Plasmodium falciparum evades immunity of anopheline mosquitoes by interacting with a Pfs47 midgut receptor

Abstract

The surface protein Pfs47 allows Plasmodium falciparum parasites to survive and be transmitted by making them “undetectable” to the mosquito immune system. P. falciparum parasites express Pfs47 haplotypes compatible with their sympatric vectors, while those with incompatible haplotypes are eliminated by the mosquito. We proposed that Pfs47 serves as a “key” that mediates immune evasion by interacting with a mosquito receptor “the lock,” which differs in evolutionarily divergent anopheline mosquitoes. Recombinant Pfs47 (rPfs47) was used to identify the mosquito Pfs47 receptor protein (P47Rec) using far-Western analysis. rPfs47 bound to a single 31-kDa band and the identity of this protein was determined by mass spectrometry. The mosquito P47Rec has two natterin-like domains and binds to Pfs47 with high affinity (17 to 32 nM). P47Rec is a highly conserved protein with submicrovillar localization in midgut cells. It has structural homology to a cytoskeleton-interacting protein and accumulates at the site of ookinete invasion. Silencing P47Rec expression reduced P. falciparum infection, indicating that the interaction of Pfs47 with the receptor is critical for parasite survival. The binding specificity of P47Rec from distant anophelines (Anopheles gambiae, Anopheles dirus, and Anopheles albimanus) with Pfs47-Africa (GB4) and Pfs47-South America (7G8) haplotypes was evaluated, and it is in agreement with the previously documented compatibility between P. falciparum parasites expressing different Pfs47 haplotypes and these three anopheline species. Our findings give further support to the role of Pfs47 in the adaptation of P. falciparum to different vectors.

Genetic Markers of Adaptation of Plasmodium falciparum to Transmission by American Vectors Identified in the Genomes of Parasites from Haiti and South America

“…∼100 million years ago ( 17 ). Evidence has recently emerged regarding the impact that novel vectors have had on the Pfs47 gene ( 31 – 34 , 39 , 40 ). Allelic changes in Pfs47 partially control infectivity for different vectors, suggesting that this and perhaps additional genes are under selection during adaptation to novel vector species.…”

“…Further, evidence has recently emerged regarding the impact that the immune systems of novel vectors have had on the parasite genome. Key mutations in the Pfs47 gene allow P. falciparum to escape the complement-like immune system of its definitive host, where different optimal combinations of the amino acid substitutions are necessary for the successful infection of vector species in different regions of the world ( 31 – 34 , 39 , 40 ). The crucial role of this gene product was first identified through linkage analysis of the progeny of a cross between GB4 (an African isolate) and 7G8 (a Brazilian isolate).…”

Nanobody generation and structural characterization ofPlasmodium falciparum6-cysteine protein Pf12p

“…falciparum, there are 14 members in the 6-cys protein family and they share a common structural feature, the 6-cys domain or otherwise referred to as the s48/45 domain. In general, the 6-cys proteins interact with specific human or mosquito proteins for entry into host tissues or to evade the host immune response to promote survival of the malaria parasites [3][4][5][6].…”

“…Through its interaction with a specific mosquito midgut receptor protein, Pfs47 is involved in a lock and key model that drives host tropism between parasite and mosquito [6]. Pf52 and Pf36 are present on the surface of sporozoites and are crucial for invasion of hepatocytes and the formation of a parasitophorous vacuole that envelopes the growing parasite.…”

A Plasmodium key fits a mosquito lock

“…With the "key" identified (Pfs47), the next question was, What is the "lock" in which the key fits? This is the subject of the article by Molina-Cruz et al in PNAS (3). The premise that the Pfs47 protein interacts with a cellular component of the mosquito midgut epithelium was tested by fractionating midgut proteins on a polyacrylamide gel, transferring them to a membrane, and incubating this membrane with a recombinant Pfs47 (rPfs47).…”