Axl Can Serve as Entry Factor for Lassa Virus Depending on the Functional Glycosylation of Dystroglycan.


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Axl Can Serve as Entry Factor for Lassa Virus Depending on the Functional Glycosylation of Dystroglycan.
Journal of virology
Fedeli C., Torriani G., Galan-Navarro C., Moraz M.L., Moreno H., Gerold G., Kunz S.
1098-5514 (Electronic)
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Issued date
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Fatal infection with the highly pathogenic Lassa virus (LASV) is characterized by extensive viral dissemination, indicating broad tissue tropism. The major cellular receptor for LASV is the highly conserved extracellular matrix receptor dystroglycan (DG). Binding of LASV depends on DG's tissue-specific posttranslational modification with the unusual O-linked polysaccharide matriglycan. Interestingly, functional glycosylation of DG does not always correlate with viral tropism observed <i>in vivo</i> The broadly expressed phosphatidylserine (PS) receptors Axl and Tyro3 were recently identified as alternative LASV receptor candidates. However, their role in LASV entry is not entirely understood. Here, we examine LASV receptor candidates in primary human cells and found coexpression of Axl with differentially glycosylated DG. To study LASV receptor use in the context of productive arenavirus infection, we employed recombinant lymphocytic choriomeningitis virus expressing LASV glycoprotein (rLCMV-LASV GP) as a validated biosafety level 2 (BSL2) model. We confirm and extend previous work showing that Axl can contribute to LASV entry in the absence of functional DG using "apoptotic mimicry" in a way similar to that of other enveloped viruses. We further show that Axl-dependent LASV entry requires receptor activation and involves a pathway resembling macropinocytosis. Axl-mediated LASV entry is facilitated by heparan sulfate and critically depends on the late endosomal protein LAMP-1 as an intracellular entry factor. In endothelial cells expressing low levels of functional DG, both receptors are engaged by the virus and can contribute to productive entry. In sum, we characterize the role of Axl in LASV entry and provide a rationale for targeting Axl in antiviral therapy. <b>IMPORTANCE</b> The highly pathogenic arenavirus Lassa virus (LASV) represents a serious public health problem in Africa. Although the principal LASV receptor, dystroglycan (DG), is ubiquitously expressed, virus binding critically depends on DG's posttranslational modification, which does not always correlate with tissue tropism. The broadly expressed phosphatidylserine receptor Axl was recently identified as an alternative LASV receptor candidate, but its role in LASV entry is unclear. Here, we investigate the exact role of Axl in LASV entry as a function of DG's posttranslational modification. We found that in the absence of functional DG, Axl can mediate LASV entry via apoptotic mimicry. Productive entry requires virus-induced receptor activation, involves macropinocytosis, and critically depends on LAMP-1. In endothelial cells that express low levels of glycosylated DG, both receptors can promote LASV entry. In sum, our study defines the roles of Axl in LASV entry and provides a rationale for targeting Axl in antiviral therapy.

A549 Cells, Antiviral Agents/pharmacology, Arenaviridae Infections/metabolism, Cell Line, Tumor, Dystroglycans/genetics, Dystroglycans/metabolism, Endosomes/metabolism, Gene Expression, Glycosylation, HEK293 Cells, HeLa Cells, Heparitin Sulfate/pharmacology, Humans, Lassa virus/drug effects, Lassa virus/pathogenicity, Lassa virus/physiology, Lymphocytic choriomeningitis virus/genetics, Lymphocytic choriomeningitis virus/metabolism, Lysosome-Associated Membrane Glycoproteins/metabolism, Pinocytosis/physiology, Protein Processing, Post-Translational, Proto-Oncogene Proteins/drug effects, Proto-Oncogene Proteins/genetics, Proto-Oncogene Proteins/physiology, RNA Interference, Receptor Protein-Tyrosine Kinases/drug effects, Receptor Protein-Tyrosine Kinases/genetics, Receptor Protein-Tyrosine Kinases/metabolism, Receptor Protein-Tyrosine Kinases/physiology, Receptors, Virus/metabolism, Signal Transduction, Tropism, Virus Attachment, Virus Internalization, Axl, Lassa virus, attachment, dystroglycan, entry factor, macropinocytosis, receptor, viral entry
Web of science
Open Access
Create date
11/01/2018 20:55
Last modification date
20/08/2019 17:03
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