Roxanna Andrade

A new study led by Yale researchers discovered a prevention method for malaria infection in mosquitoes that stops infection in mosquitoes and thus prevents the pathogen from getting transferred to humans via mosquito bites.

The researchers identified a protein, called mosGILT, that binds to early-stage malaria parasites in the saliva of infected mosquitoes. To determine whether mosGILT influences malaria infection in mosquitoes, they used CRISPR — a gene-editing tool — to reduce the gene’s expression in mosquitoes. Disrupting this gene in mosquitoes resulted in mutants that are more resistant to malaria infection. In addition, this gene resulted in abnormal ovary development and prevented egg production.

“We found that when the reproductive system of a mosquito is poorly developed, then the mosquito cannot harbor Plasmodium, the agent of malaria,” said Erol Fikrig, a senior author of the study and a School of Medicine professor of epidemiology and microbial pathogenesis. “We made a link between the reproductive fitness of a mosquito and the ability of the mosquito to harbor the pathogen.”

Only female mosquitoes need to be resistant to the malaria parasite as they are the ones that do the biting, according to first author and School of Medicine Postdoctoral Fellow Jing Yang. He said mosquitoes can actually live off of the sugar from flowers, which is how male mosquitoes survive. Female mosquitoes, however, seek out human blood for the nutrition to produce eggs — making blood feeding vital for mosquito survival.

The mosGILT gene that was targeted in the study is a homologue of the GILT gene found in mice and humans, Yang said. Previously, the team showed that mosGILT can partially reduce the activity of early-stage malaria parasites in both humans and rodents. Co-author and School of Medicine immunobiology professor Peter Cresswell explained that he was recruited for the project as his lab discovered the GILT protein first in humans and mice.

“I know Erol Fikrig very well, he’s in the same building as I am,” said Cresswell. “What happened was they identified this protein in mosquitoes, and when they did a homology search, they realized it was a homologue of GILT, which [our lab] identified in humans and then in mice.”

With this method of inducing abnormal ovary development in mosquitoes — causing infertility — Yang stated that any existing and future mosquito control strategies need to take the balance of the ecosystem into account.

Even though the team is far from developing an anti-malaria drug against mosGILT, their research is a promising step towards that goal, Yang said.

Fikrig told the News that moving forward, they are working to uncover the mechanism by which reducing the expression of mosGILT makes the ovary dysfunctional. Additionally, they want to understand why having dysfunctional ovaries changes the ability of the mosquito to be infected with Plasmodium, Fikrig said.

Yang added that when they tried to rescue the mutant mosquitoes by injecting a hormone to induce proper ovary formation, the ovaries recovered slightly, but not completely. This suggests that disrupting mosGILT also has ovary-independent effects on Plasmodium. Future experiments would involve investigating these probable secondary effects caused by mutated mosGILT.

The paper was published in the Journal of Experimental Medicine on Oct. 28, 2019.

 

Ashley Qin | ashley.qin@yale.edu