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. Author manuscript; available in PMC: 2023 Jul 3.
Published in final edited form as: Annu Rev Virol. 2022 Sep 29;9(1):437–450. doi: 10.1146/annurev-virology-091919-065806

Figure 2.

Figure 2

Current model of neuropathogenesis of Rift Valley fever (RVF) in Lewis rats: timing of clinical and virological events after exposure of Lewis rats to Rift Valley fever virus (RVFV). Events above the timeline (orange background) are those documented in studies of Lewis rats inoculated by subcutaneous (SC) injection, which represents sublethal infection. Events below the timeline (red background) are from animals with lethal neurological disease resulting from aerosol exposure. Events in the periphery are depicted in green, while events in the brain are depicted in blue. (Top) After SC infection [lethal dose 50 (LD50) > 105 plaque-forming unit (pfu)], rats develop viremia from 1 to 4 days post-inoculation (dpi), during which time the virus replicates in the liver and spleen. Transient lymphopenia occurs along with increases in cytokines in the serum. Low levels of viral RNA can be detected in the brain. However, increases in virus levels in the brain over time are not observed. Modestly increased numbers of T cells are observed in the brain at 6 dpi. Rats display no observable signs of illness. (Bottom) After aerosol exposure, the disease course from time of exposure to euthanasia due to severe disease is 7–8 days (LD50 = 120 pfu). Cells within the olfactory epithelium become heavily infected, and the virus invades the brain by crossing the cribriform plate into the olfactory bulb. RVFV then replicates to high levels in the neurons of the olfactory bulb and spreads through the cortex and into the cerebellum. Around 5–6 dpi, vascular integrity of the brain is compromised, and immune cells invade from the periphery. These cells consist primarily of macrophages and neutrophils. These cells, along with activated microglia, are infected with RVFV. Inflammatory cytokines are expressed in the brain at high levels during end-stage disease. Death of neurons and disruption of cell architecture of the brain leads to tissue destruction and severe pathology. During this time, the animals develop observable signs of illness, including weight loss, fever, and neurological manifestations (head tilt, circling in cage).