Lipid droplets of protozoan parasites: survival and pathogenicity

Lipid droplets (LDs; lipid bodies) are intracellular sites of lipid storage and metabolism present in all cell types. Eukaryotic LDs are involved in eicosanoid production during several inflammatory conditions, including infection by protozoan parasites. In parasites, LDs play a role in the acquisition of cholesterol and other neutral lipids from the host. The number of LDs increases during parasite differentiation, and the biogenesis of these organelles use specific signaling pathways involving protein kinases. In addition, LDs are important in cellular protection against lipotoxicity. Recently, these organelles have been implicated in eicosanoid and specialised lipid metabolism. In this article, we revise the main functions of protozoan parasite LDs and discuss future directions in the comprehension of these organelles in the context of pathogen virulence.

Key words:
lipid droplet; lipid bodies; protozoan; parasites; oxidative stress; lipid metabolism; eicosanoid

Authorship

Victor de Souza Tavares

Universidade Federal do Oeste da Bahia, Centro das Ciências Biológicas e da Saúde, Núcleo de Estudos de Agentes Infecciosos e Vetores, Barreiras, BA, BrasilUniversidade Federal do Oeste da BahiaBrasilBarreiras, BA, BrasilUniversidade Federal do Oeste da Bahia, Centro das Ciências Biológicas e da Saúde, Núcleo de Estudos de Agentes Infecciosos e Vetores, Barreiras, BA, Brasil

Monara Viera de Castro

Rayane da Silva Oliveira Souza

Iana Kátia Araújo Gonçalves

Jonilson Berlink Lima

Fundação Oswaldo Cruz-Fiocruz, Instituto Gonçalo Moniz, Laboratório de Inflamação e Biomarcadores, Salvador, BA, BrasilFundação Oswaldo Cruz-FiocruzBrasilSalvador, BA, BrasilFundação Oswaldo Cruz-Fiocruz, Instituto Gonçalo Moniz, Laboratório de Inflamação e Biomarcadores, Salvador, BA, Brasil

Valéria de Matos Borges

Théo Araújo-Santos ⁺+ Corresponding author: theo.santos@ufob.edu.br

http://orcid.org/0000-0001-9861-6660

+ Corresponding author: theo.santos@ufob.edu.br

VST, MVC, RSOS, JB-L, IKGA, VMB and TA-S wrote different sections, edited, and reviewed the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Figures | Tables

Figures (1)
Tables (2)

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Schematic representation of interaction between lipid droplet (LD) and protozoan organelles. Schematic drawing on transmission electron microscopy illustrating the interaction lipid droplets, outer nuclear envelop membrane, and kinetoplast. Lipid droplet is responsible to storage and metabolise cholesteryl ester, fatty acids,¹⁰10. Quittnat F, Nishikawa Y, Stedman TT, Voelker DR, Choi J-Y, Zahn MM, et al. On the biogenesis of lipid bodies in ancient eukaryotes: synthesis of triacylglycerols by a Toxoplasma DGAT1-related enzyme. Mol Biochem Parasitol. 2004; 138(1): 107-22.^,²⁴24. Toledo DAM, Roque NR, Teixeira L, Milán-Garcés EA, Carneiro AB, Almeida MR, et al. Lipid body organelles within the parasite Trypanosoma cruzi: a role for intracellular arachidonic acid metabolism. PLoS One. 2016; 11(8): e0160433.^,²⁷27. Araújo-Santos T, Rodríguez NE, Moura-Pontes S, Dixt UG, Abánades DR, Bozza PT, et al. Role of prostaglandin F2a production in lipid bodies from Leishmania infantum chagasi: insights on virulence. J Infect Dis. 2014; 210(12): 1951-61. and lipid mediators and their precursors, such as PGE₂,²⁴24. Toledo DAM, Roque NR, Teixeira L, Milán-Garcés EA, Carneiro AB, Almeida MR, et al. Lipid body organelles within the parasite Trypanosoma cruzi: a role for intracellular arachidonic acid metabolism. PLoS One. 2016; 11(8): e0160433. but the presence of specialised lipids such as resolvins, and their precursors are still uncertain. In addition, LDs participate from the lipid traffic between intracellular organelles. Note the proximity of the outer nuclear envelop membrane and outer kinetoplast membranes to the LD hemi-membrane. TEM from Leishmania amastigote. Toxoplasma gondii and Trypanosoma cruzi also present LD interactions with mitochondria and endoplasmic reticulum.¹⁰10. Quittnat F, Nishikawa Y, Stedman TT, Voelker DR, Choi J-Y, Zahn MM, et al. On the biogenesis of lipid bodies in ancient eukaryotes: synthesis of triacylglycerols by a Toxoplasma DGAT1-related enzyme. Mol Biochem Parasitol. 2004; 138(1): 107-22.^,¹⁵15. Pereira MG, Visbal G, Costa TFR, Frases S, de Souza W, Atella G, et al. Trypanosoma cruzi epimastigotes store cholesteryl esters in lipid droplets after cholesterol endocytosis. Mol Biochem Parasitol. 2018; 224(3): 6-16.

