Non - malaria mosquitoes
Transgenic malaria mosquitoes die before they become contagious
Maxim Chubik, PCR.news
Malaria is one of the most common and deadly infectious diseases. Every year, at least 500 thousand deaths from this infection are registered in the world. So, in 2021, 241 million people were infected with malaria, 627 thousand of them died. The majority of deaths occur in children under the age of five. The countries of sub-Saharan Africa are particularly affected by malaria.
Biologists from Imperial College London, with the support of the Institute for Disease Modeling of the Bill and Melinda Gates Foundation, have created a transgenic malaria mosquito Anopheles gambiae. The intestines of modified mosquitoes slow down the growth of malaria plasmodium, so that the parasites do not have time to migrate to the salivary glands of insects.
Anopheles gambiae is the main species of malaria—carrying mosquitoes in sub-Saharan Africa. According to statistics, only 10% of mosquitoes live long enough for the parasite to grow in them. Malarial plasmodia take 10 to 12 days to develop inside the mosquito's intestines. Then the sporozoites exit the mature oocysts and begin to migrate to the salivary glands.
At the same time in the wild Anopheles gambiae usually live only 10 days. The authors of the study decided to further increase the time required for plasmodia to develop in the intestine. As a result of genetic modification, it significantly increases the likelihood that mosquitoes will die of natural causes before the parasites get into their salivary glands and the insect becomes contagious to humans.
"For many years, we have been trying to create mosquitoes that cannot be infected with the parasite, or mosquitoes with an immune system capable of suppressing plasmodium, to no avail. Delaying the development of a parasite inside a mosquito is a conceptual shift that has opened up much more opportunities to block the transmission of malaria from mosquitoes to humans," says study co—author Dr. Astrid Hormann.
The authors injected into the eggs Anopheles gambiae plasmids encoding two antimicrobial peptides (AMP): magainin 2 and melittin. Magainin 2 was found in the skin secretions of the African spur frog Xenopus laevis, and melittin is the main toxic component of the venom of the honey bee Apis mellifera. A helper plasmid encoding Cas9 was also injected. The sequence encoding peptides was embedded in a mosquito gene encoding an enzyme localized in the midgut of a malaria mosquito. (Constructs in two different host genes were tried.) These enzymes are expressed when blood enters the intestines of a mosquito, thus, AMP synthesis was also included. They were separated from the host protein due to the addition of 2A peptides to the structure, self-cutting from the protein sequence, and were provided with a secretion signal. Thus, the intestine of a transgenic mosquito, after it was pumped with blood, began to secrete peptides that inhibit the development of plasmodia. Both magainin 2 and melittin disrupt the mitochondrial function and energy metabolism of parasites in the mosquito's body.
This small genetic modification inhibited the development of oocysts in two types of malaria parasite: the most dangerous for humans Plasmodium falciparum and the rodent parasite Plasmodium berghei. The release of active sporozoites is delayed for several days, and it is expected that by this time most mosquitoes will have already died in natural conditions. In addition, AMP shortens the lifespan of female transgenic mosquitoes by two days.
The project team believes that the approach of inhibiting the development of the parasite inside the mosquito has great prospects, but for this genetic modification must be distributed among wild mosquitoes. Conventional crossbreeding may not solve the problem: since modification shortens the insect's lifespan, it is likely to be eliminated quickly during natural selection.
To prevent this from happening, the authors use the previously developed technology of gene drive, which theoretically allows modifying all wild populations of malaria mosquitoes. The gene drive will force antiparasitic genetic modification to spread in the population, even if it is biologically unprofitable. (The embedded construct is copied to other parts of the genome using Cas nuclease and guide RNA.) However, the researchers acknowledged that their strategy would require careful planning to minimize any risks before field trials could begin.
Computer modeling shows that the spread of modified insects in populations of Anopheles gambiae can break the cycle of disease transmission and completely stop the spread of pathogenic plasmodia if the number of infectious bites is small. With more intensive transmission of infection, additional measures will be needed, but even in this case, the use of transgenic mosquitoes will give a head start for their deployment.
Article by Hoermann et al. Gene drive mosquitoes can aid malaria elimination by retarding Plasmodium sporogonic development is published in the journal Science Advances.
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