Abstract
Trypanosoma cruzi is the etiological agent of Chagas disease. These parasites undergo dramatic morphological and physiological changes during their life cycle. The human-infective metacyclic trypomastigotes differentiate from epimastigotes inside the midgut of the Triatominae insect vector. Our group has shown that the saliva and feces of Rhodnius prolixus contains a lysophospholipid, lysophosphatidylcholine (LPC), which modulates several aspects of T. cruzi infection in macrophages. LPC hydrolysis by a specific lysophospholipase D, autotaxin (ATX), generates lysophosphatidic acid (LPA). These bioactive lysophospholipids are multisignaling molecules and are found in human plasma ingested by the insect during blood feeding. Here, we show the role of LPC and LPA in T. cruzi proliferation and differentiation. Both lysophospholipids are able to induce parasite proliferation. We observed an increase in parasite growth with different fatty acyl chains, such as C18:0, C16:0, or C18:1 LPC. The dynamics of LPC and LPA effect on parasite proliferation was evaluated in vivo through a time- and space-dependent strategy in the vector gut. LPC but not LPA was also able to affect parasite metacyclogenesis. Finally, we determined LPA and LPC distribution in the parasite itself. Such bioactive lipids are associated with reservosomes of T. cruzi. To the best of our knowledge, this is the first study to suggest the role of surrounding bioactive lipids ingested during blood feeding in the control of parasite transmission.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Atella GC, Arruda MABCF, Masuda H, Gondim KC (2000) Fatty acid incorporation by Rhodnius prolixus midgut. Arch Insect Biochem Physiol 43:99–107. https://doi.org/10.1002/(SICI)1520-6327(200003)43:3<99::AID-ARCH1>3.0.CO;2-3
Atella GC, Shahabuddin M (2002) Differential partitioning of maternal fatty acid and phospholipid in neonate mosquito larvae. J Exp Biol 205(Pt 23):3623-30
Atella GC, Gondim KC, Machado EA, Medeiros MN, Silva-Neto MAC, Masuda H (2005) Oogenesis and egg development in triatomines: a biochemical approach. An Acad Bras Cienc 77:405–430. https://doi.org/10.1590/S0001-37652005000300005
Atella GC, Silva-Neto MAC, Golodne DM, Arefin S, Shahabuddin M (2006) Anopheles gambiae lipophorin: characterization and role in lipid transport to developing oocyte. Insect Biochem Mol Biol 36:375–386. https://doi.org/10.1016/j.ibmb.2006.01.019
Belaunzarán ML, Lammel EM, Giménez G, Wainszelbaum MJ, De Isola ELD (2009) Involvement of protein kinase C isoenzymes in Trypanosoma cruzi metacyclogenesis induced by oleic acid. Parasitol Res 105:47–55. https://doi.org/10.1007/s00436-009-1359-3
Bittencourt-Cunha PR, Silva-Cardoso L, de Oliveira GA, da Silva JR, de Silveira AB, Kluck GEG, Atella GC (2013) Perimicrovillar membrane assembly: the fate of phospholipids synthesised by the midgut of rhodnius prolixus. Mem Inst Oswaldo Cruz 108:494–500. https://doi.org/10.1590/0074-0276108042013016
Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37(8):911-917
Carneiro AB, Iaciura BMF, Nohara LL, Lopes CD, Veas EMC, Mariano VS, Silva-Neto MAC (2013) Lysophosphatidylcholine triggers TLR2- and TLR4-mediated signaling pathways but counteracts LPS-induced NO synthesis in peritoneal macrophages by inhibiting NF-?? B translocation and MAPK/ERK phosphorylation. PLoS One 8:1–9. https://doi.org/10.1371/journal.pone.0076233
Cham BE, Knowles BR (1976) A solvent system for delipidation of plasma or serum without protein precipitation. J Lipid Res 17(2):176-81
Corrêa JR, Atella GC, Batista MM, Soares MJ (2008) Transferrin uptake in Trypanosoma cruzi is impaired by interference on cytostome-associated cytoskeleton elements and stability of membrane cholesterol, but not by obstruction of clathrin-dependent endocytosis. Exp Parasitol 119:58–66. https://doi.org/10.1016/j.exppara.2007.12.010
