title: The Measles Virus Receptor SLAMF1 Can Mediate Particle Endocytosis.
abstract: The signaling lymphocyte activation molecule F1 (SLAMF1) is both a microbial sensor and entry receptor for measles virus (MeV). Herein, we describe a new role for SLAMF1 to mediate MeV endocytosis that is in contrast with the alternative, and generally accepted, model that MeV genome enters cells only after fusion at the cell surface. We demonstrated that MeV engagement of SLAMF1 induces dramatic but transient morphological changes, most prominently in the formation of membrane blebs, which were shown to colocalize with incoming viral particles, and rearrangement of the actin cytoskeleton in infected cells. MeV infection was dependent on these dynamic cytoskeletal changes as well as fluid uptake through a macropinocytosis-like pathway as chemical inhibition of these processes inhibited entry. Moreover, we identified a role for the RhoA-ROCK-myosin II signaling axis in this MeV internalization process, highlighting a novel role for this recently characterized pathway in virus entry. Our study shows that MeV can hijack a microbial sensor normally involved in bacterial phagocytosis to drive endocytosis using a complex pathway that shares features with canonical viral macropinocytosis, phagocytosis, and mechanotransduction. This uptake pathway is specific to SLAMF1-positive cells and occurs within 60 min of viral attachment. Measles virus remains a significant cause of mortality in human populations, and this research sheds new light on the very first steps of infection of this important pathogen.IMPORTANCEMeasles is a significant disease in humans and is estimated to have killed over 200 million people since records began. According to current World Health Organization statistics, it still kills over 100,000 people a year, mostly children in the developing world. The causative agent, measles virus, is a small enveloped RNA virus that infects a broad range of cells during infection. In particular, immune cells are infected via interactions between glycoproteins found on the surface of the virus and SLAMF1, the immune cell receptor. In this study, we have investigated the steps governing entry of measles virus into SLAMF1-positive cells and identified endocytic uptake of viral particles. This research will impact our understanding of morbillivirus-related immunosuppression as well as the application of measles virus as an oncolytic therapeutic.
authors.affiliation: Centre for Human Virology, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonçalves-Carneiro
authors.affiliation: Centre for Human Virology, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.|Institute for Advanced Study, Technische Universität München, Munich, Germany.
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
authors.affiliation: Centre for Human Virology, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom d.bailey@bham.ac.uk.
authors.forename: Dalan
authors.identifier: http://orcid.org/0000-0002-5640-2266
authors.initials: D
authors.lastname: Bailey
mesh_terms: D000072283:A549 Cells; D022461:Caveolins / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D003599:Cytoskeleton / Q000648:ultrastructure / Q000821:virology; D034285:Dynamin II; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D008457:Measles / Q000821:virology*; D008459:Measles virus / Q000502:physiology*; D021962:Membrane Microdomains / Q000821:virology; D015398:Signal Transduction; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1 / Q000502:physiology*; D014771:Virion / Q000502:physiology; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: D022461:Caveolins; D002966:Clathrin; C000604059:SLAMF1 protein, human; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; C000593490:DNM2 protein, human; D034285:Dynamin II; D034281:Dynamins
keywords: SLAMF1; endocytosis; fusion; macropinocytosis; measles; morbillivirus; virus attachment; virus entry