Mosquito-borne diseases, such as Dengue fever and Zika, affect over 700 million people worldwide and cause more than one million deaths annually. Yale researchers have now uncovered how a protein found in mosquito saliva facilitates viral infection in humans, which, they say, could inform new treatments for preventing deadly mosquito-borne diseases.
The researchers reported their findings in Science Immunology.
When mosquitoes bite, viruses in their saliva can be transferred to animals or humans. But there are a lot of other molecules in mosquito saliva that affect their hosts.
"That saliva is filled with pharmacologically active components," said Dr. Erol Fikrig, the Waldemar Von Zedtwitz Professor of Medicine at Yale School of Medicine and co-senior author of the study. "A lot of those are meant to help the mosquito feed, preventing blood clots for example. We wanted to know if there were components in mosquito saliva that could enhance viral infectivity."
In previous studies, Fikrig and his colleagues discovered that a protein called Nest1 found in the saliva of Aedes aegypti mosquitos - the species that carries Zika and Dengue viruses - can enhance viral infection of mice. Zika virus can cause birth defects if contracted by pregnant people, and Dengue fever, which is on the rise in the U.S. and around the world, is most often associated with muscle and joint pain.
For the new study, researchers set out to better understand how Nest1 affects viral infection in humans.
First, the researchers exposed human skin explants - samples of human tissue donated for research - to Zika virus with and without Nest1. They found that Zika virus replicated significantly more quickly in human skin when combined with Nest1.
That finding suggested Nest1 was interacting with biological molecules in human skin. To identify which, the researchers tested Nest1 against more than 2,600 human proteins, looking to see if Nest1 attached to any of them. They found that Nest1 bound strongly to a molecule called Cluster of Differentiation 47, or CD47, which is involved in a number of immune processes. In fact, Nest1 bound 26-times more strongly to CD47 than did the human protein that naturally binds to it, which came as a surprise to the researchers.
"We didn't believe it at first. We also saw that Nest1 bound very specifically to CD47," said Fikrig, who is also a professor of epidemiology (microbial diseases) at Yale School of Public Health. "So it's a very potent, exogenous molecule that a mosquito has made that inhibits a human molecule."
Through its interaction with CD47, Nest1 was able to inhibit key immune functions like phagocytosis - in which a cell ingests and neutralizes pathogens or cell debris - reduce the activity of several protective immune pathways and increase the activity of pathways involved in virus replication, the researchers found. The overall effect was one that suppressed antiviral responses in the skin and boosted viral activity.
This deeper understanding of how Nest1 affects human immune responses could inform treatment development in the future, said Fikrig.
"For instance, we could see a treatment where we block Nest1, maybe with a monoclonal antibody, which would diminish the favorable environment Nest1 creates for the virus at the mosquito bite site," said Fikrig. "That could be done alone or in combination with a traditional pathogen-based vaccine, making that vaccine more effective."
And this type of treatment would not necessarily be limited to Zika virus. Several other mosquito species, which spread diseases like West Nile virus and malaria, have salivary proteins very similar to A. aegypti's Nest1. Future studies could evaluate whether their versions of the protein facilitate viral infection in a comparable manner and whether other disease-carrying arthropods like sand flies and ticks have a Nest1-like protein as well, said Fikrig.
But Nest1 itself may also hold promise for treating human diseases.
"It's a bit of a pie in the sky idea for now but could this mosquito molecule that binds with a higher affinity than our own host molecule have functionality in maybe preventing inflammatory diseases or cancer in humans?" said Fikrig. "Maybe. It's something to pursue."
