title: Implementation of a non-human primate model of Ebola disease: Infection of Mauritian cynomolgus macaques and analysis of virus populations.
abstract: Ebola virus (EBOV) haemorrhagic fever remains a threat to global public health with an urgent need for an effective treatment. In order to achieve these goals, access to non-human primate (NHP) laboratory models is an essential requirement. Here, we present the first NHP-EBOV laboratory model readily available to the European scientific community, based on infection of Mauritian cynomolgus macaques using a Central-African EBOV strain and increasing virus challenge dose (10, 100, or 1000 focus forming units per animal). The outcome of these experiments was assessed using clinical, hematological, and biochemical criteria. All challenge doses resulted in fatal infections within 8-11 days. Symptoms appeared from day 5 after infection onwards and disease progression was slower than in previous reports based on Asian cynomolgus macaques. Thus, our model resembled human disease more closely than previous models (onset of symptoms estimated 2-21 days after infection) extending the period of time available for therapeutic intervention. To establish the dynamics of virus genome variation, the study included the first detailed analysis of major and minor genomic EBOV variants during the course of the disease. Major variants were scarce and the population of minor variants was shaped by selective pressure similar to genomic mutations observed in Nature. This primate model provides a robust baseline for future genomic studies in the context of therapeutic methods for treating Ebola virus-infected patients.
authors.affiliation: UMR "Emergence des Pathologies Virales" (EPV: Aix-Marseille University - IRD 190 - Inserm 1207 - EHESP - IHU Méditerranée Infection), Marseille, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Piorkowski
authors.affiliation: Inserm, Laboratoire P4 Jean Mérieux, Lyon, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jacquot
authors.affiliation: UMR "Emergence des Pathologies Virales" (EPV: Aix-Marseille University - IRD 190 - Inserm 1207 - EHESP - IHU Méditerranée Infection), Marseille, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Quérat
authors.affiliation: Inserm, Laboratoire P4 Jean Mérieux, Lyon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Carbonnelle
authors.affiliation: Inserm, Laboratoire P4 Jean Mérieux, Lyon, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Pannetier
authors.affiliation: Inserm, IAME, UMR 1137, Université Paris Diderot, Paris, France.
authors.forename: France
authors.initials: F
authors.lastname: Mentré
authors.affiliation: Inserm, Laboratoire P4 Jean Mérieux, Lyon, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Raoul
authors.affiliation: UMR "Emergence des Pathologies Virales" (EPV: Aix-Marseille University - IRD 190 - Inserm 1207 - EHESP - IHU Méditerranée Infection), Marseille, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: de Lamballerie
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D029043:Ebolavirus / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D016679:Genome, Viral; D019142:Hemorrhagic Fever, Ebola / Q000628:therapy / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008252:Macaca fascicularis
keywords: Ebola virus disease; Genome sequencing; Minor variants; Non-human primate model