5 years ago

Peripheral blood biomarkers of disease outcome in a monkey model of Rift Valley Fever encephalitis.

Simon M Barratt-Boyes, Elizabeth R Wonderlich, Douglas S Reed, Cynthia M McMillen, Aaron W Walters, Amy L Caroline, Amy L Hartman
Rift Valley Fever (RVF) is an emerging arboviral disease of livestock and people. Although a mosquito-borne virus, humans are infected through contact with or inhalation of virus-laden particles from contaminated animal carcasses. Some individuals infected with RVF virus (RVFV) develop meningoencephalitis resulting in morbidity and mortality. Little is known about the pathogenic mechanisms that lead to neurologic sequelae, and thus animal models that represent human disease are needed. African green monkeys (AGM) exposed to aerosols containing RVFV develop a reproducibly lethal neurological disease that resembles human illness. To understand the disease process and identify biomarkers of lethality, two groups of 5 AGM were infected by inhalation with either a lethal or sub-lethal dose of RVFV. Divergence between lethal and sub-lethal infections occurred as early as 2 days post-infection (dpi) at which point CD8+ T cells from lethally-infected AGM expressed activated caspase-3 and simultaneously failed to increase levels of MHC Class II molecules compared to surviving animals. At 4 dpi, lethally-infected animals failed to demonstrate proliferation of total CD4+ and CD8+ T cells compared to survivors. These marked changes in peripheral blood cells occur much earlier than more established indicators of severe RVF disease such as granulocytosis and fever. In addition, an early pro-inflammatory (IFN-γ, IL-6, IL-8, MCP-1) and anti-viral (IFN-α) response was seen in survivors, while very late cytokine expression was found in the lethal infections. By characterizing immunological markers of lethal disease, this study furthers our understanding of RVF pathogenesis and will allow testing of therapeutics and vaccines in the AGM model.ImportanceRift Valley Fever (RVF) is an important emerging viral disease for which we lack both an effective human vaccine and treatment. Encephalitis and neurological disease resulting from RVF leads to death or significant long-term disability in infected people. African green monkeys (AGM) develop lethal neurological disease when infected with RVF virus by inhalation. Here, we report the similarities in disease course in infected AGM compared to humans. For the first time, we examine the peripheral immune response during the course of infection in AGM and show that there are very early differences in the immune response between animals that survive infection and those that succumb. We conclude that AGM are a novel and suitable monkey model for studying the neuropathogenesis of RVF and for testing vaccines and therapeutics against this emerging viral pathogen.

Publisher URL: http://doi.org/10.1128/JVI.01662-17

DOI: 10.1128/JVI.01662-17

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