BACKGROUND: Ixodid ticks are important vectors of a wide variety of viral, bacterial and protozoan pathogens of medical and veterinary importance. Although several studies have elucidated tick responses to bacteria, little is known about the tick response to viruses. To gain insight into the response of tick cells to flavivirus infection, the transcriptomes and proteomes of two Ixodes spp cell lines infected with the flavivirus tick-borne encephalitis virus (TBEV) were analysed. METHODS: RNA and proteins were isolated from the Ixodes scapularis-derived cell line IDE8 and the Ixodes ricinus-derived cell line IRE/CTVM19, mock-infected or infected with TBEV, on day 2 post-infection (p.i.) when virus production was increasing, and on day 6 p.i. when virus production was decreasing. RNA-Seq and mass spectrometric technologies were used to identify changes in abundance of, respectively, transcripts and proteins. Functional analyses were conducted on selected transcripts using RNA interference (RNAi) for gene knockdown in tick cells infected with the closely-related but less pathogenic flavivirus Langat virus (LGTV). RESULTS: Differential expression analysis using DESeq resulted in totals of 43 and 83 statistically significantly differentially-expressed transcripts in IDE8 and IRE/CTVM19 cells, respectively. Mass spectrometry detected 76 and 129 statistically significantly differentially-represented proteins in IDE8 and IRE/CTVM19 cells, respectively. Differentially-expressed transcripts and differentially-represented proteins included some that may be involved in innate immune and cell stress responses. Knockdown of the heat-shock proteins HSP90, HSP70 and gp96, the complement-associated protein Factor H and the protease trypsin resulted in increased LGTV replication and production in at least one tick cell line, indicating a possible antiviral role for these proteins. Knockdown of RNAi-associated proteins Argonaute and Dicer, which were included as positive controls, also resulted in increased LGTV replication and production in both cell lines, confirming their role in the antiviral RNAi pathway. CONCLUSIONS: This systems biology approach identified several molecules that may be involved in the tick cell innate immune response against flaviviruses and highlighted that ticks, in common with other invertebrate species, have other antiviral responses in addition to RNAi.

Department of Veterinary Pathobiology Center for Veterinary Health Sciences Oklahoma State University Stillwater OK 74078 USA

Faculty of Science University of South Bohemia and Biology Centre Institute of Parasitology Czech Academy of Sciences Branisovska 31 České Budějovice 37005 Czech Republic

Institute for Cancer Research The Norwegian Radium Hospital Oslo University Hospital Oslo 0377 Norway

SaBio Instituto de Investigación en Recursos Cinegéticos IREC CSIC UCLM JCCM Ronda de Toledo s n Ciudad Real 13005 Spain

The Pirbright Institute Ash Road Pirbright Surrey GU24 0NF UK

The Roslin Institute and Royal School of Veterinary Studies University of Edinburgh Easter Bush Midlothian Scotland EH25 9RG UK

Veterinary Research Institute Hudcova 70 Brno 62100 Czech Republic

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