Identification of the structural motif AxxWP-RxxxA in Phenuiviridae NSs proteins and evaluation of its role in Rift Valley fever virus

Abstract

The Phenuiviridae family consists of a diverse group of single-stranded RNA viruses known for their ability to cause severe diseases in humans and animals. This family includes several genera, such as Bandavirus, Phlebovirus, and Uukuvirus, which are associated with febrile illnesses, encephalitis, and hemorrhagic fevers. Diseases caused by viruses in this family, such as Rift Valley fever virus (RVFV) and severe fever with thrombocytopenia syndrome virus (SFTSV), pose substantial public health threats due to a lack of effective countermeasures against infection and their ability to be transmitted and maintained by arthropods. It is believed that this way of transmission allows these viruses to spread over large geographical ranges, increasing the risk of outbreaks that could have high morbidity and mortality. A critical factor contributing to the virulence of these viruses is their ability to evade the immune response of the host. To a great extent, this is a result of the interaction of non-structural proteins like NSs with the host immune system. The outcome of this immune evasion complicates infection control and raises the risk of severe disease. Thus, it is necessary to understand the molecular interaction of Phenuiviridae viruses with the host cells to mitigate their threats. This research focused on the conserved motifs of NSs (non-structural proteins) of the family Phenuiviridae and their contribution to diverse functions such as immune evasion, aggregation, and overall viral fitness. With RVFV as a model, bioinformatic analysis was used to examine the conserved motifs, mutagenesis was used to evaluate the function of specific motif residues, and functional analyses were performed to evaluate the role of the conserved motifs in viral fitness. In summary, AxxWP-RxxxA, a conserved motif mainly related to immune evasion, was characterized in RVFV, a member of the Phenuiviridae virus family. The main conclusion of this thesis work is that this motif likely helps to maintain a nuclear fibril that sequesters host antiviral factors in the nucleus, thereby allowing viral replication and persistence. This has implications for the future design of strategies to block viral immune evasion.