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PLoS Negl Trop Dis. 2014 Nov 20;8(11):e3295. doi: 10.1371/journal.pntd.0003295. eCollection 2014.

Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model.

Author information

1
Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America.
2
Laboratoire de Virologie Est, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France.
3
Department of Botany and Plant Sciences, University of California Riverside, Riverside, California, United States of America.
4
Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon, United States of America.
5
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
6
Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, Oregon, United States of America.
7
Division of Neuroscience, Oregon National Primate Research Center, Portland, Oregon, United States of America.
8
Division of Comparative Medicine, Oregon National Primate Research Center, Portland, Oregon, United States of America.
9
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.
10
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.

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.

PMID:
25412185
PMCID:
PMC4238990
DOI:
10.1371/journal.pntd.0003295
[Indexed for MEDLINE]
Free PMC Article

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