Chemical pesticides are commonly used as defense against mosquitoes in countries where malaria, dengue fever, and zika virus are present. Pesticides wreak havoc on the environment and can cause pesticide resistant species to evolve. How then, are we to protect ourselves from the spread of these devastating diseases?
Recently, a new method to wipe out infected mosquito larvae has been introduced. Countries have been using a natural toxin derived from bacteria to kill certain species of mosquito larvae. However, the toxin only affects specific species. By genetically modifying the toxin, we would be able to expand the effects of this toxin to other mosquito species and stop these diseases from spreading.
The larvicide, known as BinAB, is produced by soil-dwelling bacteria. The bacteria pack the toxic molecules into tiny crystals, making them inert. Organizations have harvested these crystals and spread them over water infested with mosquito larvae. Once the crystals are ingested by the larvae, they dissolve, releasing the BinAB toxin, which enters the larvae’s cells and kills them within 48 hours.
BinAB is a binary toxin made up of two proteins; BinB targets a receptor on the surface of intestinal cells, while BinA kills the cells through initiation of pore formation. Once the crystal dissolves in the larvae gut, BinA and BinB become separated through enzymatic digestion. BinB then binds to its receptor on the cell surface and aids BinA in entering the cell.
“The toxin is this complex shape, and it has to fit with another shape on the intestine of the larvae,” said Michael Sawaya, a staff scientist at UCLA involved in the study. “If the shapes don’t match up precisely, the toxin cannot get in the cell. It’s like a lock and key.”
While BinAB is fatal to the Anopheles and Culex species of mosquito that carry malaria and filariasis, respectively, the toxin is harmless to other insects and humans. This creates a strong environmental safety argument for BinAB, which is already used in many countries to regulate mosquito populations.
An international group led by UCLA researchers decided to investigate the molecular structure of BinAB. If the structure of BinAB is understood, the specific receptor on its surface that allows entry into Anopheles and Culex cells can be modified to allow entry into other species such as Aedes mosquitoes, which spread Dengue, Zika and chikungunya viruses.
The team used an X-ray free-electron laser developed by UCLA professor emeritus of physics Claudio Pellegrini to get a distinct X-ray beam pattern of the crystals. Based on the information gained from the crystallography experiments, researchers could determine the exact structure of the peptides and amino acids that comprised the receptor sites on the molecules. This structure was the first to be examined from such small crystals, and it was the first time a completely unknown structure was solved using this approach.
“When we shine X-rays on the crystals, the X-rays are scattered into thousands of X-ray beams,” said Eisenberg, who is also a professor of chemistry, biochemistry and biological chemistry and a member of UCLA’s California NanoSystems Institute. “These beams contain information about the arrangement of the atoms that make up BinA and BinB.”
With this new found information, there is the potential to genetically modify the receptors to work on the Aedes mosquito. This would create a toxin that could affect three of the most devastating mosquito species in the world. The new laser approach is also now expected to be applied to solving other small structures such as organelles.