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

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. malaria globalization | immune evasion | anopheles immunity | Plasmodium selection | Pfs47

Mosquito Vectors and the Globalization of Plasmodium falciparum Malaria

“…Sequence analysis of Pfs47 from many different isolates collected around the world indicates that although the predicted proteins have very high protein sequence identity (approximately 99%), multiple haplotypes are present (55). Furthermore, analysis of the geographic distribution of Pfs47 has revealed striking differences between continents (55), in agreement with previous reports (2,51).…”

“…This study showed that mosquito vectors from Africa (A. gambiae), Asia (Anopheles dirus), and the Americas (A. albimanus) are highly susceptible to infection by P. falciparum isolates from the same region, but they suffer limited infection by isolates from a different continent. The study also indicated that the differences in compatibility are determined by the mosquito immune system (55). These findings raise the question of why different mosquito species are susceptible to infection with different parasite lines.…”

“…A total of 42 Pfs47 haplotypes were identified based on the predicted full-length protein of 364 different isolates. The majority of African haplotypes (30/34) never migrated to another continent, whereas two different minor haplotypes in Africa have the widest circulation in Asia and the Americas, respectively (55). In general, the reduced genetic diversity of P. falciparum outside Africa is thought to be due to genetic drift and population bottlenecks.…”

“…To test this hypothesis, colonized anopheline mosquitoes that are major malaria vectors in three different continents were infected with gametocyte cultures of P. falciparum lines from different regions (55). This made it possible to compare each line's infectivity for different mosquito vectors and to evaluate the effect of the mosquito immune system on compatibility in different parasite-mosquito combinations.…”

Mosquito vectors of ape malarias: Another piece of the puzzle

“…albimanus, are selecting the P. vivax populations circulating in the highlands and coastal areas in southern Mexico, respectively (13). Moreover, recent studies indicate that the immune system of some anopheline mosquito species can select the P. falciparum parasites circulating in a given geographic region (14).…”