Mosquito  saliva enhances virus infection through sialokinin-dependent vascular leakage

Abstract

Viruses transmitted by Aedes mosquitoes are an increasingly important global cause of disease. Defining common determinants of host susceptibility to this large group of heterogenous pathogens is key for informing the rational design of panviral medicines. Infection of the vertebrate host with these viruses is enhanced by mosquito saliva, a complex mixture of salivary-gland-derived factors and microbiota. We show that the enhancement of infection by saliva was dependent on vascular function and was independent of most antisaliva immune responses, including salivary microbiota. Instead, the Aedes gene product sialokinin mediated the enhancement of virus infection through a rapid reduction in endothelial barrier integrity. Sialokinin is unique within the insect world as having a vertebrate-like tachykinin sequence and is absent from Anopheles mosquitoes , which are incompetent for most arthropod-borne viruses, whose saliva was not proviral and did not induce similar vascular permeability. Therapeutic strategies targeting sialokinin have the potential to limit disease severity following infection with Aedes -mosquito-borne viruses.

The mechanical arthropod vectorStomoxys calcitransinfluences the outcome of lumpy skin disease virus infection in cattle

“…Whilst a strong trend, this difference did not reach statistical significance. The amount of saliva added to the inoculum was 0.5 µg of S. calcitrans saliva in each microdose, comparable with other studies which have examined the influence of arthropod saliva on disease outcome (29, 38). This may not accurately represent the amount of saliva inoculated during a S. calcitrans bite.…”

“…The influence of arthropod saliva on virus replication in cell culture is inconsistent with some studies reporting an impact (66,67,68), but others not (38).…”

“…We found that the addition of S. calcitrans secreted saliva did not influence the replication or spread of LSDV in bovine primary fibroblasts, indicating the saliva did not directly impact the infectivity of the virus, or induce an effective antiviral effect in the bovine fibroblasts. The influence of arthropod saliva on virus replication in cell culture is inconsistent with some studies reporting an impact (66, 67, 68), but others not (38).…”

“…Addition of arthropod saliva enhances disease caused by multiple biologically transmitted viruses (29, 30, 31, 32, 36, 38, 67). We hypothesised that adding saliva to a mechanically transmitted pathogen, LSDV, would likewise enhance disease.…”

“…The mechanisms underpinning arthropod disease enhancement include the Aedes aegypti venom allergen-1 which enhances viral replication in macrophages and dendritic cells (37), and Ae. aegypti protein sialokinin which increases blood vessel permeability and availability of virus permissive cells (38). While arthropod enhancement of disease has been shown for a number of biologically-transmitted pathogens, this potentiation has not been described for disease caused by mechanical vectors.…”