Type II Fatty Acid Biosynthesis Is Essential for Plasmodium falciparum Sporozoite Development in the Midgut of Anopheles Mosquitoes

Abstract

The prodigious rate at which malaria parasites proliferate during asexual blood-stage replication, midgut sporozoite production, and intrahepatic development creates a substantial requirement for essential nutrients, including fatty acids that likely are necessary for parasite membrane formation. Plasmodium parasites obtain fatty acids either by scavenging from the vertebrate host and mosquito vector or by producing fatty acids de novo via the type two fatty acid biosynthesis pathway (FAS-II). Here, we study the FAS-II pathway in Plasmodium falciparum, the species responsible for the most lethal form of human malaria. Using antibodies, we find that the FAS-II enzyme FabI is expressed in mosquito midgut oocysts and sporozoites as well as liver-stage parasites but not during the blood stages. As expected, FabI colocalizes with the apicoplast-targeted acyl carrier protein, indicating that FabI functions in the apicoplast. We further analyze the FAS-II pathway in Plasmodium falciparum by assessing the functional consequences of deleting fabI and fabB/F. Targeted deletion or disruption of these genes in P. falciparum did not affect asexual blood-stage replication or the generation of midgut oocysts; however, subsequent sporozoite development was abolished. We conclude that the P. falciparum FAS-II pathway is essential for sporozoite development within the midgut oocyst. These findings reveal an important distinction from the rodent Plasmodium parasites P. berghei and P. yoelii, where the FAS-II pathway is known to be required for normal parasite progression through the liver stage but is not required for oocyst development in the Anopheles mosquito midgut.

Functional Characterization of Anopheles Matrix Metalloprotease 1 Reveals Its Agonistic Role during Sporogonic Development of Malaria Parasites

“…Unfortunately, very little is known regarding this stage of the parasite's life cycle. Most reports refer to metabolic needs of the parasite during sporogonic development (82)(83)(84)(85). Although proposed (69), there are no data supporting the idea that mosquito molecules could function as developmental triggers for ookinete-to-oocyst transition.…”

Distinct Prominent Roles for Enzymes of Plasmodium berghei Heme Biosynthesis in Sporozoite and Liver Stage Maturation

“…The majority of apicoplast-localized proteins appear to be essential either for blood infection (e.g., key enzymes of [Fe-S] biosynthesis [45]) or during liver stage development (e.g., pyruvate dehydrogenase [PDH] [46], Plasmodiumspecific apicoplast protein important for liver merozoite formation [PALM] [43], and enzymes of phosphatidic acid biosynthesis [47]). Together with FABI and FABB/F of the fatty acid biosynthesis pathway (48), PBGD and UROD are the first apicoplast proteins with distinct essential functions during vector stage development, highlighting the specific roles of apicoplast metabolism at various phases in the complex life cycle.…”

Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum

“…The apicoplast supports three metabolic functions: type II fatty acid biosynthesis, de novo heme biosynthesis, and isoprenoid biosynthesis. Type II fatty acid and de novo heme biosynthesis are not essential during the asexual and gametocyte intraerythrocytic stages when parasites scavenge lipids and heme from the human host (15)(16)(17); however, both of these biosynthetic pathways are essential for development of liver and mosquito stages of the parasite (15)(16)(17)(18)(19)(20). In contrast, biosynthesis of the isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) is the essential metabolic function of the apicoplast in the asexual intraerythrocytic stages (21).…”