Vascular permeability in the brain is a late pathogenic event during Rift Valley fever virus encephalitis in rats

Abstract

Rift Valley fever virus (RVFV) is a zoonotic disease of livestock that causes several clinical outcomes in people including febrile disease, hemorrhagic fever, and/or encephalitis. After aerosol infection with RVFV, Lewis rats develop lethal encephalitic disease, and we use this as a model for studying disease mechanisms of RVFV infection in the brain. Permeability of the brain vasculature in relation to virus invasion and replication is not known. Here, we found that vascular permeability in the brain occurred late in the course of infection and corresponded temporally to expression of matrix metalloproteinase-9 (MMP-9). Virus replication was ongoing within the central nervous system for several days prior to detectable vascular leakage. Based on this study, vascular permeability was not required for entry of RVFV into the brain of rats. Prevention of vascular leakage late in infection may be an important component for prevention of lethal neurological disease in the rat model.

Development of Rift valley fever encephalitis in rats is mediated by early infection of olfactory epithelium and neuroinvasion across the cribriform plate

“…Our previous study found that RVFV vRNA was detectable in the OB as early as 1-2 days p.i., depending upon exposure dose [19,20]. This finding suggests that the olfactory region plays a part in CNS infection, as the virus encounters the respiratory and olfactory epithelium during inhalation.…”

“…Our previous studies have characterized the Lewis rat model of RVF encephalitis, in which rats exposed to aerosolized RVFV succumb to meningoencephalitis within 7-8 days post-infection (p.i.) [19,20]. By 1 day p.i., viral RNA (vRNA) can be detected at low levels in the brain along with a transient inflammatory leukocyte infiltration [19,20].…”

“…[19,20]. By 1 day p.i., viral RNA (vRNA) can be detected at low levels in the brain along with a transient inflammatory leukocyte infiltration [19,20]. The later stages of disease (5-7 days p.i.)…”

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

“…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].…”

Rift Valley Fever Virus Infection Causes Acute Encephalitis in the Ferret

“…Wistar-Furth and Brown Norway rats are highly susceptible and succumb to acute hepatitis regardless of the infection route (18), while August-Copenhagen-Irish rats skew toward encephalitis (19). Conversely, RVF manifestations in Lewis rats are highly dependent on route of infection: subcutaneously infected animals develop viremia but no disease signs (18), while aerosol exposure leads to uniformly lethal encephalitis (17,20,21). Syrian hamsters develop acute liver disease following subcutaneous exposure to RVFV and have also been used to evaluate vaccines and therapeutics against RVFV (22)(23)(24).…”