title: Conserved differences in protein sequence determine the human pathogenicity of Ebolaviruses.
abstract: Reston viruses are the only Ebolaviruses that are not pathogenic in humans. We analyzed 196 Ebolavirus genomes and identified specificity determining positions (SDPs) in all nine Ebolavirus proteins that distinguish Reston viruses from the four human pathogenic Ebolaviruses. A subset of these SDPs will explain the differences in human pathogenicity between Reston and the other four ebolavirus species. Structural analysis was performed to identify those SDPs that are likely to have a functional effect. This analysis revealed novel functional insights in particular for Ebolavirus proteins VP40 and VP24. The VP40 SDP P85T interferes with VP40 function by altering octamer formation. The VP40 SDP Q245P affects the structure and hydrophobic core of the protein and consequently protein function. Three VP24 SDPs (T131S, M136L, Q139R) are likely to impair VP24 binding to human karyopherin alpha5 (KPNA5) and therefore inhibition of interferon signaling. Since VP24 is critical for Ebolavirus adaptation to novel hosts, and only a few SDPs distinguish Reston virus VP24 from VP24 of other Ebolaviruses, human pathogenic Reston viruses may emerge. This is of concern since Reston viruses circulate in domestic pigs and can infect humans, possibly via airborne transmission.
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Morena
authors.initials: M
authors.lastname: Pappalardo
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Miguel
authors.initials: M
authors.lastname: Juliá
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Howard
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Rossman
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Wass
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D029043:Ebolavirus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D014644:Genetic Variation; D019142:Hemorrhagic Fever, Ebola / Q000635:transmission / Q000662:veterinary; D058507:Host Specificity; D006801:Humans; D008958:Models, Molecular; D010802:Phylogeny; D011487:Protein Conformation; D013552:Swine; D013553:Swine Diseases / Q000635:transmission / Q000821:virology; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism; D028901:alpha Karyopherins / Q000378:metabolism*
chemical_list: C000596544:KPNA5 protein, human; C446938:VP24 protein, Ebola virus; C080981:VP40 protein, virus; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D037521:Virulence Factors; D028901:alpha Karyopherins