Effect of mosquito saliva alone on the human immune response
In another area of study, Rico-Hesse and coworkers, using a 'humanized mouse' model to study dengue virus infection, found that mosquito saliva alone - in the absence of any virus - can trigger a human immune response which may significantly affect disease development not only by dengue virus, but also by other Aedes mosquito-transmitted viruses including chikungunya virus and Zika virus.
The researchers used a model system that consisted of mice naturally born without their own immune system, but which had received human stem cells which could then give rise to many of the components of the human immune system, so factors involved in disease development could be studied. These animals were injected with dengue virus either through a mosquito bite or through needle injection.
They found that animals receiving the virus through a mosquito bite developed a more human-like disease with more of a rash, more fever and other characteristics that mimic the disease presentation in humans than did the needle-injected mice.
This led the scientists to investigate the role of mosquito saliva on disease development, hypothesizing that the mosquitoes may not just be acting like ‘syringes,’ merely injecting viruses into the animals they feed on, but rather that their saliva may contribute significantly to disease development.
To test this idea, virus-free mosquitoes were allowed to feed on the humanized mice, and then the researchers took blood and a number of other tissue samples six hours, 24 hours and seven days after the mosquitoes bit the mice. They determined the levels of cytokines, as well as the number and activity of different types of immune cells, using highly sensitive techniques and compared these results with those obtained from humanized mice that had not been bitten by mosquitoes.
They discovered that mosquito-delivered saliva induced a varied and complex immune response. Both the immune cell responses and the cytokine levels were affected. At various time points, the levels and activities of other types of immune cells also increased as others decreased.
Overall, the researchers found evidence that mosquito saliva alone can trigger long-lasting immune responses – up to seven days post-bite – in multiple tissue types, including blood, skin and bone marrow. The diversity and complexity of the immune response was a surprise to the investigators.
The researchers would now like to determine which of the more than 100 proteins in mosquito saliva are mediating the effects on the immune system and whether these effects could increase disease development. Identifying these proteins could help in the design of strategies to fight transmission of chikungunya, dengue, and other viral diseases transmitted by Aedes aegypti mosquitoes.