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TABLE I
Functions and presumable composition of lipid droplets in the protozoa parasites

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TABLE II
Lipid mediators, precursors and their metabolism enzymes identified in protozoan pathogens

Schematic representation of interaction between lipid droplet (LD) and protozoan organelles. Schematic drawing on transmission electron microscopy illustrating the interaction lipid droplets, outer nuclear envelop membrane, and kinetoplast. Lipid droplet is responsible to storage and metabolise cholesteryl ester, fatty acids,¹⁰10. Quittnat F, Nishikawa Y, Stedman TT, Voelker DR, Choi J-Y, Zahn MM, et al. On the biogenesis of lipid bodies in ancient eukaryotes: synthesis of triacylglycerols by a Toxoplasma DGAT1-related enzyme. Mol Biochem Parasitol. 2004; 138(1): 107-22.^,²⁴24. Toledo DAM, Roque NR, Teixeira L, Milán-Garcés EA, Carneiro AB, Almeida MR, et al. Lipid body organelles within the parasite Trypanosoma cruzi: a role for intracellular arachidonic acid metabolism. PLoS One. 2016; 11(8): e0160433.^,²⁷27. Araújo-Santos T, Rodríguez NE, Moura-Pontes S, Dixt UG, Abánades DR, Bozza PT, et al. Role of prostaglandin F2a production in lipid bodies from Leishmania infantum chagasi: insights on virulence. J Infect Dis. 2014; 210(12): 1951-61. and lipid mediators and their precursors, such as PGE₂,²⁴24. Toledo DAM, Roque NR, Teixeira L, Milán-Garcés EA, Carneiro AB, Almeida MR, et al. Lipid body organelles within the parasite Trypanosoma cruzi: a role for intracellular arachidonic acid metabolism. PLoS One. 2016; 11(8): e0160433. but the presence of specialised lipids such as resolvins, and their precursors are still uncertain. In addition, LDs participate from the lipid traffic between intracellular organelles. Note the proximity of the outer nuclear envelop membrane and outer kinetoplast membranes to the LD hemi-membrane. TEM from Leishmania amastigote. Toxoplasma gondii and Trypanosoma cruzi also present LD interactions with mitochondria and endoplasmic reticulum.¹⁰10. Quittnat F, Nishikawa Y, Stedman TT, Voelker DR, Choi J-Y, Zahn MM, et al. On the biogenesis of lipid bodies in ancient eukaryotes: synthesis of triacylglycerols by a Toxoplasma DGAT1-related enzyme. Mol Biochem Parasitol. 2004; 138(1): 107-22.^,¹⁵15. Pereira MG, Visbal G, Costa TFR, Frases S, de Souza W, Atella G, et al. Trypanosoma cruzi epimastigotes store cholesteryl esters in lipid droplets after cholesterol endocytosis. Mol Biochem Parasitol. 2018; 224(3): 6-16.

TABLE I Functions and presumable composition of lipid droplets in the protozoa parasites

