Neutrophil and macrophage influx into the central nervous system are inflammatory components of lethal Rift Valley fever encephalitis in rats

Abstract

Rift Valley fever virus (RVFV) causes severe disease in livestock concurrent with zoonotic transmission to humans. A subset of people infected with RVFV develop encephalitis, and significant gaps remain in our knowledge of how RVFV causes pathology in the brain. We previously found that, in Lewis rats, subcutaneous inoculation with RVFV resulted in subclinical disease while inhalation of RVFV in a small particle aerosol caused fatal encephalitis. Here, we compared the disease course of RVFV in Lewis rats after each different route of inoculation in order to understand more about pathogenic mechanisms of fatal RVFV encephalitis. 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. Despite this, prevention of neutrophil infiltration into the brain did not ameliorate disease. Unexpectedly, in subcutaneously-inoculated rats with subclinical disease, detectable viral RNA was found in the brain along with T-cell infiltration. This study sheds new light on the pathogenic mechanisms of RVFV encephalitis.

Physiological and immunological changes in the brain associated with lethal eastern equine encephalitis virus in macaques

“…After perfusion of macaques with saline, brains were removed, weighed and used for cell isolation as described [ 40 ]. For each brain, 1 gram pieces dissected from the frontal, temporal, occipital, parietal, cerebellar regions were covered with digestion buffer consisting of modified HBSS without calcium and magnesium, 10mg/ml DNase I (Sigma 10104159001), 20mg/ml of collagenase (Sigma C2674) and mechanically digested using a scalpel.…”

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

“…Indeed, whatever the routes of inoculation, RVFV RNA was detected in the brain of infected rats confirming the virus neurotropism [78], but aerosol exposure to RVFV caused earlier and more severe neuropathology in the murine model and fatal encephalitis in primates [75,76]. 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].…”

“…The route of transmission and prompt robust immune response could be a determining factor of the RVF neurologic disease course [77]. Indeed, whatever the routes of inoculation, RVFV RNA was detected in the brain of infected rats confirming the virus neurotropism [78], but aerosol exposure to RVFV caused earlier and more severe neuropathology in the murine model and fatal encephalitis in primates [75,76]. 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].…”

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

“…Animal models of encephalitic RVF are crucial research tools for illuminating the mechanism of infection that separates cases of self-limiting febrile disease from severe CNS outcomes. When exposed to infectious aerosols of RVFV, Lewis rats develop lethal encephalitis within 7-8 days [31], and we have previously used this model to dissect the neuropathogenic mechanisms of RVFV infection [19,20,31,42]. Our previous work illustrated the temporal spread of leukocyte infiltration and virus replication within the brain of infected rats; however, a major unknown has been the timing and route of entry of RVFV into the CNS after aerosol infection.…”