TIM-1 acts a dual-attachment receptor for Ebolavirus by interacting directly with viral GP and the PS on the viral envelope.

Shuai Yuan,Xiangxi Wang,Yutao Chen,Yao Sun,Liguo Zhang,Xuyuan Zhang,Lei Cao,Dan Su,Zihe Rao,Minghao Dang,Hui Ling

doi:10.1007/s13238-015-0220-y

Abstract

Ebolavirus can cause hemorrhagic fever in humans with a mortality rate of 50%–90%. Currently, no approved vaccines and antiviral therapies are available. Human TIM1 is considered as an attachment factor for EBOV, enhancing viral infection through interaction with PS located on the viral envelope. However, reasons underlying the preferable usage of hTIM-1, but not other PS binding receptors by filovirus, remain unknown. We firstly demonstrated a direct interaction between hTIM-1 and EBOV GP in vitro and determined the crystal structures of the Ig V domains of hTIM-1 and hTIM-4. The binding region in hTIM-1 to EBOV GP was mapped by chimeras and mutation assays, which were designed based on structural analysis. Pseudovirion infection assays performed using hTIM-1 and its homologs as well as point mutants verified the location of the GP binding site and the importance of EBOV GP-hTIM-1 interaction in EBOV cellular entry.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-015-0220-y) contains supplementary material, which is available to authorized users.

Highlights

Ebolavirus (EBOV) and Marburgvirus, belonging to the Filoviridae family, cause hemorrhagic fever during the course of their infections in humans
A number of lines of evidence indicate that hTIM-1 enhances infection of a variety of enveloped viruses by binding to virion-associated PS and does not require viral entry protein (Moller-Tank et al, 2013; Meertens et al, 2012; Jemielity et al, 2013), hTIM-1 is generally described as an attachment factor
Structural analysis reporting that the membrane of flaviviruses are occluded by tightly-arranged viral glycoproteins further weakens the argument that TIM-1 is an accessory protein that enhances PS-mediated viral uptake (Zhang et al, 2003a, 2003b)

Summary

Introduction

Ebolavirus (EBOV) and Marburgvirus, belonging to the Filoviridae family, cause hemorrhagic fever during the course of their infections in humans. Recent studies indicate that hTIM-1, with some other but not all phosphatidylserine (PS) binding receptors, functions as a common attachment factor for a range of enveloped viruses, including filoviruses, flaviviruses, HIV, etc., through direct interaction with PS of the viral envelope (Li et al, 2014; Moller-Tank et al, 2013; Meertens et al, 2012; Jemielity et al, 2013). Recently hTIM-1 was shown to interact with NPC1, a fusion receptor for filovirus. This interaction was important for the entry of EBOV into host cell (Côté et al 2011; Kuroda et al, 2015), raising an important question on whether hTIM-1 functions as an attachment factor or it is a bona fide receptor for EBOV

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