An international team of scientists led by researchers from the Wellcome Sanger Institute and the NIH created the first mosquito immune cell atlas to understand how the insects fight malaria and other mosquito-borne infections. The mosquito host is essential for the malaria parasite to complete its life cycle. Any disruption would drastically reduce the transmission of one of the world’s deadliest diseases.
The results of the new study, recently published in Science in an article titled “Immunity of Mosquito Cells Upon Disintegration,” discussed the discovery of new types of immune cells against mosquitoes, including a rare cell type that is involved in limiting malaria infection could be. The authors also identified molecular pathways involved in fighting the malaria parasite.
“We conducted the first large-scale study of the mosquito immune system, using single cell sequencing technology to find immune cell types and cell states never seen before,” said lead researcher Gianmarco Raddi. PhD, postdoctoral fellow at the Wellcome Sanger Institute. “We also looked at mosquitoes infected with the Plasmodium parasite and for the first time we can examine their immune response in molecular detail and determine which cells and pathways are involved.”
Malaria is a life-threatening disease that affects more than 200 million people worldwide and caused an estimated 405,000 deaths in 2018 alone, most of which were children under the age of five. It is caused by Plasmodium parasites that spread via the bites of female Anopheles mosquitoes. Breaking the chain of transmission from humans to mosquitoes to humans is the key to reducing the burden of malaria.
The current study results offer an opportunity to discover new ways to prevent mosquitoes from transmitting the malaria parasite to humans and possibly preventing the transmission of malaria. The atlas will also be a valuable resource for researchers trying to understand and control other mosquito-borne diseases such as dengue or zika.
The mosquito immune system controls how the insect can tolerate or transmit parasites or viruses. Little is known about the exact cell types, however. In this first in-depth study of mosquito immune cells, a team of researchers looked at two types of mosquitoes: Anopheles gambiae, which transmits malaria, and Aedes aegypti, which carries the viruses that cause dengue, chikungunya and Zika infections.
Using state-of-the-art single cell techniques, the researchers analyzed more than 8,500 individual immune cells to see exactly which genes were turned on in each cell and to identify specific molecular markers for each individual cell type. The team found that there were at least twice as many types of immune cells as before and used the markers to find and quantify these cells in the circulation or in the intestines and other parts of the mosquito. They were then able to follow how Anopheles mosquitoes and their immune cells reacted to infection with the Plasmodium parasite.
“We profiled the transcriptomes of 8,506 hemocytes from Anopheles gambiae and Aedes aegypti mosquito vectors,” the authors wrote. “Our data show the functional diversity of hemocytes, with different subtypes of granulocytes expressing different and evolutionarily conserved subsets of effector genes. A previously unidentified cell type in An. Gambiae, which we refer to as “Megacyte”, is defined by a specific transmembrane protein marker (TM7318) and a high level of expression of the lipopolysaccharide-induced tumor necrosis factor α-transcription factor 3 (LL3). Knockdown experiments show that LL3 mediates hemocyte differentiation during immune priming. We identify and validate two major hemocyte lines and find evidence of the proliferation of granulocyte populations. “
Interestingly, an earlier study by the NIH team had shown that a process called immune priming can limit mosquitoes’ ability to transmit malaria by activating the mosquito’s immune system to successfully fight the parasite. In this study, the researchers found that one of the newly discovered immune cell types has a high level of key molecules needed for immune expression and could be involved in this process.
“We have discovered a rare but important new cell type we call megacytes that may be involved in immune priming and that appear to turn on additional immune responses to the Plasmodium parasite,” noted Oliver Billker, PhD, a former senior group leader at Wellcome Sanger Institute and now at Molecular Infection Medicine Sweden, Umeå University. “This is the first time a specific type of mosquito cell has been involved in regulating the control of malaria infections, and it’s a really exciting discovery. We now need to do more studies to validate this and better understand these cells and their role. “
Eventually, the researchers showed that certain types of immune cells – granulocytes – increased in number in response to infection, and showed that some of them could develop into other immune cells. They also discovered that immune cells in the mosquito’s gut and other tissues are actively recruited into the circulation to fight infection after resting on the mosquito fat body.
“The team created the first atlas for mosquito immune cells to shed light on how mosquitoes’ immune systems fight infections. Mosquitoes appear to have a sweet spot of immunity to parasites like malaria, with sufficient immunity to the infection that won’t kill the mosquito, but not enough to remove the parasite, study co-author Sarah Teichmann, PhD concluded Group leader at the Wellcome Sanger Institute. “This atlas provides an important resource for further research that could reveal ways to modify mosquito immune responses to disrupt the chain of disease transmission.”