Type II fatty acid synthesis is essential only for malaria parasite late liver stage development

Abstract

SummaryIntracellular malaria parasites require lipids for growth and replication. They possess a prokaryotic type II fatty acid synthesis (FAS II) pathway that localizes to the apicoplast plastid organelle and is assumed to be necessary for pathogenic blood stage replication. However, the importance of FAS II throughout the complex parasite life cycle remains unknown. We show in a rodent malaria model that FAS II enzymes localize to the sporozoite and liver stage apicoplast. Targeted deletion of FabB/F, a critical enzyme in fatty acid synthesis, did not affect parasite blood stage replication, mosquito stage development and initial infection in the liver. This was confirmed by knockout of FabZ, another critical FAS II enzyme. However, FAS II-deficient Plasmodium yoelii liver stages failed to form exo-erythrocytic merozoites, the invasive stage that first initiates blood stage infection. Furthermore, deletion of FabI in the human malaria parasite Plasmodium falciparum did not show a reduction in asexual blood stage replication in vitro. Malaria parasites therefore depend on the intrinsic FAS II pathway only at one specific life cycle transition point, from liver to blood.

Triclosan inhibit the growth of the late liver‐stage of Plasmodium

“…We hypothesize that fatty acid biosynthesis is one of the limiting factors in the liver-stage parasite growth. Our hypothesis is also supported by the recent findings (22,23).…”

“…The other enzymes of FAS-II pathway Fab B/F, and FabZ knockout in P. yoelii, lead to normal parasite (blood stage) development but completely fail to form infective merozoites during the liver-stage growth (22). These studies (22,23) also highlighted the importance of FAS-II pathway enzymes during the development of late liver-stage parasites as the early stages of liver parasites show normal development (22,23). Together FAS-II gene disruption data appear to make a compelling case for the importance of de novo fatty acid biosynthesis in the successful production of thousands of infectious merozoites produced per liver schizont.…”

“…Zhou et al (21) predicted that the liver-stage parasites might also be prone to inhibitors that interfere with Type-II fatty acid biosynthesis. Recent knockout (of FAS-II enzymes) studies further support the importance of this pathway in the development of liver-stage parasites (22,23).…”

Phospholipases during membrane dynamics in malaria parasites

“…Plasmodium can also synthesize FAs de novo via the fatty acid synthase II (FASII) pathway located in the apicoplast, a relict plastid of algal origin that arose through secondary endosymbiosis (e.g reviewed in van Dooren and Striepen, 2013). FA synthesis via FASII, though, occurs primarily in the mosquito-resident and intrahepatic stages (van Schaijk et al, 2014;Vaughan et al, 2009;Yu et al, 2008).…”

Role of phosphatidic acid in plant galactolipid synthesis

“…Attempt to disrupt PfGPAT were unsuccessful suggesting an essential role of the protein. Regarding the apicoplast lipid synthesis pathway, it is well established that the prokaryotic type II fatty acid synthesis (FASII) is essential for Apicomplexa [42,43]. Homologues of chloroplast ATS1 and ATS2, PfATS1 and PfATS2, were predicted as apicoplast proteins in P. falciparum [39].…”