Protection against lethal Rift Valley fever virus (RVFV) infection in transgenic IFNAR(-/-) mice induced by different DNA vaccination regimens.
ABSTRACT In this work, plasmid constructs encoding two different M segment ORFs, as well as the nucleoprotein N, have been used in different vaccination regimes to test protection against a RVFV-MP12 virus challenge in a transgenic mouse model with impaired interferon type I response (IFNAR(-/-)). We obtained dose dependent protection in animals immunized with a construct encoding both mature glycoproteins (pCMV-M4), whereas only partial protection in animals vaccinated with either N construct (pCMV-N) or a combination of both plasmids (pCMV-M4+pCMV-N). The protection elicited by the expression of the mature glycoproteins could be directly related to the induction of neutralizing antibodies against them. Interestingly, the combination of both vaccine constructs induced specific lymphoblast proliferation upon stimulation with a recombinant nucleoprotein.
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ABSTRACT: Schmallenberg virus (SBV), a novel orthobunyavirus, was discovered in Europe in late 2011. It causes mild and transient disease in adult ruminants, but fetal infection can lead to abortion or severe malformations. There is considerable demand for SBV research, but in vivo studies in large animals are complicated by their long gestation periods and the cost of high containment housing. The goal of this study was to investigate whether type I interferon receptor knock-out (IFNAR(-/-)) mice are a suitable small animal model for SBV. Twenty IFNAR(-/-) mice were inoculated with SBV, four were kept as controls. After inoculation, all were observed and weighed daily; two mice per day were sacrificed and blood, brain, lungs, liver, spleen, and intestine were harvested. All but one inoculated mouse lost weight, and two mice died spontaneously at the end of the first week, while another two had to be euthanized. Real-time RT-PCR detected large amounts of SBV RNA in all dead or sick mice; the controls were healthy and PCR-negative. IFNAR(-/-) mice are susceptible to SBV infection and can develop fatal disease, making them a handy and versatile tool for SBV vaccine research.PLoS ONE 01/2012; 7(7):e40380. · 4.09 Impact Factor
Article: Anti-nucleocapsid protein immune responses counteract pathogenic effects of Rift Valley fever virus infection in mice.[show abstract] [hide abstract]
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.PLoS ONE 01/2011; 6(9):e25027. · 4.09 Impact Factor