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To battle mosquito-borne disease, SLAC x-ray laser provides new view of insecticides

lcls_insecticide_v02Mosquitoes continue to spread devastating diseases such as malaria, West Nile virus, dengue fever and Zika virus throughout the world. There are no medications or vaccines for many of these deadly diseases, so it’s critical to prevent mosquito bites.

A cost effective way to eliminate these disease-bearing insects is to use specialized insecticides that target the larval stage of a mosquito. These larvicides, like BinAB, kill some mosquito species, but they are currently ineffective against Aedes mosquitoes that transmit Zika and dengue fever. Now, an international team of researchers is working to develop a new toxin that will kill a broader range of mosquito species, including Aedes.

The existing larvicide BinAB is composed of two proteins, BinA and BinB, which pair together to form nanocrystals inside Lysinibacillus sphaericus soil bacteria. When these bacteria are distributed on the surface of stagnant water locations where mosquitoes breed, the mosquito larvae eat the bacteria — dissolving the nanocrystals that bind to their gut, activating the deadly BinAB toxin and killing the larvae.

The proteins are toxic to the mosquitoes, but harmless to humans and other animals. Unfortunately, previous research has shown that BinAB is also harmless to an Aedes mosquito, because the protein never binds to the insect’s gut so the toxin isn’t activated.

“Part of the appeal is that the larvicide’s safe because it’s so specific, but that’s also part of its limitation,” said Michael Sawaya, PhD, a scientist at the University of California, Los Angeles-Department of Enery Molecular Biology Institute, in a recent news release.

Now, the researchers are adapting the BinAB toxin to attack mosquito species that are insecticide resistant. In order to do this, they needed to understand the 3-D structure of the BinAB proteins and how they work. This was a challenge, because the nanocrystals were so tiny and their structural details were a mystery.

The research team increased the size of the nanocrystals using genetic engineering, and then blasted them with an intense beam of bright, fast pulses of light using the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory. This allowed the team to collect detailed structural data from the tiny crystals and create 3-D maps of the electron density of the BinAB protein, as reported in a recent paper in Nature.

The LCLS experiments helped the researchers fully understand how the BinAB protein forms and functions. They are now engineering a modified version of the protein that will kill a broader range of mosquito species.

“The most immediate need is to now expand the spectrum of action of the BinAB toxin to counter the progression of Zika, in particular,” said Jacques-Philippe Colletier, PhD, a scientist at the Institut de Biologie Structurale in France, in the news release. “BinAB is already effective against Culex [carrier of West Nile encephalitis] and Anopheles [carrier of malaria] mosquitoes. With the results of the study, we now feel more confident that we can design the protein to target Aedes mosquitoes.”

Previously: Zika’s effect on developing cranial neural crest cells shown by new Stanford study and Zika is just one of many tropical viruses headed our way, says Stanford expert
Illustration, of LCLS x-ray pulses blasting BinAB nanocrystals composed of protein BinA (yellow) and BinB (blue), courtesy of SLAC National Accelerator Laboratory

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