Abstract
The known virulence factor of Rift Valley fever virus (RVFV), the NSs protein, counteracts the antiviral effects of the type I interferon response. In this study we evaluated the expression of several genes in the liver and spleen involved in innate and adaptive immunity of mice immunized with a RVFV recombinant nucleocapsid protein (recNP) combined with Alhydrogel adjuvant and control animals after challenge with wild type RVFV. Mice immunized with recNP elicited an earlier IFNβ response after challenge compared to non-immunized controls. In the acute phase of liver infection in non-immunized mice there was a massive upregulation of type I and II interferon, accompanied by high viral titers, and the up- and downregulation of several genes involved in the activation of B- and T-cells, indicating that both humoral and cellular immunity is modulated during RVFV infection. Various genes involved in pro-inflammatory responses and with pro-apoptotic effects were strongly upregulated and anti-apoptotic genes were downregulated in liver of non-immunized mice. Expression of many genes involved in B- and T-cell immunity were downregulated in spleen of non-immunized mice but normal in immunized mice. A strong bias towards apoptosis and inflammation in non-immunized mice at an acute stage of liver infection associated with suppression of several genes involved in activation of humoral and cellular immunity in spleen, suggests that RVFV evades the host immune response in more ways than only by inhibition of type I interferon, and that immunopathology of the liver plays a crucial role in RVF disease progression.
Highlights
Rift Valley fever virus (RVFV), a mosquito borne Phlebovirus of the Bunyaviridae family, causes irregular but large outbreaks characterized by high fatality rates in young domestic ruminants and abortion storms in pregnant animals [1,2,3]
The results from this study suggest that an earlier type I interferon response in recombinant nucleocapsid protein (recNP)/Alhydrogel immunized mice contribute to decreased challenge virus replication, whereas upregulation of genes with the ability to result in immunopathology, combined with uncontrolled challenge virus replication, in non-immunized mice probably contributed to liver damage and morbidity, and downregulation of humoral and cellular immunity in the spleen possibly contributed to immune evasion
It was recently shown that mice displaying an earlier and stronger type I interferon response were less susceptible to RVFV infection than mice with a delayed and partial response which suggests some additional evasive or regulatory effects on innate or adaptive immune mechanisms enabling its replication [33]
Summary
Rift Valley fever virus (RVFV), a mosquito borne Phlebovirus of the Bunyaviridae family, causes irregular but large outbreaks characterized by high fatality rates in young domestic ruminants and abortion storms in pregnant animals [1,2,3]. The L segment encodes a viral RNAdependent RNA polymerase, the M segment encodes two structural glycoproteins, two non-structural proteins, and the S segment encodes the nucleocapsid protein (NP) and a nonstructural protein (NSs) [4,5]. The known virulence factor of RVFV, the NSs protein, counteracts the antiviral effects of the type I interferon response. The nucleocapsid protein (NP) of the virus does not induce production of neutralizing antibodies, anti-NP antibodies have been shown to be protective in mice [12,13,14,15,16,17]. Humoral responses against the RVFV glycoproteins effectively neutralize the virus and are believed to solely protect against challenge [14,16,18,19,20]
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