Species	Roles of LD	Components	References
Leishmania infantum	Virulence Eicosanoid metabolism Lipid traffic and organelle membrane interactions	Prostaglandin F2 α synthase, and Arachidonic Acid*	Araújo-Santos et al.²⁷27. Araújo-Santos T, Rodríguez NE, Moura-Pontes S, Dixt UG, Abánades DR, Bozza PT, et al. Role of prostaglandin F2a production in lipid bodies from Leishmania infantum chagasi: insights on virulence. J Infect Dis. 2014; 210(12): 1951-61.
Leishmania amazonensis	Increase during cell death induced by oxidative stress	Undetermined	da Silva Rodrigues et al.¹⁹19. Rodrigues JHS, Miranda N, Volpato H, Ueda-Nakamura T, Nakamura CV. The antidepressant clomipramine induces programmed cell death in Leishmania amazonensis through a mitochondrial pathway. Parasitol Res. 2019; 118(3): 977-89.
Toxoplasma gondii	Cholesterol, DAG, and TAG metabolism Storage of neutral lipids	Cholesterol, TAG, and DAG molecules TgACAT1, TgACAT2, TgDGAT, and Tglipin enzymes^#	Quittnat et al.¹⁰10. Quittnat F, Nishikawa Y, Stedman TT, Voelker DR, Choi J-Y, Zahn MM, et al. On the biogenesis of lipid bodies in ancient eukaryotes: synthesis of triacylglycerols by a Toxoplasma DGAT1-related enzyme. Mol Biochem Parasitol. 2004; 138(1): 107-22. Nishikaea et al.¹¹11. Nishikawa Y, Quittnat F, Stedman TT, Voelker DR, Choi J-Y, Zahn M, et al. Host cell lipids control cholesteryl ester synthesis and storage in intracellular Toxoplasma. Cell Microbiol. 2005; 7(6): 849-67. Lige et al.¹²12. Lige B, Sampels V, Coppens I. Characterization of a second sterol-esterifying enzyme in Toxoplasma highlights the importance of cholesterol storage pathways for the parasite. Mol Microbiol. 2013; 87(5): 951-67.
Trypanosoma brucei	Growth and differentiation TAG and phospholipids metabolism	TAG; Phospholipids; LDK; TbLpn enzyme^#	Flaslohper et al.⁶6. Flaspohler JA, Jensen BC, Saveria T, Kifer CT, Parsons M. A novel protein kinase localized to lipid droplets is required for droplet biogenesis in trypanosomes. Eukaryot Cell. 2010; 9(11): 1702-10. Dawoody et al.¹⁷17. Nejad LD, Serricchio M, Jelk J, Hemphill A, Bütikofer P. TbLpn, a key enzyme in lipid droplet formation and phospholipid metabolism, is essential for mitochondrial integrity and growth of Trypanosoma brucei: role of lipin in T. brucei growth. Mol Microbiol. 2018; 109(1): 105-20.
Trypanosoma cruzi	Lipid traffic, storage, and metabolism Organelle communications Eicosanoid production	Neutral lipids, sterols, cholesterol, cholesteryl esters, acylglycerols, phospholipids, fatty acids, arachidonic acid, and PGE₂	Toledo et al.²⁴24. Toledo DAM, Roque NR, Teixeira L, Milán-Garcés EA, Carneiro AB, Almeida MR, et al. Lipid body organelles within the parasite Trypanosoma cruzi: a role for intracellular arachidonic acid metabolism. PLoS One. 2016; 11(8): e0160433. Pereira et al.¹⁵15. Pereira MG, Visbal G, Costa TFR, Frases S, de Souza W, Atella G, et al. Trypanosoma cruzi epimastigotes store cholesteryl esters in lipid droplets after cholesterol endocytosis. Mol Biochem Parasitol. 2018; 224(3): 6-16.
Plasmodium falciparum	Replication and membrane generation of the parasites Heme detoxification effects Induces β-hematin formation in the digestive vesicles.	Neutral lipids and PfDGAT enzyme^#	Vielemeyer et al.⁹9. Vielemeyer O, McIntosh MT, Joiner KA, Coppens I. Neutral lipid synthesis and storage in the intraerythrocytic stages of Plasmodium falciparum. Mol Biochem Parasitol. 2004; 135(2): 197-209. Jackson et al.³⁰30. Jackson KE, Klonis N, Ferguson DJP, Adisa A, Dogovski C, Tilley L. Food vacuole-associated lipid bodies and heterogeneous lipid environments in the malaria parasite, Plasmodium falciparum. Mol Microbiol. 2004; 54(1): 109-22. Ambele et al.³²32. Ambele MA, Sewell BT, Cummings FR, Smith PJ, Egan TJ. Synthetic Hemozoin (ß-Hematin) crystals nucleate at the surface of neutral lipid droplets that control their sizes. Cryst Growth Des. 2013; 13(10): 4442-52.

