Research Article: Pathophysiologic and Transcriptomic Analyses of Viscerotropic Yellow Fever in a Rhesus Macaque Model

Date Published: November 20, 2014

Publisher: Public Library of Science

Author(s): Flora Engelmann, Laurence Josset, Thomas Girke, Byung Park, Alex Barron, Jesse Dewane, Erika Hammarlund, Anne Lewis, Michael K. Axthelm, Mark K. Slifka, Ilhem Messaoudi, Thomas Geisbert.

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.

Partial Text: Yellow fever virus (YFV) is a member of the flavivirus genus and is endemic or intermittently epidemic in 45 countries (32 in Africa and 13 in South America) [1], [2]. YFV causes ∼200,000 cases and 30,000 deaths annually [3]. There are two main life cycles for YFV: in the urban cycle, YFV is transmitted between humans primarily through the bite of infected Aedes aegypti mosquitoes; in the jungle cycle, YFV is transmitted between nonhuman primates via Hemagogus mosquitoes in South America and Aedes africanus in Africa [4].

Yellow fever virus represents one of the most prevalent hemorrhagic fever viruses in the world today [39] and yet our understanding of YFV pathogenesis remains limited. In this study, we sought to address this gap in knowledge by characterizing yellow fever disease progression in rhesus macaques infected with the virulent strain, YFV-DakH1279. To further our understanding of the molecular basis of fatal versus non-fatal yellow fever disease, we also compared gene expression in PBMC collected on days 0 and 3 post-infection with YFV-DakH1279 or the attenuated vaccine strain, YFV-17D.



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