title: Positive Selection Drives Evolution at the Host-Filovirus Interaction Surface.
abstract: Filovirus infection is mediated by engagement of the surface-exposed glycoprotein (GP) by its cellular receptor, NPC1 (Niemann-Pick C1). Two loops in the C domain of NPC1 (NPC1-C) bind filovirus GP. Herein, we show that filovirus GP and NPC1-C evolve under mutual selective pressure. Analysis of a large mammalian phylogeny indicated that strong functional/structural constraints limit the NPC1 sequence space available for adaptive change and most sites at the contact interface with GP are under negative selection. These constraints notwithstanding, we detected positive selection at NPC1-C in all mammalian orders, from Primates to Xenarthra. Different codons evolved adaptively in distinct mammals, and most selected sites are located within the two NPC1-C loops that engage GP, or at their anchor points. In Homininae, NPC1-C was a preferential selection target, and the T419I variant possibly represents a human-specific adaptation to filovirus infection. On the other side of the arms-race, GP evolved adaptively during filovirus speciation. One of the selected sites (S142Q) establishes several atom-to-atom contacts with NPC1-C. Additional selected sites are located within epitopes recognized by neutralizing antibodies, including the 14G7 epitope, where sites selected during the recent EBOV epidemic also map. Finally, pairs of co-evolving sites in Marburgviruses and Ebolaviruses were found to involve antigenic determinants. These findings suggest that the host humoral immune response was a major selective pressure during filovirus speciation. The S142Q variant may contribute to determine Ebolavirus host range in the wild. If this were the case, EBOV/BDBV (S142) and SUDV (Q142) may not share the same reservoir(s).
authors: Scientific Institute IRCCS E.MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors: Chiara
authors: C
authors: Pontremoli
authors: Scientific Institute IRCCS E.MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors: Diego
authors: D
authors: Forni
authors: Scientific Institute IRCCS E.MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors: Rachele
authors: R
authors: Cagliani
authors: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy.
authors: Giulia
authors: G
authors: Filippi
authors: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy.
authors: Luca
authors: L
authors: De Gioia
authors: Scientific Institute IRCCS E.MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors: Uberto
authors: U
authors: Pozzoli
authors: Department of Physiopathology and Transplantation, University of Milan, Milan, Italy Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.
authors: Mario
authors: M
authors: Clerici
authors: Scientific Institute IRCCS E.MEDEA, Bioinformatics, Bosisio Parini, Italy manuela.sironi@bp.lnf.it.
authors: Manuela
authors: M
authors: Sironi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D002352:Carrier Proteins / Q000235:genetics; D029043:Ebolavirus / Q000235:genetics; D000939:Epitopes; D019143:Evolution, Molecular; D016563:Filoviridae / Q000235:genetics / Q000502:physiology*; D058507:Host Specificity; D054884:Host-Pathogen Interactions; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D010802:Phylogeny; D012641:Selection, Genetic; D033921:Vesicular Transport Proteins / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D000939:Epitopes; D008562:Membrane Glycoproteins; D033921:Vesicular Transport Proteins; D014759:Viral Envelope Proteins
keywords: Ebolavirus; NPC1; arm race; positive selection