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.
Highlights
Africa suffers from periodic outbreaks of Rift Valley fever (RVF), a disease of both livestock animals and humans
People infected with Rift Valley fever virus can develop different clinical outcomes, including hemorrhagic fever or encephalitis
We used a rat model of Rift Valley fever encephalitis to understand the mechanisms underlying lethal neurological disease compared to subclinical infection
Summary
Africa suffers from periodic outbreaks of Rift Valley fever (RVF), a disease of both livestock animals and humans. Neurological signs consist of hypersalivation, confusion, coma, hallucination, and signs of meningeal irritation [9] Both the hemorrhagic/hepatotropic and encephalitic manifestations of RVF have high mortality rates in humans (~50% for hospitalized patients) [8]. Development of severe disease outcomes is associated with exposure to RVFV when handling infected animals [6, 10]. In both laboratory animals and humans, vaccines and therapeutic drugs that can protect from hepatotropic and hemorrhagic RVF often fail to protect from neurological manifestations [11,12,13,14,15]. A more detailed understanding of the neuropathogenic mechanisms of RVF is merited
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