Role of a patatin-like phospholipase in<i>Plasmodium falciparum</i>gametogenesis and malaria transmission

Singh, Pallavi; Alaganan, Aditi; More, Kunal R.; Lorthiois, Audrey; Thiberge, Sabine; Gorgette, Olivier; Blisnick, Micheline Guillotte; Guglielmini, Julien; Aguilera, Shivani Shankar; Touqui, Lhousseine; Singh, Shailja; Chitnis, Chetan E.

doi:10.1073/pnas.1900266116

Cited by 27 publications

(34 citation statements)

References 30 publications

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“…For example, upon PbPPLP2 deletion, male gametes can disrupt the PVM normally but fail to rupture the RBC membrane, thus forming a super‐flagellum, where multiple axonemes are sheathed together by the RBC membrane (Deligianni et al, 2013; Wirth et al, 2014). A phospholipase (PfPATPL1) has been found to be important for the re‐localization of the PPLP2‐containing vesicles, thus affecting gamete egress (Singh et al, 2019). Interestingly, the male OB‐associated protein PyMiGS in P. yoelii does not affect egress or formation of flagella, but it affects exflagellation (Tachibana et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

A conserved malaria parasite antigen Pb22 plays a critical role in male gametogenesis inPlasmodium berghei

Liu

Yang

Wang

et al. 2020

Cellular Microbiology

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Gametogenesis, the formation of gametes from gametocytes, an essential step for malaria parasite transmission, is targeted by transmission‐blocking drugs and vaccines. We identified a conserved protein (PBANKA_0305900) in Plasmodium berghei, which encodes a protein of 22 kDa (thus named Pb22) and is expressed in both asexual stages and gametocytes. Its homologues are present in all Plasmodium species and its closely related, Hepatocystis, but not in other apicomplexans. Pb22 protein was localised in the cytosols of schizonts, as well as male and female gametocytes. During gamete‐to‐ookinete development, Pb22 became localised on the plasma membranes of gametes and ookinetes. Compared to the wild‐type (WT) parasites, P. berghei with pb22 knockout (KO) showed a significant reduction in exflagellation (~89%) of male gametocytes and ookinete number (~97%) during in vitro ookinete culture. Mosquito feeding assays showed that ookinete and oocyst formation of the pb22‐KO line in mosquito midguts was almost completely abolished. These defects were rescued in parasites where pb22 was restored. Cross‐fertilisation experiments with parasite lines defective in either male or female gametes confirmed that the defects in the pb22‐KO line were restricted to the male gametes, whereas female gametes in the pb22‐KO line were fertile at the WT level. Detailed analysis of male gametogenesis showed that 30% of the male gametocytes in the pb22‐KO line failed to assemble the axonemes, whereas ~48.9% of the male gametocytes formed flagella but failed to egress from the host erythrocyte. To explore its transmission‐blocking potential, recombinant Pb22 (rPb22) was expressed and used to immunise mice. in vitro assays showed that the rPb22‐antisera significantly inhibited exflagellation by ~64.8% and ookinete formation by ~93.4%. Mosquitoes after feeding on rPb22‐immunised mice also showed significant decreases in infection prevalence (83.3–93.3%) and oocyst density (93.5–99.6%). Further studies of the Pb22 orthologues in human malaria parasites are warranted.

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Section: Discussionmentioning

confidence: 99%

A conserved malaria parasite antigen Pb22 plays a critical role in male gametogenesis inPlasmodium berghei

Liu

Yang

Wang

et al. 2020

Cellular Microbiology

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“…In case of PLA2, it is an important energy source enzyme and crucial in the development of Clonorchis sinensis mediated hepatic fibrosis 61 . PLA2 has been reported its role on membrane remodelling and vesicle secretion in several organisms for example P. falciparum 62 and Leishmania amazonensis 63 . Plasmodial PLA2 involves the egress of merozoites from liver-stage schizonts 64 and merozoite invasion of red blood cells 58 .…”