Contreras VT, Araujo-Jorge TC, Bonaldo MC, Thomaz N, Barbosa HS, Meirelles Mde N, Goldenberg S (1988) Biological aspects of the DM28C clone of Trypanosoma cruzi after metacylogenesis in chemically defined media. Mem Inst Oswaldo Cruz 83(1):123-33.https://doi.org/10.1590/S0074-02761988000100016
da Silva Augusto L, Moretti NS, Ramos TC, de Jesus TC, Zhang M, Castilho BA, Schenkman S (2015) A membrane-bound eIF2 alpha kinase located in endosomes is regulated by heme and controls differentiation and ROS levels in Trypanosoma cruzi. PLoS Pathog 11(2):e1004618. https://doi.org/10.1371/journal.ppat.1004618
de Almeida Nogueira NP, de Souza CF, de Souza Saraiva FM, Sultano PE, Dalmau SR, Bruno RE, Paes MC (2011) Heme-induced ROS in Trypanosoma cruzi activates Camkii-like that triggers epimastigote proliferation. One helpful effect of ROS. PLoS One 6:e25935. https://doi.org/10.1371/journal.pone.0025935
De Cicco NNT, Pereira MG, Corrêa JR, Andrade-Neto VV, Saraiva FB, Chagas-Lima AC, Gondim KC, Torres-Santos EC, Folly E, Saraiva EM, Cunha-e-Silva NL, Soares MJ, Atella GC (2012) LDL uptake by Leishmania amazonensis: involvement of membrane lipid microdomains. Exp Parasitol 130:330–340. https://doi.org/10.1016/j.exppara.2012.02.014
de Godoy LMF, Marchini FK, Pavoni DP, Rampazzo Rde C, Probst CM, Goldenberg S, Krieger MA (2012) Quantitative proteomics of Trypanosoma cruzi during metacyclogenesis. Proteomics 12:2694–2703. https://doi.org/10.1002/pmic.201200078
De Melo LDB, Nepomuceno-Silva JL, Sant'Anna C, Eisele N, Ferraro RB, Meyer-Fernandes JR, Lopes UG (2004) TcRho1 of Trypanosoma cruzi: role in metacyclogenesis and cellular localization. Biochem Biophys Res Commun 323:1009–1016. https://doi.org/10.1016/j.bbrc.2004.08.197
de Souza W, Sant'Anna C, Cunha-e-Silva NL (2009) Electron microscopy and cytochemistry analysis of the endocytic pathway of pathogenic protozoa. Prog Histochem Cytochem 44(2):67–124. https://doi.org/10.1016/j.proghi.2009.01.001
Dos Santos GRRM, Nepomuceno-Silva JL, de Melo LDB, Meyer-Fernandes JR, Salmon D, Azevedo-Pereira RL, Lopes UG (2012) The GTPase TcRjl of the human pathogen Trypanosoma cruzi is involved in the cell growth and differentiation. Biochem Biophys Res Commun 419:38–42. https://doi.org/10.1016/j.bbrc.2012.01.119
dos Ximenes AA, Silva-Cardoso L, De Cicco NNT, Pereira MG, Lourenço DC, Fampa P, Atella GC (2015) Lipophorin drives lipid incorporation and metabolism in insect trypanosomatids. Protist 166:297–309. https://doi.org/10.1016/j.protis.2015.04.003
Drzazga A, Sowinska A, Koziolkiewicz M (2014) Lysophosphatidylcholine and lysophosphatidylinosiol novel promissing signaling molecules and their possible therapeutic activity. Acta Pol Pharm 71:887–899
East JE, Kennedy AJ, Tomsig JL, De Leon AR, Lynch KR, Macdonald TL (2010) Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX). Bioorg Med Chem Lett 20(23):7132–7136. https://doi.org/10.1016/j.bmcl.2010.09.030
Ferreira LRP, Dossin FDM, Ramos TC, Freymüller E, Schenkman S (2008) Active transcription and ultrastructural changes during Trypanosoma cruzi metacyclogenesis. An Acad Bras Cienc 80:157–166. https://doi.org/10.1590/S0001-37652008000100011
Ferry G, Moulharat N, Pradère JP, Desos P, Try A, Genton A, Boutin J (2008) S32826, a nanomolar inhibitor of autotaxin: discovery, synthesis and applications as a pharmacological tool. J Pharmacol Exp Ther 327:809–819. https://doi.org/10.1124/jpet.108.141911.cytes
Gazos-Lopes F, Oliveira MM, Hoelz LV, Vieira DP, Marques AF, Nakayasu ES, Gomes MT, Salloum NG, Pascutti PG, Souto-Padrón T, Monteiro RQ, Lopes AH, Almeida IC (2014) Structural and Functional Analysis of a Platelet-Activating Lysophosphatidylcholine of Trypanosoma cruzi. PLoS Negl Trop Dis 8(8):e3077. https://doi.org/10.1371/journal.pntd.0003077
Golodne DM, Monteiro RQ, Graca-Souza AV, Silva-Neto MAC, Atella GC (2003) Lysophosphatidylcholine acts as an anti-hemostatic molecule in the saliva of the blood-sucking bug Rhodnius prolixus. J Biol Chem 278:27766–27771. https://doi.org/10.1074/jbc.M212421200
