title: Role of the phosphatidylserine receptor TIM-1 in enveloped-virus entry.
abstract: The cell surface receptor T cell immunoglobulin mucin domain 1 (TIM-1) dramatically enhances filovirus infection of epithelial cells. Here, we showed that key phosphatidylserine (PtdSer) binding residues of the TIM-1 IgV domain are critical for Ebola virus (EBOV) entry through direct interaction with PtdSer on the viral envelope. PtdSer liposomes but not phosphatidylcholine liposomes competed with TIM-1 for EBOV pseudovirion binding and transduction. Further, annexin V (AnxV) substituted for the TIM-1 IgV domain, supporting a PtdSer-dependent mechanism. Our findings suggest that TIM-1-dependent uptake of EBOV occurs by apoptotic mimicry. Additionally, TIM-1 enhanced infection of a wide range of enveloped viruses, including alphaviruses and a baculovirus. As further evidence of the critical role of enveloped-virion-associated PtdSer in TIM-1-mediated uptake, TIM-1 enhanced internalization of pseudovirions and virus-like proteins (VLPs) lacking a glycoprotein, providing evidence that TIM-1 and PtdSer-binding receptors can mediate virus uptake independent of a glycoprotein. These results provide evidence for a broad role of TIM-1 as a PtdSer-binding receptor that mediates enveloped-virus uptake. Utilization of PtdSer-binding receptors may explain the wide tropism of many of these viruses and provide new avenues for controlling their virulence.
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Moller-Tank
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kondratowicz
authors.forename: Robert A
authors.initials: RA
authors.lastname: Davey
authors.forename: Paul D
authors.initials: PD
authors.lastname: Rennert
authors.forename: Wendy
authors.initials: W
authors.lastname: Maury
mesh_terms: D000524:Alphavirus / Q000737:chemistry / Q000502:physiology; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D016367:Baculoviridae / Q000737:chemistry / Q000502:physiology; D002460:Cell Line; D029043:Ebolavirus / Q000737:chemistry / Q000502:physiology*; D000072596:Hepatitis A Virus Cellular Receptor 1; D054884:Host-Pathogen Interactions; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D014161:Transduction, Genetic; D053586:Virus Internalization
chemical_list: D017304:Annexin A5; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D010718:Phosphatidylserines; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; C408123:phosphatidylserine receptor