Molecular Analysis of Pfs47-Mediated Plasmodium Evasion of Mosquito Immunity

Malaria is a life-threatening disease caused by Plasmodium falciparum parasites that is transmitted through the bites of infected anopheline mosquitoes. P. falciparum dispersal from Africa, as a result of human migration, required adaptation of the parasite to several different indigenous anopheline species. The mosquito immune system can greatly limit infection and P. falciparum evolved a strategy to evade these responses that is mediated by the Pfs47 gene. Pfs47 is a polymorphic gene with signatures of diversifying selection and a strong geographic genetic structure at a continental level. Here, we investigated the role of single four amino acid differences between the Pfs47 gene from African (GB4 and NF54) and a New World (7G8) strains that differ drastically in their ability to evade the immune system of A. gambiae L35 refractory mosquitoes. Wild type NF54 and GB4 parasites can survive in this mosquito strain, while 7G8 parasites are eliminated. Our studies indicate that replacement in any of these four single amino acids in Pfs47 from the NF54 strain by those present in 7G8, completely disrupts the ability of NF54 parasites to hide from the mosquito immune system. One of these amino acid replacements had the opposite effect on A. albimanus mosquitoes, and enhanced infection. We conclude that malaria transmission involves a complex interplay between the genetic background of the parasite and the mosquito and that Pfs47 can be critical in this interaction as it mediates Plasmodium immune evasion through molecular interactions that need to be precise in some parasite/vector combinations.