Mosquito-borne viruses; targeting the bite.

The climate crisis is making mosquito-borne virus infections an increasing threat to human health. These viruses, such as those that cause Zika and dengue, are infecting more people and spreading to new countries as the climate warms and globalisation helps mosquitoes spread. Defining common determinants of patient susceptibility to this large group of heterogenous pathogens are key for informing the rational design of new pan-viral medicines.
Mosquito-borne viruses are transmitted to people when biting mosquitoes spit virus into the skin. This is a key stage of infection that is common to all such infections. We have recently shown that mosquito-derived factors in mosquito saliva, co-injected with virus, have a highly significant enhancing effect on infection. Excitingly, we have already identified one salivary factor, sialokinin (SK), that is part-responsible. SK works by inducing blood endothelial barrier dysfunction, which enables a super-influx of leukocytes into the bite, which consequently become infected and replicate virus.
Objectives
This project will transform our understanding of this key stage of mosquito-borne virus infection with the aim of identifying a novel pan-viral therapeutic strategy by,
1.) defining how factors in mosquito saliva, including sialokinin, modulate blood endothelial barrier function, and so modulate host susceptibility to virus
2.) defining whether vaccination of mice against factors in mosquito saliva can interfere with its ability to enhance virus infection
Experimental approach - we will utilise a combination of approaches to
1.) define the parameters by which saliva induces barrier dysfunction in primary cultures of blood endothelia (barrier function assays and transcriptome analysis)
2.) undertake a targeted siRNA-based screen of mosquito salivary genes to define the role of identified salivary genes in modulating endothelial barrier function (in vitro, in vivo and in cultured human skin explants)
3.) target mosquito salivary components with IgG-inducing vaccines in vivo
This interdisciplinary project will uniquely combine immunology, vector biology, virology and vascular biology. It has potential to inform our understanding of virus transmission at the arthropod/mammalian interface and the development of novel vaccines that target mosquito saliva to reduce disease burden. The use of anti-saliva vaccines may have wide applicability, as enhancement of infection by saliva is widely observed for these viruses.