1. A pigtailed macaque model of Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus pathogenesis
- Author
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Gail L. Sturdevant, Patrick W. Hanley, Rebecca Rosenke, Abhilash I. Chiramel, Sonja M. Best, Kristin L. McNally, Rebecca M. Broeckel, Greg Saturday, Friederike Feldmann, Angela L. Rasmussen, Shelly J. Robertson, Dana P. Scott, Jamie Lovaglio, Fadila Bouamr, and Jacqueline M. Leung
- Subjects
Viral Diseases ,B Cells ,Physiology ,Viral pathogenesis ,Pathogenesis ,Disease ,Monkeys ,Pathology and Laboratory Medicine ,Vascular Medicine ,White Blood Cells ,Medical Conditions ,Animal Cells ,Immune Physiology ,Chlorocebus aethiops ,Medicine and Health Sciences ,Medicine ,Biology (General) ,Mammals ,Clotting factor ,Innate Immune System ,Eukaryota ,Body Fluids ,Hemorrhagic Fevers ,Blood ,Infectious Diseases ,Vertebrates ,Cytokines ,Female ,Macaca nemestrina ,Anatomy ,Cellular Types ,Encephalitis, Tick-Borne ,Macaque ,Research Article ,Primates ,Hemorrhagic Fevers, Viral ,QH301-705.5 ,Immune Cells ,Immunology ,Hemorrhage ,Viremia ,Microbiology ,Virus ,Encephalitis Viruses, Tick-Borne ,Lymphatic System ,Signs and Symptoms ,Virology ,Old World monkeys ,Genetics ,Animals ,Humans ,Antibody-Producing Cells ,Vero Cells ,Molecular Biology ,Blood Cells ,Biology and life sciences ,business.industry ,Organisms ,Cell Biology ,RC581-607 ,Molecular Development ,medicine.disease ,Disease Models, Animal ,HEK293 Cells ,Immune System ,Amniotes ,Tissue tropism ,Parasitology ,Lymph Nodes ,Immunologic diseases. Allergy ,Clinical Medicine ,business ,Zoology ,Kyasanur forest disease ,Developmental Biology - Abstract
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., Author summary Kyasanur Forest disease virus (KFDV) and Alkhurma hemorrhagic disease virus (AHFV) are tick-borne flaviviruses that cause viral hemorrhagic fevers in India and the Arabian Peninsula, respectively. Bonnet macaques and black-faced langurs are susceptible to KFDV infection, but these animals do not experience hemorrhagic signs as seen in human cases with KFDV. This work characterizes for the first time experimental infection of KFDV and AHFV in pigtailed macaques (PTMs). Infected PTMs can develop moderate to severe disease that models multiple features of human disease, including some hemorrhagic signs. Together these data describe the PTM model for KFDV and AHFV as a valuable tool for future work to study viral pathogenesis and for assessing the efficacy of vaccines and antivirals.
- Published
- 2021
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