Our immune systems rely on antibodies to target pathogens like malaria parasites through their ability to recognize specific proteins and other tell-tale molecules. Mosquitoes, however, do not have these antibodies and rely instead on a recently-discovered gene.
Researchers at the Hopkins Bloomberg School of Public Health pinpointed one Mosquito gene, AgDscam, as the blueprint for numerous proteins that act as the mosquito’s equivalent of antibodies. The group, which published their results in last month’s Cell, found that the mosquito can produce a large variety of proteins from the single AgDscam gene by combining various parts of the gene in different combinations. These proteins can then target different pathogens, which may have significance for mosquito-related health issues, including the spread of malaria.
George Dimopoulos, a professor of Molecular Microbiology and Immunology at the School of Public Health, and his lab have been conducting research on malaria with a focus on how mosquitoes fight off pathogens.
“We have shown over the years that the mosquito’s innate immune system is a significant factor in limiting the transmission of these pathogens to humans,” Dimopoulos said.
His group first came across the AgDscan gene and published their findings in 2006, describing a large number of exons, regions that encode protein sequences, discovered within the gene.
“It has a complex gene organization, as well call it, and has over 100 exons,” Dimopoulos said. “What is interesting is that it can, through a mechanism called alternative splicing, produce different proteins by combining different exons.”
These exons encode immunoglobins, protein segments that can recognize different proteins or other molecules that a pathogen would display. The mosquito’s immune system can combine these in many different combinations to produce a protein with tailored properties.
“Mathematically based on the number of the exons this genes has, this gene can produce roughly 31 or 32 thousand proteins,” he said.
The key finding that Dimopoulos and his group showed was the involvement of AgDscan’s protein products in targeting the pathogen and leading to its destruction by the immune system.
“What we have shown is that if you challenge a mosquito with a pathogen ... this gene will produce proteins that have a higher affinity to these pathogens and mediate their destruction,” he said.
The team demonstrated that AgDscam also interacts with IMD and NF-kB, key pathways in the immune system, which regulate the immune response and consequently control the production of proteins from AgDscam.
“What we show in this work now is that the IMD pathway is also responsible for guiding the splicing machinery so that the AgDscam gene produces the specific protein for the pathogen,” he said.
To better explain the difference between antibodies and the proteins produced by AgDscam, Dimopulos compared them to the capacity of harpoons versus fishing nets. Whereas one can specifically target one fish, the other can act on a larger pool of fish but may capture more than originally desired.
“[AgDscam] is more like a net, there is a specificity, but is not like the human antibody, which would be more like a harpoon,” he said.
While mosquito nets and insecticide have done their part to combat the spread of malaria in human populations, researchers have been working on a new approach from the vectors, mosquitoes.
At first glance it sounds counter-intuitive, but an enhancement to the mosquito immune system might be able to reduce the spread of the malaria parasite.
“Our goal is to understand the mosquito’s immune system and genetically engineer mosquitoes that have an improved immune response against the pathogens they transmit,” Dimopoulos said.
Researchers typically rely on the classical approach in genetic engineering of taking one gene that encodes a protein and overexpressing it to achieve a specific effect. Dimopoulos found this approach flawed when dealing with a pathogen that has multiple strains and recognizes that a different approach is needed.
“One problem with that approach is that there are numerous strains of the parasite that causes human malaria, which complicates the targeting because they look slightly different,” he said.
According to Dimopoulos, the next step in advancing this research toward combating malaria involves finding how these results can be used to target multiple strains of the parasite, but this segment of the research is in an early state.
The Malaria Research Institute is a collection of research labs at Hopkins tackling malaria through a variety of research routes and possible intervention methods. Dimopoulos himself is not affiliated with the institute, but believes they have the potential to be a major player in this field.
“It’s possible for Johns Hopkins to be a leader in malaria research,” he said.