Intact Type I Interferon Receptor Signaling Prevents Hepatocellular Necrosis but Not Encephalitis in a Dose-Dependent Manner in Rift Valley Fever Virus Infected Mice

Abstract

Rift Valley fever (RVF) is a zoonotic and emerging disease, caused by the RVF virus (RVFV). In ruminants, it leads to “abortion storms” and enhanced mortality rates in young animals, whereas in humans it can cause symptoms like severe hemorrhagic fever or encephalitis. The role of the innate and adaptive immune response in disease initiation and progression is still poorly defined. The present study used the attenuated RVFV strain clone 13 to investigate viral spread, tissue tropism, and histopathological lesions after intranasal infection in C57BL/6 wild type (WT) and type I interferon (IFN-I) receptor I knockout (IFNAR−/−) mice. In WT mice, 104 PFU RVFV (high dose) resulted in a fatal encephalitis, but no hepatitis 7–11 days post infection (dpi), whereas 103 PFU RVFV (low dose) did not cause clinical disease or significant histopathological lesions in liver and the central nervous system (CNS). In contrast, IFNAR−/− mice infected with 103 PFU RVFV developed hepatocellular necrosis resulting in death at 2–5 dpi and lacked encephalitis. These results show that IFNAR signaling prevents systemic spread of the attenuated RVFV strain clone 13, but not the dissemination to the CNS and subsequent fatal disease. Consequently, neurotropic viruses may be able to evade antiviral IFN-I signaling pathways by using the transneuronal instead of the hematogenous route.

The lipopeptide Pam3CSK4 inhibits Rift Valley fever virus infection and protects from encephalitis

“…Previous studies of RVFV have shown that type I interferon (IFN) responses are important in controlling infection peripherally [ 34 – 36 ]. However, it has not been tested if IFNs are protective in the brain, as IFN-treated neurons remain susceptible to some viral infections [ 25 , 26 , 28 , 30 , 37 ]. We tested this in vitro using the biosafety level two strain RVFV MP-12, which is attenuated by nine amino acid substitutions across all three genomic segments [ 38 ].…”

The Rift Valley fever (RVF) vaccine candidate 40Fp8 shows an extreme attenuation in IFNARKO mice following intranasal inoculation

“…Animal models are very useful for the study of viral infections; in particular, mice have become a powerful tool for RVFV research focused on the development of effective control measures such as vaccines and antivirals as well as for studies of viral pathogenesis [39][40][41][42][43].…”

Immune correlates of protection of the four-segmented Rift Valley fever virus candidate vaccine in mice

“…This might be the reason why a robust T cell response induced by hRVFV-4s immunization did not translate into protective efficacy. A slow progressing RVFV encephalitis model [ 30 ] might be more suitable for testing the protective efficacy of virus-specific T cells induced by hRVFV-4s vaccination. Nevertheless, the efficiency with which VN antibodies induced after hRVFV-4s vaccination protected mice from developing severe hepatic disease promotes the assessment of VN titres in future clinical trials.…”