November 30, 2015

Genetically Modifying Mosquitoes to Be Malaria-Resistant

Malaria is one of the world’s leading health problems. More than 40 percent of the world’s population live in areas where there is a risk of contracting the disease. According to the Centers for Disease Control and Prevention, 300 million to 500 million cases of malaria occur each year, and nearly 1 million people die of the disease annually – largely infants, young children and pregnant women, most of them in Africa. Although the disease can be treated, in some parts of the world—sub-Saharan Africa, in particular—the medicines needed are often unavailable. And worse, the parasite that causes malaria is becoming more and more resistant to the drugs we have to fight it.

Using a groundbreaking gene editing technique, University of California scientists have created a strain of mosquitoes capable of rapidly introducing malaria-blocking genes into a mosquito population through its progeny, ultimately eliminating the insects’ ability to transmit the disease to humans.


An Anopheles stephensi mosquito obtains a blood meal from a human host through its pointed proboscis. A known malarial vector, the species can found from Egypt all the way to China. Jim Gathany / CDC

This new model represents a notable advance in the effort to establish an antimalarial mosquito population, which with further development could help eradicate a disease that sickens millions worldwide each year.

To create this breed, researchers at the Irvine and San Diego campuses inserted a DNA element into the germ line of Anopheles stephensi mosquitoes that resulted in the gene preventing malaria transmission being passed on to an astonishing 99.5 percent of offspring. A. stephensi is a leading malaria vector in Asia.

The study underlines the growing utility of the Crispr method, a powerful gene editing tool that allows access to a cell’s nucleus to snip DNA to either replace mutated genes or insert new ones. Results appear this week in the early online edition of Proceedings of the National Academy of Sciences.

The UC Irvine team worked on the genome of Anopheles stephensi mosquitoes, which are a main vector of malaria in India, where there are more than 1 million cases annually and more than 500 deaths. There’s reason to believe the technique would work in other species as well,

PNAS - Plasmodium evasion of mosquito immunity and global malaria transmission: The lock-and-key theory



Significance

Plasmodium falciparum malaria originated in Africa but became global as humans migrated around the world. It is now transmitted by many different anopheline mosquito species, but little is known about the adaptation of Plasmodium to different vectors. Here, we show that the mosquito immune system is a major barrier for some P. falciparum isolates to infect mosquitoes from a different continent. Pfs47 is a protein that makes parasites “invisible” to the mosquito immune system. We found that parasites expressing a Pfs47 haplotype compatible with a given vector species can evade mosquito immunity. These findings suggest that Pfs47-mediated evasion of the mosquito immunity was critical for malaria globalization and may be a key target to disrupt disease transmission.

Abstract
Plasmodium falciparum malaria originated in Africa and became global as humans migrated to other continents. During this journey, parasites encountered new mosquito species, some of them evolutionarily distant from African vectors. We have previously shown that the Pfs47 protein allows the parasite to evade the mosquito immune system of Anopheles gambiae mosquitoes. Here, we investigated the role of Pfs47-mediated immune evasion in the adaptation of P. falciparum to evolutionarily distant mosquito species. We found that P. falciparum isolates from Africa, Asia, or the Americas have low compatibility to malaria vectors from a different continent, an effect that is mediated by the mosquito immune system. We identified 42 different haplotypes of Pfs47 that have a strong geographic population structure and much lower haplotype diversity outside Africa. Replacement of the Pfs47 haplotypes in a P. falciparum isolate is sufficient to make it compatible to a different mosquito species. Those parasites that express a Pfs47 haplotype compatible with a given vector evade antiplasmodial immunity and survive. We propose that Pfs47-mediated immune evasion has been critical for the globalization of P. falciparum malaria as parasites adapted to new vector species. Our findings predict that this ongoing selective force by the mosquito immune system could influence the dispersal of Plasmodium genetic traits and point to Pfs47 as a potential target to block malaria transmission. A new model, the “lock-and-key theory” of P. falciparum globalization, is proposed, and its implications are discussed.


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