title: Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model.
abstract: Infection with yellow fever virus (YFV), an explosively replicating flavivirus, results in viral hemorrhagic disease characterized by cardiovascular shock and multi-organ failure. Unvaccinated populations experience 20 to 50% fatality. Few studies have examined the pathophysiological changes that occur in humans during YFV infection due to the sporadic nature and remote locations of outbreaks. Rhesus macaques are highly susceptible to YFV infection, providing a robust animal model to investigate host-pathogen interactions. In this study, we characterized disease progression as well as alterations in immune system homeostasis, cytokine production and gene expression in rhesus macaques infected with the virulent YFV strain DakH1279 (YFV-DakH1279). Following infection, YFV-DakH1279 replicated to high titers resulting in viscerotropic disease with ∼72% mortality. Data presented in this manuscript demonstrate for the first time that lethal YFV infection results in profound lymphopenia that precedes the hallmark changes in liver enzymes and that although tissue damage was noted in liver, kidneys, and lymphoid tissues, viral antigen was only detected in the liver. These observations suggest that additional tissue damage could be due to indirect effects of viral replication. Indeed, circulating levels of several cytokines peaked shortly before euthanasia. Our study also includes the first description of YFV-DakH1279-induced changes in gene expression within peripheral blood mononuclear cells 3 days post-infection prior to any clinical signs. These data show that infection with wild type YFV-DakH1279 or live-attenuated vaccine strain YFV-17D, resulted in 765 and 46 differentially expressed genes (DEGs), respectively. DEGs detected after YFV-17D infection were mostly associated with innate immunity, whereas YFV-DakH1279 infection resulted in dysregulation of genes associated with the development of immune response, ion metabolism, and apoptosis. Therefore, WT-YFV infection is associated with significant changes in gene expression that are detectable before the onset of clinical symptoms and may influence disease progression and outcome of infection.
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America.
authors.forename: Flora
authors.initials: F
authors.lastname: Engelmann
authors.affiliation: Laboratoire de Virologie Est, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Josset
authors.affiliation: Department of Botany and Plant Sciences, University of California Riverside, Riverside, California, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Girke
authors.affiliation: Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Byung
authors.initials: B
authors.lastname: Park
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Barron
authors.affiliation: Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
authors.forename: Jesse
authors.initials: J
authors.lastname: Dewane
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Portland, Oregon, United States of America.
authors.forename: Erika
authors.initials: E
authors.lastname: Hammarlund
authors.affiliation: Division of Comparative Medicine, Oregon National Primate Research Center, Portland, Oregon, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Lewis
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America; Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Axthelm
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Portland, Oregon, United States of America.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Slifka
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America; Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America; Division of Neuroscience, Oregon National Primate Research Center, Portland, Oregon, United States of America.
authors.forename: Ilhem
authors.initials: I
authors.lastname: Messaoudi
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015967:Gene Expression Regulation, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D007668:Kidney / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008231:Lymphopenia / Q000821:virology; D008253:Macaca mulatta; D009102:Multiple Organ Failure / Q000821:virology; D009336:Necrosis; D013154:Spleen / Q000473:pathology; D059467:Transcriptome / Q000502:physiology*; D014613:Vaccines, Attenuated / Q000276:immunology; D015004:Yellow Fever / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D022341:Yellow Fever Vaccine / Q000276:immunology; D015005:Yellow fever virus / Q000276:immunology / Q000502:physiology*
chemical_list: D000956:Antigens, Viral; D014613:Vaccines, Attenuated; D022341:Yellow Fever Vaccine