Structure and Function of Innate Immune Signalling in Mosquito Vectors

Over the course of a long evolutionary history vector-borne pathogens have developed mechanisms to successfully disrupt natural defences in both their mammalian hosts and insect vectors in order to survive and establish infection. A better understanding of the interplay between host, vector and pathogen may contribute towards the development of preventive and control strategies against vector-borne diseases such as Dengue, Zika and Malaria. This is why my group is interested in unravelling the molecular mechanisms involved in mosquito’s innate immunity against viruses and parasites.

Insects have three major signalling pathways that regulate innate immunity. These comprise the Toll, the Immune deficiency (Imd) and the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways. Considerable insight into innate immune signalling has been gathered from studies conducted in Drosophila (1, 2). Studies in mosquitoes have lagged behind. The number of immune genes has undergone a major expansion in sequenced mosquitoes compared to Drosophila melanogaster, probably in response to the increased microbial burden linked to their hematophagic diet.

This PhD project will use a range of structural and functional techniques to answer the following questions: what are the roles of duplicated immune receptors in mosquitoes? In particular, your aim will be to determine the structure and mechanism of activation of these molecules. So far, we know that the extracellular region of Toll-related receptors comprises one or two leucine-rich repeat domains involved in ligand binding with a degree of promiscuity by analogy with the well-characterised Drosophila proteins. This research project will use various expression systems to produce mosquito proteins, which will be purified using liquid chromatography techniques. Structure determination will be carried out by X-ray crystallography or cryo-electron microscopy as appropriate. You will be looking at Spätzle isoforms as interaction partners with known receptors. Ligand screening for orphan receptors will be carried out by mass spectrometry. Mosquito cell signalling will be assessed in functional studies involving RT-qPCR, proteomics and confocal microscopy. We are particularly interested in characterising the link between immune signalling and anti-viral or anti-plasmodial activity.

The ideal candidate will have a solid knowledge of structural biology and experience in one or more of the areas mentioned above. He or she must be highly motivated to drive an independent research project.