*: localisation in lipid droplets was not demonstrated; ^#: localisation in endoplasmic reticulum. Enzymes involved in the biogenesis of lipid droplets; TAG: triacylglycerol; Tg: Toxoplasma gondii; Pf: Plasmodium falciparum; ACAT: Acyl-CoA cholesterol acyltransferase; DGAT: Diacyl-CoA:cholesterol acyltransferase; LDK: lipid droplet kinase; COX: cyclooxygenase; PGFS: prostaglandin F_2α synthase; PGE₂: prostaglandin E₂; TbLpn: Trypanosoma brucei Lipin.

TABLE II Lipid mediators, precursors and their metabolism enzymes identified in protozoan pathogens

Species	Lipid mediators and precursors	Proteins	References
Leishmania sp.	Linoneic acid-derived metabolites (9,10-DiHOME, 9,10-DiHODE, 15,16-DiHODE, 9-HODE, 10-HODE, 12-HODE, 13-HODE, 15-HODE, 5(S)-HETrE, 8(S)-HETrE, 12(S)-HETrE, 15(S)-HETrE) Arachidonic acid-derived metabolites (5-HETE, 8-HETE, 11-HETE, 12-HETE, 15-HETE, 18-HETE, 8(9)-EpETrE, PGE₂, PGD₂, PGF_2α) Docosahexaenoic acid- derived metabolites (4-HDoHE, 7-HDoHE, 8-HDoHE, 10-HDoHE, 11-HDoHE, 13-HDoHE, 14-HDoHE, 16-HDoHE, 17-HDoHE, 20-HDoHE) Eicosapentaenoic acid-derived metabolites (7(8)-EpDPE, 10(11)-EpDPE, 13(14)-EpDPE, 16(17)-EpDPE, 19(20)-EpDPE, 10,11-DiHDPE, 13,14-DiHDPE, 16,17-DiHDPE)	PLA₂/PAF-AH, PGFS, COX-like enzyme, CYP1, CYP2, CYP3	Araújo-Santos et al.²⁷27. Araújo-Santos T, Rodríguez NE, Moura-Pontes S, Dixt UG, Abánades DR, Bozza PT, et al. Role of prostaglandin F2a production in lipid bodies from Leishmania infantum chagasi: insights on virulence. J Infect Dis. 2014; 210(12): 1951-61. Azevedo et al.³³33. De Azevedo AF, Dutra JLL, Santos MLB, Santos DA, Alves PB, De Moura TR, et al. Fatty acid profiles in Leishmania spp. isolates with natural resistance to nitric oxide and trivalent antimony. Parasitol Res. 2014; 113(1): 19-27. Alves-Ferreira et al.⁵⁷57. Alves-Ferreira EVC, Ferreira TR, Walrad P, Kaye PM, Cruz AK. Leishmania braziliensis prostaglandin F2a synthase impacts host infection. Parasit Vectors. 2020; 13(1): 9. Pawlowic et al.⁵⁸58. Pawlowic MC, Zhang K. Leishmania parasites possess a platelet-activating factor acetylhydrolase important for virulence. Mol Biochem Parasitol. 2012; 186(1): 11-20. Estrada-Figueroa et al.⁴⁷47. Estrada-Figueroa LA, Díaz-Gandarilla JA, Hernández-Ramírez VI, Arrieta-González MM, Osorio-Trujillo C, Rosales-Encina JL, et al. Leishmania mexicana gp63 is the enzyme responsible for cyclooxygenase (COX) activity in this parasitic protozoa. Biochimie. 2018; 151: 73-84. Kabututu et al.⁴⁹49. Kabututu Z, Martin SK, Nozaki T, Kawazu S, Okada T, Munday CJ, et al. Prostaglandin production from arachidonic acid and evidence for a 9,11-endoperoxide prostaglandin H2 reductase in Leishmania. Int J Parasitol. 2003; 33(2): 221-8. Paloque et al.⁵¹51. Paloque L, Perez-Berezo T, Abot A, Dalloux-Chioccioli J, Bourgeade-Delmas S, Le Faouder P, et al. Polyunsaturated fatty acid metabolites: biosynthesis in Leishmania and role in parasite/host interaction. J Lipid Res. 2019; 60(3): 636-47.
Trypanosoma brucei	Arachidonic acid-derived metabolites (PGE₂, PGD₂, PGF_2α)	PLA₂, PGFS	Kubata et al.⁵⁴54. Kubata BK, Duszenko M, Kabututu Z, Rawer M, Szallies A, Fujimori K, et al. Identification of a novel prostaglandin f(2alpha) synthase in Trypanosoma brucei. J Exp Med. 2000; 192(9): 1327-38.^,⁵⁵55. Kubata BK, Duszenko M, Martin KS, Urade Y. Molecular basis for prostaglandin production in hosts and parasites. Trends Parasitol. 2007; 23(7): 325-31.
