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Title: Targeting the chemokine signalling pathway using tick saliva peptides
Author: Alenazi, Yara
ISNI:       0000 0004 7966 1599
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Chemokines are signalling proteins that function to recruit immune cells from the innate and adaptive immune response. Chemokines are classified based on the position of their cysteine residues at the N-terminus as CC, CXC, CX3C or XC (C-cysteine, X-amino acid). Increased expression of chemokines is one of the key findings in a range of inflammatory diseases. Chemokines operate in a network, where multiple chemokines bind a single receptor, and vice versa, and multiple chemokine receptors are expressed on immune and inflammatory cells. While chemokines are validated therapeutic targets, targeting a single chemokine or receptor has failed as a therapeutic approach in inflammatory disease. Ticks, blood-feeding parasites, feed on their hosts for several days to weeks without eliciting their hosts immune response. Ticks achieve this through secreting numerous anti-inflammatory peptides into their hosts, during feeding. Evasins are proteins identified from tick saliva that bind and neutralize multiple chemokines and are thought to reduce inflammation at the site of the tick bite. Systemic administration of evasins effectively reduce inflammation in a range of preclinical models of inflammatory disease, suggesting that they could be used as therapeutics for such diseases. Limitations of published evasins include lack of binding to important chemokines (e.g. CCL2, CCL13, CXCL10), and inability of a single evasin to target both CC and CXC chemokines. Therefore, this thesis aimed to expand the chemokine-binding repertoire of identified evasins and hypothesised that other tick species would have novel evasins that are also capable of modulating chemokine activity. Using bioinformatic analysis of eight tick species from the Amblyomma, Rhipicephalus and Ixodes genera, 352 evasin-like sequences were identified, and constructed into a yeast surface display library. This library was screened using fluorescently labelled CC and CXC chemokines to identify individual clones that bound. 16 novel evasins were identified, including P1156 and P1243. P1156 binds six ELR+ CXC chemokines with high affinity and neutralises CXC chemokine function. P1243 evasin binds 21 CC chemokines with high affinity and neutralises CC chemokine function. Typically, both CC and CXC chemokines are expressed in inflammatory disease. To develop agents that can target both chemokine classes, genetically engineered 'two-warhead' evasins were created and were shown to be capable of simultaneously binding CC and CXC chemokines and neutralising their function, in vitro. Thus, the two-warhead evasin provides a concept of achieving precision targeting of disease-relevant CC and CXC chemokine subsets, as a single agent.
Supervisor: Bhattacharya, Shoumo ; Kawamura, Akane Sponsor: Saudi Arabian Cutural Bureau
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Tick saliva ; Evasin ; Yeast surface display ; Chemokine network ; Chemokine ; Inflammation ; Chemokine binding protein