Gomes MT, Monteiro RQ, Grillo LA, Leite-Lopes F, Stroeder H, Ferreira-Pereira A, Alviano CS, Barreto-Bergter E, Neto HC, Cunha ESNL, Almeida IC, Soares RM, Lopes A (2005) H. Platelet-activating factor-like activity isolated from Trypanosoma cruzi. Int J Parasitol 36:165–173. https://doi.org/10.1016/j.ijpara.2005.09.016
Grillo LAM, Majerowicz D, Gondim KC (2007) Lipid metabolism in Rhodnius prolixus (Hemiptera: Reduviidae): role of a midgut triacylglycerol-lipase. Insect Biochem Mol Biol 37:579–588. https://doi.org/10.1016/j.ibmb.2007.03.002
Harrison SM, Knifley T, Chen M, O’ Connor KL (2013) LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells. BMC Cancer 13:501. https://doi.org/10.1186/1471-2407-13-501
Houben AJS, Moolenaar WH (2011) Autotaxin and LPA receptor signaling in cancer. Cancer Metastasis Rev 30:557–565. https://doi.org/10.1007/s10555-011-9319-7
Ishii I, Fukushima N, Ye X, Chun J (2004) Lysophospholipid receptors: signaling and biology. Annu Rev Biochem 73:321–354. https://doi.org/10.1146/annurev.biochem.73.011303.073731
Kollien AH, Schaub GA (1998) Trypanosoma cruzi in the rectum of the bug Triatoma infestans: effects of blood ingestion by the starved vector. Am J Trop Med Hyg 59:166–170. https://doi.org/10.1007/s004360050339
Kollien AH, Schaub GA (2000) The development of Trypanosoma cruzi in triatominae. Parasitol Today 16:381–387. https://doi.org/10.1016/S0169-4758(00)01724-5
Liu S, Murph M, Panupinthu N, Mills GB (2009) ATX-LPA receptor axis in inflammation and cancer. Cell Cycle 8:3695–3701. https://doi.org/10.4161/cc.8.22.9937
Lopes AH, Gomes MT, Dutra FL, Vermelho AB, Meyer-fernandes JR, Silva-Neto MAC, Vieira DP (2010) Intracellular signaling pathways involved in cell differentiation in trypanosomatids. Open Parasitol J 4:102–110. https://doi.org/10.2174/1874421401004010102
Mesquita RD, Carneiro AB, Bafica A, Gazos-Lopes F, Takiya CM, Souto-Padron T, Silva-Neto MAC (2008) Trypanosoma cruzi infection is enhanced by vector saliva through immunosuppressant mechanisms mediated by lysophosphatidylcholine. Infect Immun 76:5543–5552. https://doi.org/10.1128/IAI.00683-08
Mesquita RD, Vionette-Amaral RJ, Lowenberger C, Rivera-Pomar R, Monteiro FA, Minx P, Oliveira PL (2015) Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection. Proc Natl Acad Sci U S A 112:14936–14941. https://doi.org/10.1073/pnas.1506226112
Nogueira NP, Saraiva FMS, Sultano PE, Cunha PRBB, Laranja GAT, Justo GA, Paes MC (2015) Proliferation and differentiation of Trypanosoma cruzi inside its vector have a new trigger: redox status. PLoS One 10:e0116712. https://doi.org/10.1371/journal.pone.0116712
Paes MC, Cosentino-Gomes D, De Souza CF, Nogueira NPDA, Meyer-Fernandes JR (2011) The role of heme and reactive oxygen species in proliferation and survival of Trypanosoma cruzi. J Parasitol Res 2011:174614–174618. https://doi.org/10.1155/2011/174614
Parodi-Talice A, Monteiro-Goes V, Arrambide N, Avila AR, Duran R, Correa A, Robello C (2007) Proteomic analysis of metacyclic trypomastigotes undergoing Trypanosoma cruzi metacyclogenesis. J Mass Spectrom 42:1422–1432. https://doi.org/10.1002/jms.1267
Pereira MG, VIisbal G, Salgado LT, Vidal JC, Godinho JL, De Cicco NN, Atella GC, De Souza W, Cunha-e-Silva N (2015) Trypanosoma cruzi epimastigotes are able to manage internal cholesterol levels under nutritional lipid stress conditions. PLoS One 10(6):e0128949. https://doi.org/10.1371/journal.pone.0128949
Porto-Carreiro I, Attias M, Miranda K, De Souza W, Cunha-e-Silva N (2000) Epimastigote endocytic pathway: cargo enters the cytostome and passes through an early endosomal network before storage in reservosomes. Eur J Cell Biol 79(11):858-869. https://doi.org/10.1078/0171-9335-00112
Ribeiro JMC, Genta FA, Sorgine MHF, Logullo R, Mesquita RD, Paiva-Silva GO, Oliveira PL (2014) An insight into the transcriptome of the digestive tract of the bloodsucking bug, Rhodnius prolixus. PLoS Negl Trop Dis 8:27. https://doi.org/10.1371/journal.pntd.0002594
