TickTools: Development of tools to monitor and control tick-borne diseases of humans and livestock

Tick-borne diseases cause a significant health burden on both the human and domestic livestock populations within the United Kingdom (UK). This includes the recently detected tick-borne encephalitis virus, a common cause of encephalitis in humans across Europe, and the livestock disease caused by louping ill virus. Both are types of flaviviruses and are closely related, and both are now endemic within the UK. Many questions remain concerning the biology of these viruses and there are key gaps in understanding virus distribution within tick vector populations, fundamental questions on flavivirus virus pathogenesis and a clear lack of serological tests that can distinguish between antibodies to either virus in order to tell which is circulating in the different host species. To address these gaps, the TickTools project aims to conduct a series of studies, each coordinated by one of the project partners. The Animal and Plant Health Agency (APHA) will conduct field surveys for adult ticks from across the UK and determine the microbiological make-up present within each sample, which will identify all viruses and bacteria present. This approach will also capture the genome of each tick that can be used to assess the relationships between tick-populations within the country, which in turn could reveal the interactions between these populations and how ticks, and their pathogens disperse. APHA will support the University of Glasgow Centre for Virus Research (CVR) in establishing a virus infection model to determine the pathogenesis of tick-borne flaviviruses. This will be achieved by comparing the virulent virus with an attenuated virus. This approach will identify potential therapeutic targets for prevention and control of flavivirus infection with the aim of preventing the most severe manifestations of virus infection. From these studies, CVR will supply organ tissue (spleen) to the University of Nottingham (UoN) to support their development of scFv antibodies that can be used to further study both viruses but also have potential as treatments for people or pets that become infected. The UoN will also develop antigen (peptide) panels that will discriminate between serological responses to infection with either TBEV or LIV. Using assays developed by UoN, serological surveillance in both human and animal populations will be possible.

The TickTools proposal will enhance the ability of the United Kingdom (UK) to respond to the emergence and spread of tick-borne diseases caused by flaviviruses. This includes the recently emerged tick-borne encephalitis virus (TBEV) and the endemic pathogen of sheep, louping ill virus (LIV). This will be achieved through the acquisition of fundamental knowledge of the tick microbiome and the generation of an interactome map of endosymbionts, both bacterial and viral, and pathogenic viruses. A pilot study has shown the great diversity of microbial agents present in tick populations within the south of England and the discovery of novel viruses. In addition, the genetic structure of UK tick populations will be determined and used to reveal the interrelationships between different populations. This offers the potential to understand both tick and virus dispersal. The development of a murine pathogenesis model for both virulent and attenuated viruses, generated by re-encoding for non-optimised codons, will identify cytokine/chemokine responses and potential therapeutic targets at the molecular level. This approach has previously identified the cytokine IL-6 as a target for control during tick-borne virus infection. A further challenge is the discrimination of serological responses to closely related tick-borne viruses such as TBEV and LIV. The project will develop the Soluble Phage Array (SPAr) linked to next generation sequencing, a process termed next generation phage display (NGDP) to generate peptide panels that achieve this within a single serological test. Preliminary results have provided proof-of-principle of this method. The TickTools project will further validate these findings and through collaboration with all three partners develop a surveillance tool to accurately monitor serological responses to tick-borne flaviviruses in both human and animal populations.