Aedes mosquitoes express vertebrate-like factor in saliva to enhance arbovirus infection
Published: 29 March 2021
Research involving Centre for Virus Research scientists has provided new insights into the mosquito factors hijacked by viruses to efficiently establish infection in the mammalian host and may explain how mosquito-borne viruses are so efficiently spread by Aedes mosquitoes.
New research involving Centre for Virus Research scientists has provided new insights into the mosquito factors hijacked by viruses to efficiently establish infection in the mammalian host and may explain in part, how mosquito-borne viruses are so efficiently spread by Aedes mosquitoes.
The study, a collaboration between the CVR and the universities of Leeds, Surrey, Lausanne, Tartu, and Edinburgh, was recently published as a pre-print by bioRxiv.
Mosquito females must take a blood meal from a vertebrate to develop their eggs. For this reason, the mosquito Aedes aegypti, which lives in tropical and sub-tropical regions, can act as vector of arthropod-borne viruses (arboviruses), such as Zika, dengue and chikungunya viruses.
These Aedes mosquito-transmitted viruses pose an increasing global threat to human and animal health, with a substantial increase in their incidence and geographical range. At the present time, there are no vaccines or treatments for most of these viruses.
Due to the diversity of such viruses, their common clinical features and their unpredictable epidemiology, the development of a pan-viral vaccine efficacious against multiple viruses would be highly advantageous.
When a mosquito female takes a blood meal on an arbovirus-infected vertebrate host, the virus is ingested along with the blood and then infects the mosquito gut cells.
After replication in the gut, the virus disseminates in the mosquito body to infect different organs including the salivary glands. Once in the salivary glands, the virus can pass in the saliva. During a subsequent blood meal, while depositing saliva into the skin, the female will then infect a new host.
Dr Emilie Pondeville, an expert in mosquito physiology and interactions with arboviruses, and Dr Clive McKimmie, an expert in immunology and viral infectious diseases at the University of Leeds, and others previously showed that skin inflammatory early responses to mosquito saliva significantly enhances infection with a broad range of mosquito-borne viruses through infection of some specific immune cells, white blood cells, recruited to the biting site.
However, it remained unknown what causes the recruitment of these particular cells and what in the mosquito saliva was responsible for this.
In this new study, Dr Daniella Lefteri et al. identified sialokinin as the Aedes mosquito peptide that enhances arbovirus infection of skin following biting.
Sialokinin belongs to the tachykinin peptide family, the largest families of neuropeptides, found from amphibians to mammals.
Remarkably, sialokinin possess a tachykinin domain more similar to vertebrate tachykinins than to insect ones and is likely able to bind mammalian receptors in the skin. Sialokinin was previously known to facilitate blood feeding by its vasodilatory action.
Lefteri et al. show that, in addition to its vasodilatory function, sialokinin rapidly induces blood vessel permeability. This leads to oedema and a sudden influx of white blood cells, which can be infected with arboviruses.
Viral replication in these cells provides an early replicative boost for virus that fuels higher viremia and thereby worsens clinical disease outcome with different arboviruses. When this peptide is absent from Aedes mosquito saliva (after genetic depletion), saliva does not enhance arbovirus infection.
Interestingly, this protein does not exist in Anopheles mosquitoes (malaria vectors), whose saliva does not enhance arbovirus infection and does not induce vascular permeability.
This highly suggests that efficiency of arbovirus transmission by Aedes mosquitoes is in part due to the viruses utilising this Aedes-specific sialokinin.
Dr Pondeville explained: “Viruses transmitted by Aedes mosquitoes are an increasingly important health burden.
"Since transmission of virus from biting mosquitoes to vertebrate host is an important feature common to all mosquito-borne virus infections, host response to mosquito saliva constitutes an ideal target to block transmission of such viruses.
"Unravelling the factors and mechanistic basis by which mosquito saliva increases arbovirus infection in mammals will likely help the development of strategies to limit arbovirus transmission and spread, such as pan-viral vaccines targeting saliva molecules or genetically modified mosquitoes lacking such proviral factors.
"On a more fundamental point of view, I find it amazing that a mosquito protein whose function is to facilitate blood feeding is used by viruses to facilitate their infection.”
Mosquito saliva sialokinin-dependent enhancement of arbovirus infection through endothelial barrier leakage
- Daniella A Lefteri, Steven R Bryden, Marieke Pingen, Sandra Terry, Emily F Beswick, Georgi Georgiev, Marleen Van der Laan, Valeria Mastrullo, Paola Campagnolo, Robert Waterhouse, Margus Varjak, Andres Merits, Rennos Fragkoudis, Stephen Griffin, Kave Shams, Emilie Pondeville, Clive S McKimmie.
chematic representation of Aedes aegypti female and saliva-induced enhancement of arbovirus infection.
Image credit: Dr Emilie Pondeville
First published: 29 March 2021