (BSL4) pathogens possess a broad mammalian host range [2], animal-to-human, and human-to-human transmission [1,3], and pose bio- and agro-terrorism threats to global health and economy. Membrane fusion is essential for syncytium formation (cell-cell fusion), a pathological hallmark of paramyxoviral infections such as that of NiV and HeV [8] and a mechanism of cell-to-cell viral spread [3,9,10]. There is a significant knowledge gap on the mechanism(s) by which HN/ H/G couples receptor binding to F-triggering [3,9,10]

Methods

Results

Discussion

Conclusion