A pigtailed macaque model of Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus pathogenesis

• Published in: PLoS pathogens Vol. 17; no. 12; p. e1009678
• Main Authors: Broeckel, Rebecca M, Feldmann, Friederike, McNally, Kristin L, Chiramel, Abhilash I, Sturdevant, Gail L, Leung, Jacqueline M, Hanley, Patrick W, Lovaglio, Jamie, Rosenke, Rebecca, Scott, Dana P, Saturday, Greg, Bouamr, Fadila, Rasmussen, Angela L, Robertson, Shelly J, Best, Sonja M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2021; Public Library of Science (PLoS)
• Subjects: Animal models; Animal models in research; Animals; Antiviral agents; Appetite; Appetite loss; Arachnids; Biology and life sciences; Brain research; Chlorocebus aethiops; Clotting; Cytokines - blood; Dehydration; Development and progression; Diarrhea; Disease Models, Animal; Encephalitis; Encephalitis Viruses, Tick-Borne - genetics; Encephalitis Viruses, Tick-Borne - immunology; Encephalitis Viruses, Tick-Borne - pathogenicity; Encephalitis, Tick-Borne - immunology; Encephalitis, Tick-Borne - pathology; Encephalitis, Tick-Borne - virology; Female; Fever; Gastrointestinal symptoms; Gastrointestinal system; Gastrointestinal tract; Gene expression; Health risks; HEK293 Cells; Hemorrhage; Hemorrhagic disease; Hemorrhagic fever; Hemorrhagic Fevers, Viral - immunology; Hemorrhagic Fevers, Viral - pathology; Hemorrhagic Fevers, Viral - virology; Humans; Illnesses; Infections; Infectious diseases; Inoculation; Lymph Nodes - virology; Lymphopenia; Macaca nemestrina; Macaques; Medicine and Health Sciences; Pathogenesis; Physiological aspects; Proteins; Public health; Thrombocytopenia; Tropism; Vaccines; Vero Cells; Viremia; Viruses; Vomiting; United States; India
• DOI: 10.1371/journal.ppat.1009678
• ISSN: 1553-7374; 1553-7366

Kyasanur Forest disease virus (KFDV) and the closely related Alkhurma hemorrhagic disease virus (AHFV) are emerging flaviviruses that cause severe viral hemorrhagic fevers in humans. Increasing geographical expansion and case numbers, particularly of KFDV in southwest India, class these viruses as a public health threat. Viral pathogenesis is not well understood and additional vaccines and antivirals are needed to effectively counter the impact of these viruses. However, current animal models of KFDV pathogenesis do not accurately reproduce viral tissue tropism or clinical outcomes observed in humans. Here, we show that pigtailed macaques (Macaca nemestrina) infected with KFDV or AHFV develop viremia that peaks 2 to 4 days following inoculation. Over the course of infection, animals developed lymphocytopenia, thrombocytopenia, and elevated liver enzymes. Infected animals exhibited hallmark signs of human disease characterized by a flushed appearance, piloerection, dehydration, loss of appetite, weakness, and hemorrhagic signs including epistaxis. Virus was commonly present in the gastrointestinal tract, consistent with human disease caused by KFDV and AHFV where gastrointestinal symptoms (hemorrhage, vomiting, diarrhea) are common. Importantly, RNAseq of whole blood revealed that KFDV downregulated gene expression of key clotting factors that was not observed during AHFV infection, consistent with increased severity of KFDV disease observed in this model. This work characterizes a nonhuman primate model for KFDV and AHFV that closely resembles human disease for further utilization in understanding host immunity and development of antiviral countermeasures.