Targeted delivery of novel antiviral treatments to Aedes aegypti by exploiting its behaviour

The arboviral diseases dengue, Zika, chikungunya and yellow fever cause significant mortality and morbidity worldwide, and their global incidences are forecast to increase further due to global change. Aedes aegypti thrives in complex dense urban environments where it is responsible for outbreaks of increasing frequency and magnitude, where the impossibility of sustaining adequate coverage and where insecticide resistance are major barriers to success. The remarkable potential of Wolbachia-based control methods will not be realised everywhere and additional affordable control methods that are appropriate and effective in high density urban communities are still required to reduce the burden of arboviral disease. Promoting DIY practices that empower the householder and bypass the need for expensive vertical programme, have the greatest potential.

Our studies on mosquito flight reveal previously unseen behaviours we can exploit to target vectors more efficiently and safely, reducing the quantity while increasing the range of potential treatments. Now we have shown that insecticide treatments applied to minimal key indoor locations by the householder in <10 minutes can target and kill all Aedes aegypti adults within 24hr. We propose to exploit this behaviour one step further by deploying antiviral chemistries at those key locations. The use of an antiviral has several advantages over conventional insecticides that kill the vector, in that they offer potentially safe and specific approaches, targeting only the viruses within, mitigating or potentially eliminating selection pressure for the emergence of resistance in the mosquito.

This highly collaborative project capitalises on greatly expanded range of known antiviral agents following the unprecedented expansion of screening during the SARS-CoV-2 pandemic. Determined by on their skillset and primary area of study, the successful student will join an active team working to:

1) Explore the efficacy of a range of antiviral molecules and any synergistic interactions between chemistries; select candidates to screen for anti-viral activity in vivo, long-term stability and insecticidal properties.

2) Test methods for anti-viral molecules delivery to mosquitoes and where required, modify properties of the anti-viral or delivery platform to optimise balance between rapid transfer/uptake and stability/persistence;

3) Quantify in whole-room bioassays the actual potential for safe sustainable, affordable control in dengue -endemic areas.

This research will lay the foundations for developing novel antivirals suitable for use as surface residues at contamination points to which mosquitoes are attracted, inhibiting development and transmission of arboviruses within the mosquito, termed Anti-Viral Attractive Targeted Surface Areas or AVATSAs

Where does the project lie on the Translational Pathway?

T1 (Basic Research) + T3 (Evidence into Practice)

Expected Outputs

The project will determine which antiviral can be delivered to mosquitoes by touch and provide and understanding on how these can influence virus development in the mosquito. Combined with the vector behaviour aspects, we will have all the elements required for a AVATSA’.

The project will produce high quality REF returnable 3*/4* publications and will provide the evidence base for large scale research council funding in a global priority area. Previous and current PhD students from GLH, PMcC and GB have all published one or several high-quality first author papers, and have all moved to postdoctoral positions, head of regional vector control programmes or government bodies or are working in industry. Recent collaborative work between GLH and PMcC resulted in review in the prestigious Microbiome Journal, while GLH and GB have severa)l collaborative projects and published papers.

Training Opportunities

•            Courses using R to examining big data sets.

•            Vector biology and training to work with high containment pathogens.

•            Workshops on machine learning and artificial intelligence.

•            Point pattern and spatiotemporal analyses.

Skills Required

A general understanding of vector biology, virology, and behaviour, as well as interest in statistics and coding.

Key Publications associated with this project

Murray GPD, Lissenden N, Jones J,  V Voloshin, KH Toé, E Sherrard-Smith, GM Foster, TS Churcher, JEA Parker, CE Towers, WM Guelbeogo, Sagnon N’Falé, H. Ranson, D. Towers, P. J. McCall (2020) Barrier bednets target malaria vectors and expand the range of usable insecticides. Nature Microbiol.5(1):40-47. https://rdcu.be/bZ6ip

Saldaña MA*, Etebari K, Hart CE*, Widen SG, Wood TG, Thangamani S, Asgari S, Hughes GL. (2017) Zika virus alters the microRNA expression profile and elicits an RNAi response in Aedes aegypti mosquitoes. PLoS Neglected Tropical Disease 11(7):e0005760.

Parker JEA, Angarita-Jaimes N, Abe M, Towers CE, Towers, D & McCall, PJ. (2015) Infrared video tracking of Anopheles gambiae at insecticide-treated bed nets reveals rapid decisive impact after brief localised net contact. Scientific Reports, 5, 13392.  https://doi.org/10.1038/srep13392 

Etebari K, Hedge S*, Saldaña MA*, Widen SG, Wood TG, Thangamani S, Asgari S, Hughes GL. (2017) Global transcriptome analysis of Aedes aegypti mosquitoes in response to Zika virus infection. mSphere. 6 (2): 300456-17.

Lynd A & McCall PJ. (2013) Clustering of host-seeking activity of Anopheles gambiae mosquitoes at the top surface of a human-baited bednet. Malaria J, 12, 267. https://doi.org/10.1186/1475-2875-12-267

Jeffreys L, Pennington SH, Jack Duggan J, Breen A, Jinks J, Ardrey A, Donnellan S, Patterson EI, Hughes GL, Hong D, O’Neill PM, Aljayyoussi G, Owen A, Ward SA, Biagini GA (2020). Remdesivir-Ivermectin combination displays synergistic interaction with improved in vitro antiviral activity against SARS-CoV-2. BioRxiv.  doi: https://doi.org/10.1101/2020.12.23.424232

LSTM Themes and Topics – Key Words

Resistance Research & Management, Malaria & other vector-borne disease, Neglected Tropical Disease.