Journal article
TIM-1 Mediates Dystroglycan-Independent Entry of Lassa Virus
Journal of virology, Vol.92(16), e00093-18
08/15/2018
DOI: 10.1128/JVI.00093-18
PMCID: PMC6069209
PMID: 29875238
Abstract
Lassa virus (LASV) is an Old World arenavirus responsible for hundreds of thousands of infections in West Africa every year. LASV entry into a variety of cell types is mediated by interactions with glycosyltransferase LARGE-modified O-linked glycans present on the ubiquitous receptor α-dystroglycan (αDG). However, cells lacking αDG are permissive to LASV infection, suggesting that alternative receptors exist. Previous studies demonstrated that the phosphatidylserine (PtdSer)-binding receptors Axl and Tyro3 along with C-type lectin receptors mediate αDG-independent entry. Here, we demonstrate that another PtdSer receptor, TIM-1, mediates LASV glycoprotein (GP)-pseudotyped virion entry into αDG-knocked-out HEK 293T and wild-type (WT) Vero cells, which express αDG lacking appropriate glycosylation. To investigate the mechanism by which TIM-1 mediates enhancement of entry, we demonstrate that mutagenesis of the TIM-1 IgV domain PtdSer-binding pocket abrogated transduction. Furthermore, the human TIM-1 IgV domain-binding monoclonal antibody ARD5 blocked transduction of pseudovirions bearing LASV GP in a dose-dependent manner. Finally, as we showed previously for other viruses that use TIM-1 for entry, a chimeric TIM-1 protein that substitutes the proline-rich region (PRR) from murine leukemia virus envelope (Env) for the mucin-like domain served as a competent receptor. These studies provide evidence that, in the absence of a functional αDG, TIM-1 mediates the entry of LASV pseudoviral particles through interactions of virions with the IgV PtdSer-binding pocket of TIM-1.
PtdSer receptors, such as TIM-1, are emerging as critical entry factors for many enveloped viruses. Most recently, hepatitis C virus and Zika virus have been added to a growing list. PtdSer receptors engage with enveloped viruses through the binding of PtdSer embedded in the viral envelope, defining them as GP-independent receptors. This GP-independent entry mechanism should effectively mediate the entry of all enveloped viruses, yet LASV GP-pseudotyped viruses were previously found to be unresponsive to PtdSer receptor enhancement in HEK 293T cells. Here, we demonstrate that LASV pseudovirions can utilize the PtdSer receptor TIM-1 but only in the absence of appropriately glycosylated α-dystroglycan (αDG), the high-affinity cell surface receptor for LASV. Our studies shed light on LASV receptor utilization and explain why previous studies performed with α-DG-expressing cells did not find that LASV pseudovirions utilize PtdSer receptors for virus uptake.
Details
- Title: Subtitle
- TIM-1 Mediates Dystroglycan-Independent Entry of Lassa Virus
- Creators
- Kai J Rogers - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USARachel B Brouillette - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAAshley L Cooney - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAElisabeth K Phillips - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAChioma Okeoma - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USARadhika Patel - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAWendy Maury - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USA wendy-maury@uiowa.eduWadie Mahauad-Fernandez - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USASven Moller-Tank - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAJacob A Dillard - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USALuis Martinez-Sobrido - Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA
- Resource Type
- Journal article
- Publication Details
- Journal of virology, Vol.92(16), e00093-18
- DOI
- 10.1128/JVI.00093-18
- PMID
- 29875238
- PMCID
- PMC6069209
- ISSN
- 0022-538X
- eISSN
- 1098-5514
- Grant note
- T32 GM067795 / NIGMS NIH HHS R21 AI121550 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS R21 AI128097 / NIAID NIH HHS R01 AI077519 / NIAID NIH HHS T32 AI007533 / NIAID NIH HHS
- Language
- English
- Date published
- 08/15/2018
- Academic Unit
- Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics
- Record Identifier
- 9984083876002771
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