title: Filovirus receptor NPC1 contributes to species-specific patterns of ebolavirus susceptibility in bats.
abstract: Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other filoviruses remain enigmatic. While filoviruses infect diverse mammalian cell lines, we report that cells from African straw-colored fruit bats (Eidolon helvum) are refractory to EBOV infection. This could be explained by a single amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 interaction. We found signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with the strongest signal at the same residue that controls EBOV infection in Eidolon helvum cells. Our work identifies NPC1 as a genetic determinant of filovirus susceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filovirus replication and virulence. A single viral mutation afforded escape from receptor control, revealing a pathway for compensatory viral evolution and a potential avenue for expansion of filovirus host range in nature.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States.
authors.forename: Melinda
authors.initials: M
authors.lastname: Ng
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States.
authors.forename: Esther
authors.initials: E
authors.lastname: Ndungo
authors.affiliation: Department of Integrative Biology, University of Texas at Austin, Austin, United States.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Kaczmarek
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, United States.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Herbert
authors.affiliation: Institute of Virology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Tabea
authors.initials: T
authors.lastname: Binger
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, United States.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Kuehne
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States.
authors.forename: Rohit K
authors.initials: RK
authors.lastname: Jangra
authors.affiliation: Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Hawkins
authors.affiliation: University of Glasgow MRC Virology Unit, Glasgow, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gifford
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States.
authors.forename: Rohan
authors.initials: R
authors.lastname: Biswas
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, United States.
authors.forename: Ann
authors.initials: A
authors.lastname: Demogines
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, United States.
authors.forename: Rebekah M
authors.initials: RM
authors.lastname: James
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, , Singapore.
authors.forename: Meng
authors.initials: M
authors.lastname: Yu
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan, The Netherlands.
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
authors.affiliation: Institute of Virology, University of Bonn Medical Center, Bonn, Germany.|German Centre for Infectious Diseases Research, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Drosten
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, , Singapore.
authors.forename: Lin-Fa
authors.initials: LF
authors.lastname: Wang
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, United States.
authors.forename: Jens H
authors.identifier: http://orcid.org/0000-0002-7800-6045
authors.initials: JH
authors.lastname: Kuhn
authors.affiliation: Institute of Virology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Müller
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, United States.|BioFrontiers Institute, University of Colorado Boulder, Boulder, United States.|Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Sawyer
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States.
authors.forename: Kartik
authors.identifier: http://orcid.org/0000-0003-0232-7077
authors.initials: K
authors.lastname: Chandran
mesh_terms: D000818:Animals; D002460:Cell Line; D002685:Chiroptera; D016563:Filoviridae / Q000502:physiology*; D058507:Host Specificity; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D053585:Virus Attachment
chemical_list: D008562:Membrane Glycoproteins; D011991:Receptors, Virus
keywords: Ebola virus; Filovirus; NPC1; Niemann-Pick C1; Positive selection; Virus-host co-evolution; bats; evolutionary biology; genomics; host range; infectious disease; microbiology; viral receptor; viruses