Axl can serve as entry factor for Lassa virus depending on the functional glycosylation of dystroglycan.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
MetadataShow full item record
AbstractFatal 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 post-translational modification with the unusual O-linked polysaccharide matriglycan. Interestingly, functional glycosylation of DG does not always correlate with viral tropism observed in vivo 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 examined LASV receptor candidates in primary human cells and found co-expression 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-LASVGP) as validated BSL2 model. We confirm and extend previous work, showing that Axl can contribute to LASV entry in absence of functional DG using "apoptotic mimicry", similar to other enveloped virus. 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 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 to target Axl in anti-viral therapy.IMPORTANCEThe highly pathogenic arenavirus Lassa (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 post-translational modification, which does not always correlate with tissue tropism. The broadly expressed phosphatidylserine receptor Axl was recently identified as alternative LASV receptor candidate, but its role in LASV entry is unclear. Here we investigated the exact role of Axl in LASV entry as a function of DG's post-translational modification. We found that in 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 to target Axl in anti-viral therapy.
CitationAxl can serve as entry factor for Lassa virus depending on the functional glycosylation of dystroglycan. 2017 J. Virol.
AffiliationHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
JournalJournal of virology
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
- Lassa Virus Cell Entry via Dystroglycan Involves an Unusual Pathway of Macropinocytosis.
- Authors: Oppliger J, Torriani G, Herrador A, Kunz S
- Issue date: 2016 Jul 15
- The Role of Receptor Tyrosine Kinases in Lassa Virus Cell Entry.
- Authors: Fedeli C, Moreno H, Kunz S
- Issue date: 2020 Aug 6
- Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus.
- Authors: Herrador A, Fedeli C, Radulovic E, Campbell KP, Moreno H, Gerold G, Kunz S
- Issue date: 2019 Mar 26
- TIM-1 Mediates Dystroglycan-Independent Entry of Lassa Virus.
- Authors: Brouillette RB, Phillips EK, Patel R, Mahauad-Fernandez W, Moller-Tank S, Rogers KJ, Dillard JA, Cooney AL, Martinez-Sobrido L, Okeoma C, Maury W
- Issue date: 2018 Aug 15
- Binding of Lassa virus perturbs extracellular matrix-induced signal transduction via dystroglycan.
- Authors: Rojek JM, Moraz ML, Pythoud C, Rothenberger S, Van der Goot FG, Campbell KP, Kunz S
- Issue date: 2012 Jul