Ruiz JI, Ochoa B (1997) Quantification in the subnanomolar range of phospholipids and neutral lipids by monodimensional thin-layer chromatography and image analysis. J Lipid Res 38(7):1482-9
Schmitz G, Ruebsaamen K (2010) Metabolism and atherogenic disease association of lysophosphatidylcholine. Atherosclerosis 208:10–18. https://doi.org/10.1016/j.atherosclerosis.2009.05.029
Sevastou I, Kaffe E, Mouratis MA, Aidinis V (2013) Lysoglycerophospholipids in chronic inflammatory disorders: the PLA2/LPC and ATX/LPA axes. Biochim Biophys Acta 1831:42–60. https://doi.org/10.1016/j.bbalip.2012.07.019
Silva-Cardoso L, Dias FA, Fampa P, Pereira MG, Atella GC (2018) Evaluating the effects of anticoagulants on Rhodnius prolixus artificial blood feeding. PLoS One 13(11):e0206979. https://doi.org/10.1371/journal.pone.0206979 eCollection 2018
Silva-Neto MAC, Carneiro AB, Vieira DP, Mesquita RD, Lopes AHCS (2002) Platelet-activating factor (PAF) activates casein kinase 2 in the protozoan parasite Herpetomonas muscarum muscarum. Biochem Biophys Res Commun 293(5):1358-1363. https://doi.org/10.1016/S0006-291X(02)00395-9
Silva-Neto MAC, Carneiro AB, Silva-Cardoso L, Atella GC (2012) Lysophosphatidylcholine: a novel modulator of Trypanosoma cruzi transmission. J Parasitol Res 2012:625838–625838. https://doi.org/10.1155/2012/625838
Silva-Neto MAC, Atella GC, Lopes AH (2016) Here, there, and everywhere: the ubiquitous distribution of the immunosignaling molecule lysophosphatidylcholine and its role on chagas disease. Front Immunol 7:62. https://doi.org/10.3389/fimmu.2016.00062
Souza CF, Carneiro AB, Silveira AB, Laranja GAT, Silva-Neto MAC, de Costa SCG, Paes MC (2009) Heme-induced Trypanosoma cruzi proliferation is mediated by CaM kinase II. Biochem Biophys Res Commun 390:541–546. https://doi.org/10.1016/j.bbrc.2009.09.135
Tonelli RR, da Silva Augusto L, Castilho BA, Schenkman S (2011) Protein synthesis attenuation by phosphorylation of eIF2α is required for the differentiation of Trypanosoma cruzi into infective forms. PLoS One 6(11):e27904. https://doi.org/10.1371/journal.pone.0027904
Acknowledgments
We wish to express our gratitude to Desenir Adriano Pedro, Yasmin de Paule Gutierrez Simão, Mileane S. Busch, Lilian Soares da Cunha Gomes, and Heloisa Coelho for the excellent technical assistance.
In memoriam to professor Dr. Mário Alberto Cardoso Silva Neto for essential contribution to this work.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethics approval and consent to participate
All the animal care and experimental protocols were conducted in accordance with the guidelines of the institutional animal care and use committee (Comissão de Avaliação do Uso de Animais em Pesquisa da Universidade Federal do Rio de Janeiro, CAUAP-UFRJ) and the NIH Guide for the Care and Use of Laboratory Animals (ISBN 0-309-05377-3). The protocols were approved by CEUA-UFRJ (Comissão de Ética no Uso de Animais da Universidade Federal do Rio de Janeiro) under registry number #115/13. Technicians at the animal facility of the Institute of Medical Biochemistry Leopoldo de Meis (UFRJ) performed the entire rabbit husbandry under strict guidelines to ensure careful and consistent handling of the animals.
Financial support
This work was supported by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (www.faperj.br) and by Conselho Nacional de Pesquisa e Desenvolvimento (CNPq) (www.cnpq.br). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Additional information
Section Editor: Marta Teixeira
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Chagas-Lima, A.C., Pereira, M.G., Fampa, P. et al. Bioactive lipids regulate Trypanosoma cruzi development. Parasitol Res 118, 2609–2619 (2019). https://doi.org/10.1007/s00436-019-06331-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-019-06331-9