Heritable, programmable anti-viral immunity in the dengue mosquito Aedes aegypti

Dengue, Zika, chikungunya and other arboviruses threaten approximately half the world's population, with over 500 million infections annually - according to WHO, vector-borne diseases comprise 17% of all human infectious disease. Dengue is long-established but Zika and chikungunya emerged as major epidemics this century, highlighting the risk of further such epidemics. However, these viruses are completely dependent on mosquitoes for transmission; this provides an attractive target for breaking the transmission cycle. What if we could vaccinate the mosquito population? This is impractical for all sorts of reasons, but this project aims to develop something analogous, exploiting new information about mosquito immunity to engineer mosquitoes to be resistant to these viruses. If translated to the field - beyond the scope of this lab-based project, but a vision for future use - this would give a population of mosquitoes still filling their ecological niche, indeed still biting people, but no longer transmitting these viruses. In this project, we aim to 'reprogramme' a naturally-occurring mosquito system to control mosquito-borne viruses. This involves inserting fragments of virus to 'teach' the mosquito to recognise them; in our preliminary studies this gave extremely strong resistance to Zika virus. Furthermore, this programming is heritable, providing multi-generational immunity. We will develop such a system in the major arboviral vector mosquito Aedes aegypti, targeting the key viruses it transmits, including dengue, chikungunya, Zika and yellow-fever viruses. The aim is to develop working prototype strains and assess their performance in the laboratory, primarily in relation to their ability to protect against infection with these viruses, but also looking at any impairment to the mosquito ("fitness costs") which might affect their persistence in a field population. No field releases are envisioned within the scope of this project. The twin Aims are therefore to (i) better understand this mosquito immunity system and (ii) to manipulate it to provide resistance to key viruses. This will be achieved through a series of linked Objectives. In preliminary work we have made a strain, AGG2280, engineered to target several viruses and shown that it is extremely effective against the first of these that we tested, Zika virus. In Objective1 we will analyse this strain, providing new knowledge and data facilitating design of improved variants - which we will undertake in Objective 2. Key questions include: Are all viruses similarly affected (Obj1.1) - we have very clear data for Zika virus, what of other viruses? Can we use our engineered variant to further dissect precise molecular details of the system (Obj1.2)? Based on our existing data, and informed by output from Obj1, undertake iterative development of new strains, aiming to achieve strong protection against multiple viruses of human health importance (Objective2), and exploring the possibility of non-viral targets. This proposal clearly relates to UKRI/BBSRC priorities of world-class people, ideas, innovation, and, particularly, advancing applied insect synthetic biology, an area of transformative potential for public health (disease vectors), agricultural pests and biodiversity (e.g. invasive species) and where the UK has strategic strength in world-leading groups at multiple institutions.