title: Cell entry by a novel European filovirus requires host endosomal cysteine proteases and Niemann-Pick C1.
abstract: Lloviu virus (LLOV), a phylogenetically divergent filovirus, is the proposed etiologic agent of die-offs of Schreibers's long-fingered bats (Miniopterus schreibersii) in western Europe. Studies of LLOV remain limited because the infectious agent has not yet been isolated. Here, we generated a recombinant vesicular stomatitis virus expressing the LLOV spike glycoprotein (GP) and used it to show that LLOV GP resembles other filovirus GP proteins in structure and function. LLOV GP must be cleaved by endosomal cysteine proteases during entry, but is much more protease-sensitive than EBOV GP. The EBOV/MARV receptor, Niemann-Pick C1 (NPC1), is also required for LLOV entry, and its second luminal domain is recognized with high affinity by a cleaved form of LLOV GP, suggesting that receptor binding would not impose a barrier to LLOV infection of humans and non-human primates. The use of NPC1 as an intracellular entry receptor may be a universal property of filoviruses.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, United States.
authors.forename: Melinda
authors.initials: M
authors.lastname: Ng
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, United States.
authors.forename: Esther
authors.initials: E
authors.lastname: Ndungo
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, United States.
authors.forename: Rohit K
authors.initials: RK
authors.lastname: Jangra
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Yingyun
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Elena
authors.initials: E
authors.lastname: Postnikova
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, United States.
authors.forename: Sheli R
authors.initials: SR
authors.lastname: Radoshitzky
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.affiliation: National Center of Microbiology, Instituto de Salud Carlos III, 28220 Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Ramírez de Arellano
authors.affiliation: National Center of Microbiology, Instituto de Salud Carlos III, 28220 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Negredo
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, United States.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Palacios
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Jens H
authors.initials: JH
authors.lastname: Kuhn
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, United States. Electronic address: kartik.chandran@einstein.yu.edu.
authors.forename: Kartik
authors.initials: K
authors.lastname: Chandran
mesh_terms: D000818:Animals; D000914:Antibodies, Viral; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D057056:Cysteine Proteases / Q000378:metabolism*; D011992:Endosomes / Q000201:enzymology; D005347:Fibroblasts / Q000821:virology*; D016563:Filoviridae / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D000077296:Niemann-Pick C1 Protein; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D014709:Vero Cells; D053586:Virus Internalization
chemical_list: D000914:Antibodies, Viral; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D057056:Cysteine Proteases
keywords: Cuevavirus; Ebola; Endosomal cysteine proteases; Filoviridae; Filovirus; Lloviu virus; NPC1; Niemann–Pick C1; Viral entry; Viral glycoprotein; Viral membrane fusion; Viral receptor