Abstract
BackgroundLouping ill virus (LIV) and tick-borne encephalitis virus (TBEV) are tick-borne flaviviruses that are both transmitted by the major European tick, Ixodes ricinus. Despite the importance of I. ricinus as an arthropod vector, its capacity to acquire and subsequently transmit viruses, known as vector competence, is poorly understood. At the molecular scale, vector competence is governed in part by binary interactions established between viral and cellular proteins within infected tick cells.MethodsTo investigate virus-vector protein–protein interactions (PPIs), the entire set of open reading frames for LIV and TBEV was screened against an I. ricinus cDNA library established from three embryonic tick cell lines using yeast two-hybrid methodology (Y2H). PPIs revealed for each viral bait were retested in yeast by applying a gap repair (GR) strategy, and notably against the cognate protein of both viruses, to determine whether the PPIs were specific for a single virus or common to both. The interacting tick proteins were identified by automatic BLASTX, and in silico analyses were performed to expose the biological processes targeted by LIV and TBEV.ResultsFor each virus, we identified 24 different PPIs involving six viral proteins and 22 unique tick proteins, with all PPIs being common to both viruses. According to our data, several viral proteins (pM, M, NS2A, NS4A, 2K and NS5) target multiple tick protein modules implicated in critical biological pathways. Of note, the NS5 and pM viral proteins establish PPI with several tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins, which are essential adaptor proteins at the nexus of multiple signal transduction pathways.ConclusionWe provide the first description of the TBEV/LIV-I. ricinus PPI network, and indeed of any PPI network involving a tick-borne virus and its tick vector. While further investigation will be needed to elucidate the role of each tick protein in the replication cycle of tick-borne flaviviruses, our study provides a foundation for understanding the vector competence of I. ricinus at the molecular level. Indeed, certain PPIs may represent molecular determinants of vector competence of I. ricinus for TBEV and LIV, and potentially for other tick-borne flaviviruses.Graphical
Highlights
Louping ill virus (LIV) and tick-borne encephalitis virus (TBEV) are tick-borne flaviviruses that are both transmitted by the major European tick, Ixodes ricinus
These tick proteins are involved in 20 different Protein–protein interaction (PPI) with louping ill virus (LIV) and 19 with TBEV: of these PPIs, eight were common to both viruses at this step (Fig. 2a, b)
The present study, providing the PPI network established between two tick-borne flaviviruses (TBEV and LIV) and their arthropod vector I. ricinus, represents the first published protein–protein interaction for a tick-borne virus with its arthropod host
Summary
Louping ill virus (LIV) and tick-borne encephalitis virus (TBEV) are tick-borne flaviviruses that are both transmitted by the major European tick, Ixodes ricinus. In Europe, two of the major tick-borne viruses, tick-borne encephalitis virus (TBEV) and louping ill virus (LIV), are members of the genus Flavivirus of the family Flaviviridae [2]. Both viruses are principally transmitted by the major tick species of northern Europe, Ixodes ricinus [3], which is the most significant arthropod vector in Europe and responsible for the transmission of multiple pathogens of medical and veterinary importance. Occasional human cases of LIV, diagnosed in farmers, butchers, abattoir and laboratory workers, appear to be related to occupational exposure rather than tick bites [10]
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