The Impact of the Non-Structural Small Segment Gene on Host Immune Responses Against Rift Valley Fever Virus


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Rift Valley fever virus (RVFV) is responsible for large periodic outbreaks of enzootic hepatitis of ruminants. Inevitably, due to the close proximity and relationship between, the mosquito vector species, livestock, and humans, infection spreads to humans causing a range of mild to severe clinical conditions. The severe health and economic impacts RVFV exerts on endemic regions demands the urgent development of effective preventive and therapeutic interventions. To address the need for livestock and human vaccines, several live attenuated vaccine platforms have been proposed. Primarily the MP-12 strain which contains multiple amino acid mutations collectively contributing to attenuation, and Clone 13 which has a single large deletion in the S-segment non-structural gene (NSs). When used in vaccination of animals both vaccine constructs show promising results. However, extensive investigation on the fundamental differences in innate immune responses, which ultimately impact the quality, intensity and duration of host immune defenses has not been undertaken. Additionally, detailed analysis on the susceptibility and host responses of human innate immune cells, such as macrophages, has not been reported. To address the deficiencies in understanding host-virus interaction of RVFV vaccines and human innate immunity, I investigated the cellular responses of human primary macrophage cells to RVFV infections containing NSs-intact and NSs-deleted genotypes. The use of cDNA based transcriptional analysis allowed for detailed and specific identification of modulated gene expression induced by RVFV and the functions of NSs. Findings from these studies revealed that removal of NSs function lead to more dramatic host defense response that was reflected at the transcriptional and protein levels. Further bioinformatics analysis of the differentially expressed genes identified signaling pathways and biological functions which are relevant to antiviral processes, immune regulation, and pathogenesis. The experimental approach provided an excellent means of identifying host responses which were compromised by NSs activity. The major benefit is that these differences can be used for hypothesis generation to identify the critical host components modulated during RVFV infection which may assist or compromise the development of immunity. Specifically, the alteration of RIG-I signaling, cytokine production, and antigen presentation mechanisms by NSs may potentially be exploited as targets for rationally improve RVFV vaccines.



Macrophage, Innate Immune, Interferon, Microarray, NSs, Cytokine, Vaccine, Virus