Pathogenic differences of cynomolgus macaques after Taï Forest virus infection depend on the viral stock propagation

• Published in: PLoS pathogens Vol. 20; no. 6; p. e1012290
• Main Authors: Fletcher, Paige, Clancy, Chad S, O'Donnell, Kyle L, Doratt, Brianna M, Malherbe, Delphine C, Rhoderick, Joseph F, Feldmann, Friederike, Hanley, Patrick W, Takada, Ayato, Messaoudi, Ilhem, Marzi, Andrea
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2024; Public Library of Science (PLoS)
• Subjects: Alphavirus Infections - pathology; Alphavirus Infections - virology; Animal models; Animal models in research; Animals; Biology and life sciences; Cytokines; Development and progression; Disease Models, Animal; Enzymes; Epidemics; Genomic analysis; Glycoproteins; Health aspects; Humans; Immunoglobulin G; Infections; Inoculation; Kra; Liver; Macaca fascicularis; Medicine and Health Sciences; Mice; Mice, Knockout; Necropsy; Pathogenicity; Pathogens; Pest outbreaks; Phenotypes; R&D; Receptor, Interferon alpha-beta - genetics; Research & development; Research and Analysis Methods; RNA polymerase; RNA virus infections; RNA viruses; Survival; Thrombocytopenia; Tissue analysis; Viremia; Virus Replication; Viruses; United States; West Africa
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012290

Taï Forest virus (TAFV) is a negative-sense RNA virus in the Filoviridae family. TAFV has caused only a single human infection, but several disease outbreaks in chimpanzees have been linked to this virus. Limited research has been done on this human-pathogenic virus. We sought to establish an animal model to assess TAFV disease progression and pathogenicity at our facility. We had access to two different viral stock preparations from different institutions, both originating from the single human case. Type I interferon receptor knockout mice were inoculated with TAFV stock 1 or stock 2 by the intraperitoneal route. Inoculation resulted in 100% survival with no disease regardless of viral stock preparation or infectious dose. Next, cynomolgus macaques were inoculated with TAFV stock 1 or stock 2. Inoculation with TAFV stock 1 resulted in 100% survival and robust TAFV glycoprotein-specific IgG responses including neutralizing antibodies. In contrast, macaques infected with TAFV stock 2 developed disease and were euthanized 8-11 days after infection exhibiting viremia, thrombocytopenia, and increased inflammatory mediators identified by transcriptional analysis. Histopathologic analysis of tissue samples collected at necropsy confirmed classic filovirus disease in numerous organs. Genomic differences in both stock preparations were mapped to several viral genes which may have contributed to disease severity. Taken together, we demonstrate that infection with the two TAFV stocks resulted in no disease in mice and opposing disease phenotypes in cynomolgus macaques, highlighting the impact of viral stock propagation on pathogenicity in animal models.