Section: Discussionmentioning

confidence: 99%

Lipid profile of Trichinella papuae muscle-stage larvae

Mangmee

Adisakwattana

Tipthara

et al. 2020

Sci Rep

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Outbreaks of trichinellosis caused by Trichinella papuae have been reported in SouthEast Asia. Mebendazole and thiabendazole are the treatments of choice for trichinellosis; however, both drugs result in significant side effects and are less effective for muscle-stage larvae (L1). An alternative therapeutic agent is needed to improve treatment. Information on lipid composition and metabolic pathways may bridge gaps in our knowledge and lead to new antiparasitics. The T. papuae L1 lipidome was analysed using a mass spectrometry-based approach, and 403 lipid components were identified. Eight lipid classes were found and glycerophospholipids were dominant, corresponding to 63% of total lipids, of which the glycerolipid DG (20:1[11Z]/22:4[7Z,10Z,13Z,16Z]/0:0) (iso2) was the most abundant. Overall, 57% of T. papuae lipids were absent in humans; therefore, lipid metabolism may be dissimilar in the two species. Proteins involved T. papuae lipid metabolism were explored using bioinformatics. We found that 4-hydroxybutyrate coenzyme A transferase, uncharacterized protein (A0A0V1MCB5) and ML-domain-containing protein are not present in humans. T. papuae glycerophospholipid metabolic and phosphatidylinositol dephosphorylation processes contain several proteins that are dissimilar to those in humans. These findings provide insights into T. papuae lipid composition and metabolism, which may facilitate the development of novel trichinellosis treatments. Trichinella is a genus of parasitic roundworms that cause trichinosis, also known as trichinellosis, which infect domestic and sylvatic animals. The number of global outbreaks appears to have sharply increased, reflecting changes in the parasites' epidemiology 1. In SouthEast Asia, outbreaks of trichinellosis caused by T. papuae occurred in 2006 2 and 2007 3. T. papuae, which belongs to the non-encapsulated trichinella clade, lives predominantly in tropical rainforests 4. Ingestion of raw meat containing parasite cysts leads to infection, and the larvae released from adult females invade host muscles resulting in trichinellosis pathology. Common symptoms are eye puffiness, splinter haemorrhaging, nonspecific gastroenteritis, and muscle pain 5. Trichinosis treatment is based on anti-inflammatory drugs and anthelmintics, such as mebendazole and albendazole 6 ; however, the effectiveness of anthelmintic treatment is an issue of debate. In the treatment of myositis during a trichinellosis outbreak in Thailand, mebendazole and thiabendazole were found to be more efficient than placebo or fluconazole. However, 30% of volunteers could not tolerate the side effects of thiabendazole 7. In addition, in a trial during an outbreak in Italy, between 3% and 45% of patients had a recurrence of various symptoms after a 10-day mebendazole course 8. Generally, anthelmintic therapy is only considered effective during the intestinal phase of infection, and the drug has poor drug effectiveness in the muscle phase 9. To improve the effectiveness of the treatment, an alternative therapeutic agent may...

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“…Such changes in phospholipid compositions have had been observed in the PNPLA1-KO lines.PNPLA1 is one of four PNPLAs identified in P. falciparum, and, to date, only for PNPLA1 functional data were collected. In a recent publication,Singh et al (2019) reported a role for PNPLA1 (termed PATPL1 in this study) in malaria transmission. In accord with our data, the authors detected PNPLA1/ PATPL1 in the cytosol of the asexual and sexual blood stages of P. falciparum.…”

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confidence: 55%

A patatin‐like phospholipase functions during gametocyte induction in the malaria parasite Plasmodium falciparum

Flammersfeld

Panyot

Yamaryo‐Botté

et al. 2019

Cellular Microbiology

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Patatin-like phospholipases (PNPLAs) are highly conserved enzymes of prokaryotic and eukaryotic organisms with major roles in lipid homeostasis. The genome of the malaria parasite Plasmodium falciparum encodes four putative PNPLAs with predicted functions during phospholipid degradation. We here investigated the role of one of the plasmodial PNPLAs, a putative PLA 2 termed PNPLA1, during blood stage replication and gametocyte development. PNPLA1 is present in the asexual and sexual blood stages and here localizes to the cytoplasm. PNPLA1-deficiency due to gene disruption or conditional gene-knockdown had no effect on intraerythrocytic growth, gametocyte development and gametogenesis. However, parasites lacking PNPLA1 were impaired in gametocyte induction, while PNPLA1 overexpression promotes gametocyte formation. The loss of PNPLA1 further leads to transcriptional downregulation of genes related to gametocytogenesis, including the gene encoding the sexual commitment regulator AP2-G. Additionally, lipidomics of PNPLA1-deficient asexual blood stage parasites revealed overall increased levels of major phospholipids, including phosphatidylcholine (PC), which is a substrate of PLA 2 . PC synthesis is known to be pivotal for erythrocytic replication, while the reduced availability of PC precursors drives the parasite into gametocytogenesis; we thus hypothesize that the higher PC levels due to PNPLA1-deficiency prevent the blood stage parasites from entering the sexual pathway. K E Y W O R D Smalaria, Plasmodium falciparum, gametocyte induction, patatin-like phospholipase, sexual commitment, phosphatidylcholine

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Role of a patatin-like phospholipase inPlasmodium falciparumgametogenesis and malaria transmission

Cited by 27 publications

References 30 publications

A conserved malaria parasite antigen Pb22 plays a critical role in male gametogenesis inPlasmodium berghei

A conserved malaria parasite antigen Pb22 plays a critical role in male gametogenesis inPlasmodium berghei

Lipid profile of Trichinella papuae muscle-stage larvae

A patatin‐like phospholipase functions during gametocyte induction in the malaria parasite Plasmodium falciparum

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