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

Molina-Cruz A1, Canepa GE2, Kamath N2, Pavlovic NV2, Mu J2, Ramphul UN2, Ramirez JL2, Barillas-Mury C1.
Source: Proc Natl Acad Sci USA
Publication Date: (2015)
Issue: 49: 15178(83)
Research Area:
Cells used in publication:
Plasmodium falciparum
Species: unicellular
Tissue Origin:
4D-Nucleofector™ X-Unit
Briefly, the transfection mixture consisting of 20 µL of packed RBCs, 5 µg of each plasmid DNA (1 µg/µL) (Qiagen plasmid Maxiprep kit), and of 70 µL of Amaxa SE solution, resulting in a final volume of 100 µL, was prepared at room temperature (RT). The transfection mixture was transferred to an Amaxa Nucleocuvette (Lonza), and transfections were performed at RT using an Amaxa 4D-Nucleofector. After applying the CM-162 pulse, electroporated RBCs were processed as mentioned above. Culture media were changed daily and selection drugs (2.5 µM Blasticidin HCl and 200 µg/mL Geneticin) were added 24 h after electroporation and maintained continuously in the asexual cultures, unless stated otherwise. Once parasites were observed (day 18), parasites were cloned by minimal dilution in 96-well plates.
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.