title: SLAM- and nectin-4-independent noncytolytic spread of canine distemper virus in astrocytes.
abstract: Measles and canine distemper viruses (MeV and CDV, respectively) first replicate in lymphatic and epithelial tissues by using SLAM and nectin-4 as entry receptors, respectively. The viruses may also invade the brain to establish persistent infections, triggering fatal complications, such as subacute sclerosis pan-encephalitis (SSPE) in MeV infection or chronic, multiple sclerosis-like, multifocal demyelinating lesions in the case of CDV infection. In both diseases, persistence is mediated by viral nucleocapsids that do not require packaging into particles for infectivity but are directly transmitted from cell to cell (neurons in SSPE or astrocytes in distemper encephalitis), presumably by relying on restricted microfusion events. Indeed, although morphological evidence of fusion remained undetectable, viral fusion machineries and, thus, a putative cellular receptor, were shown to contribute to persistent infections. Here, we first showed that nectin-4-dependent cell-cell fusion in Vero cells, triggered by a demyelinating CDV strain, remained extremely limited, thereby supporting a potential role of nectin-4 in mediating persistent infections in astrocytes. However, nectin-4 could not be detected in either primary cultured astrocytes or the white matter of tissue sections. In addition, a bioengineered "nectin-4-blind" recombinant CDV retained full cell-to-cell transmission efficacy in primary astrocytes. Combined with our previous report demonstrating the absence of SLAM expression in astrocytes, these findings are suggestive for the existence of a hitherto unrecognized third CDV receptor expressed by glial cells that contributes to the induction of noncytolytic cell-to-cell viral transmission in astrocytes.
  
  
  OBJECTIVE
  While persistent measles virus (MeV) infection induces SSPE in humans, persistent canine distemper virus (CDV) infection causes chronic progressive or relapsing demyelination in carnivores. Common to both central nervous system (CNS) infections is that persistence is based on noncytolytic cell-to-cell spread, which, in the case of CDV, was demonstrated to rely on functional membrane fusion machinery complexes. This inferred a mechanism where nucleocapsids are transmitted through macroscopically invisible microfusion events between infected and target cells. Here, we provide evidence that CDV induces such microfusions in a SLAM- and nectin-4-independent manner, thereby strongly suggesting the existence of a third receptor expressed in glial cells (referred to as GliaR). We propose that GliaR governs intercellular transfer of nucleocapsids and hence contributes to viral persistence in the brain and ensuing demyelinating lesions.
authors: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland Division of Neurological Sciences, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors: Lisa
authors: L
authors: Alves
authors: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors: Mojtaba
authors: M
authors: Khosravi
authors: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors: Mislay
authors: M
authors: Avila
authors: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors: Nadine
authors: N
authors: Ader-Ebert
authors: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors: Fanny
authors: F
authors: Bringolf
authors: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Andreas
authors: A
authors: Zurbriggen
authors: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland Division of Neurological Sciences, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Switzerland.
authors: Marc
authors: M
authors: Vandevelde
authors: Division of Neurological Sciences, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Bern, Switzerland philippe.plattet@vetsuisse.unibe.ch.
authors: Philippe
authors: P
authors: Plattet
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000821:virology*; D001921:Brain / Q000378:metabolism / Q000821:virology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004216:Distemper / Q000378:metabolism / Q000635:transmission / Q000821:virology; D004217:Distemper Virus, Canine / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D004285:Dogs; D005814:Genes, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D008459:Measles virus / Q000472:pathogenicity; D000075983:Nectins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013344:Subacute Sclerosing Panencephalitis / Q000209:etiology; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D000075983:Nectins; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D011994:Recombinant Proteins; D014764:Viral Proteins; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1