Transcriptional and proteomic dynamics of severe fever with thrombocytopenia syndrome virus infection in Rhipicephalus microplus cells identify antiviral host factors.

Ticks are vectors of arboviruses in many parts of the world. The rising incidence and emergence of tick-borne arboviral infections across human populations indicates that further transmission control strategies including those based on vectors, will be required to reduce the burden of disease. However, arbovirus-tick interactions at the cellular level remain poorly understood in general, and particularly neglected for negative strand RNA arboviruses. In this study we developed a proteomics informed by transcriptomics approach to characterize the cellular response of Rhipicephalus microplus-derived cell cultures to infection with the tick-borne pathogen severe fever with thrombocytopenia syndrome virus (SFTSV, Phenuiviridae). For this, we generated the first de novo transcriptomes and confirmed proteomes of SFTSV- or mock-infected tick cell cultures derived from a vector species that transmits the virus in nature. Through comprehensive annotation of genes, proteins and pathway analysis, we identified core host responses and regulatory processes mediated in response to SFTSV infection. Moreover, examining the interactome of the virally encoded nucleoprotein (N) allowed us to integrate host responses with the analysis of cellular factors required for viral replication. The influence of specific host genes on SFTSV replication was systematically assessed through dsRNA-mediated gene silencing. This functional genomics approach pinpointed two tick-derived RNA helicases as critical antiviral factors capable of restricting SFTSV infection: the DexD/box helicase (DHX9) and the Up-Frameshift Protein 1 (UPF1). Collectively, our findings enrich the repository of resources available for understanding the antiviral response to SFTSV infection in Rh. microplus vector cells and support the identification of SFTSV-antiviral restrictions factors.