Abstract
Rift Valley fever (RVF) is a zoonotic disease caused by RVF Phlebovirus (RVFV). The RVFV MP-12 vaccine strain is known to exhibit residual virulence in the case of a deficient interferon type 1 response. The hypothesis of this study is that virus replication and severity of lesions induced by the MP-12 strain in immunocompromised mice depend on the specific function of the disturbed pathway. Therefore, 10 strains of mice with deficient innate immunity (B6-IFNARtmAgt, C.129S7(B6)-Ifngtm1Ts/J, B6-TLR3tm1Flv, B6-TLR7tm1Aki, NOD/ShiLtJ), helper T-cell- (CD4tm1Mak), cytotoxic T-cell- (CD8atm1Mak), B-cell- (Igh-Jtm1DhuN?+N2), combined T- and B-cell- (NU/J) and combined T-, B-, natural killer (NK) cell- and macrophage-mediated immunity (NOD.Cg-PrkdcscidIl2rgtm1WjI/SzJ (NSG) mice) were subcutaneously infected with RVFV MP-12. B6-IFNARtmAgt mice were the only strain to develop fatal disease due to RVFV-induced severe hepatocellular necrosis and apoptosis. Notably, no clinical disease and only mild multifocal hepatocellular necrosis and apoptosis were observed in NSG mice, while immunohistochemistry detected the RVFV antigen in the liver and the brain. No or low virus expression and no lesions were observed in the other mouse strains. Conclusively, the interferon type 1 response is essential for early control of RVFV replication and disease, whereas functional NK cells, macrophages and lymphocytes are essential for virus clearance.
Highlights
One Rift Valley fever virus (RVFV)-infected NOD.Cg-Prkdcscid Il2rgtm1WjI /SzJ (NSG) mouse had to be euthanized at 11 dpi due to similar severe clinical signs
Innate immunity is a key component of early RVFV detection and activation of further effector cells, e.g., macrophages, via release of cellular mediators including IFNs [24,27,34,45,70]
The B6-IFNARtmAgt mice lack the IFN type I receptor (IFNAR) and showed severe Rift Valley fever (RVF) characterized by severe clinical signs, necrotizing hepatitis and virus spread to various organs as described previously [37,50]
Summary
In addition to impactful outbreaks in Africa, opportunities of RVF introduction into Europe and North America include accidental emergence via animal trading, the spread of mosquito vectors during the course of global warming or bioterrorist attack scenarios [2,4,10]. Because of these threats, RVFV has been named an “agent of concern” by the United States Department of Agriculture (USDA) and the Center for Disease Control and Prevention (CDC) [4]. It is under surveillance by the International Organization for Animal Health (OIE) as well as being a subject of ongoing scientific interest [11,12,13]
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