Peripheral Blood Biomarkers of Disease Outcome in a Monkey Model of Rift Valley Fever Encephalitis

Abstract

Rift Valley Fever (RVF) is an emerging arboviral disease of livestock and humans. Although the disease is caused by 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 a sublethal dose of RVFV. Divergence between lethal and sublethal infections occurred as early as 2 days postinfection (dpi), at which point CD8 T cells from lethally infected AGM expressed activated caspase-3 and simultaneously failed to increase levels of major histocompatibility complex (MHC) class II molecules, in contrast to surviving animals. At 4 dpi, lethally infected animals failed to demonstrate proliferation of total CD4 and CD8 T cells, in contrast 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 proinflammatory (gamma interferon [IFN-γ], interleukin 6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1]) and antiviral (IFN-α) response was seen in survivors, while very late cytokine expression was found in animals with lethal infections. By characterizing immunological markers of lethal disease, this study furthers our understanding of RVF pathogenesis and will allow the testing of therapeutics and vaccines in the AGM model. Rift 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 lead to death or significant long-term disability for 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 between infected AGM and 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.

SARS-CoV-2 infection of African green monkeys results in mild respiratory disease discernible by PET/CT imaging and prolonged shedding of infectious virus from both respiratory and gastrointestinal tracts

“…While used less frequently in biomedical research than rhesus or cynomolgus macaques, AGMs are an old-world NHP species and a natural host for simian immunodeficiency virus (SIV) (5). In addition to SIV, AGMs have been used as models for infectious diseases such as Rift Valley fever, pneumonic plague, human parainfluenza virus, SARS-CoV-1, and Nipah virus (6)(7)(8)(9)(10). To fully understand the pathogenesis of human isolates of SARS-CoV-2 in AGM, it is critical to determine if there are differences between aerosol and mucosal exposure routes, to assess whether clinical-grade imaging of NHPs can be used to detect subclinical infections, and to understand the real-time dynamics of virus shedding.…”

CD4 T Cells, CD8 T Cells, and Monocytes Coordinate To Prevent Rift Valley Fever Virus Encephalitis

“…However, recent data from a nonhuman primate (NHP) model of WT RVFV infection are also supportive of a role for T cells in protection. Wonderlich et al reported that sublethal infection was associated with activation of both CD4 and CD8 T cells, while this was not observed in lethally infected animals, all of which succumbed to encephalitis (32). These data are consistent with a role for T cells in protection from encephalitis in an NHP model of WT RVFV infection.…”

The challenging management of Rift Valley Fever in humans: literature review of the clinical disease and algorithm proposal

“…In aerosol-infected rats with lethal encephalitis, neutrophils and macrophages were the major cell types infiltrating the CNS, and this was concomitant with microglia activation and extensive cytokine inflammation [78]. Differences in the peripheral blood biomarkers during the course of the neurological disease in African green monkeys were measured with defect in early T-cells, proinflammatory and antiviral responses in lethal encephalitis [79]. Other immune disorders and alteration in vascular permeability in the brain could be more involved in delayed forms [80].…”