Conserved differences in protein sequence determine the human pathogenicity of Ebolaviruses

This work describes the analysis of 196 Ebolavirus genomes and the identification of specificity determining positions (SDPs) in all nine Ebolavirus proteins that distinguish the non human pathogenic Reston viruses from the four human pathogenic Ebolaviruses. 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 emerg