Trypanosoma cruzi	Hydroxydocosahexaenoic acid precursors 17-HDHA, 14-HDHA, 7-HDHA, 4-HDHA Arachidonic acid-derived metabolites (PGE₂ PGD₂, PGF_2α, TXA₂, 5-HETE, 12-HETE, 15-HETE, 5S,15S-DiHETE, 5-HEPE, 12-HEPE, 15-HEPE, 18-HEPE, 5S,15S-DiHEPE, TXA₂, PGE₂, PGD₂, PGF_2α) Docosahexaenoic acid-derived metabolites (RvD1, RvD5) Eicosapentaenoic acid-derived metabolites (RvE2)	PGFS, PGES, TcTP, PLA₂, TXA₂S	Toledo et al.²⁴24. Toledo DAM, Roque NR, Teixeira L, Milán-Garcés EA, Carneiro AB, Almeida MR, et al. Lipid body organelles within the parasite Trypanosoma cruzi: a role for intracellular arachidonic acid metabolism. PLoS One. 2016; 11(8): e0160433. Colas et al.⁴⁸48. Colas RA, Ashton AW, Mukherjee S, Dalli J, Akide-Ndunge OB, Huang H, et al. Trypanosoma cruzi produces the specialized proresolving mediators resolvin D1, resolvin D5, and resolvin E2. Infect Immun. 2018; 86(4): 1-10. Okamoto et al.⁵⁰50. Okamoto N, Yamaguchi K, Mizohata E, Tokuoka K, Uchiyama N, Sugiyama S, et al. Structural insight into the stereoselective production of PGF2a by old yellow enzyme from Trypanosoma cruzi. J Biochem (Tokyo). 2011; 150(5): 563-8. Murkherjee et al.⁵³53. Mukherjee S, Sadekar N, Ashton AW, Huang H, Spray DC, Lisanti MP, et al. Identification of a functional prostanoid-like receptor in the protozoan parasite, Trypanosoma cruzi. Parasitol Res. 2013; 112(4): 1417-25. Kubata et al.⁵⁵55. Kubata BK, Duszenko M, Martin KS, Urade Y. Molecular basis for prostaglandin production in hosts and parasites. Trends Parasitol. 2007; 23(7): 325-31.^,⁵⁶56. Kubata BK, Kabututu Z, Nozaki T, Munday CJ, Fukuzumi S, Ohkubo K, et al. A key role for old yellow enzyme in the metabolism of drugs by Trypanosoma cruzi. J Exp Med. 2002; 196(9): 1241-51.
Toxoplasma gondii Plasmodium falciparum Trypanosoma congolense	Not determined	PLA₂	Kubata et al.⁵⁵55. Kubata BK, Duszenko M, Martin KS, Urade Y. Molecular basis for prostaglandin production in hosts and parasites. Trends Parasitol. 2007; 23(7): 325-31.

DiHOME: dihydroxyoctadecaenoic acid; DiHODE: dihydroxyoctadecadienoic acid; HODE: hydroxyoctadecadienoic acid; HETrE: hydroxyeicosatrienoic acid; HETE: hydroxyeicosatetraenoic acid; DiHETE: hydroxyeicosatetraenoic acid; EpETrE: epoxyeicosatrienoic acid; HDoHE: hydroxydocosahexaenoic acid; EpDPE: epoxydocosapentaenoic acid; DiHDPE: dihydroxydocosapentaenoic acid; PG: prostaglandin; TX: thromboxane; HDHA: hydroxydocosahexaenoic acid; HEPE: hydroxyeicosapentaenoic acid; DiHEPE: dihydroxyeicosapentaenoic acid; Rv: resolvin; TcTP: T. cruzi thromboxane receptor; PLA₂: phospholipase A₂; PAF-AH: platelet-activating factor-acetylhydrolase; PGFS: prostaglandin F synthase; PGES: prostaglandin E synthase; TXA2S: thromboxane A₂ synthase; CYP: cytochrome P450 enzymes.

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Lipid droplets of protozoan parasites: survival and pathogenicity

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[1] + Corresponding author: theo.santos@ufob.edu.br