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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Mini-Review Article

The Complexity of Purinergic Signaling During Toxoplasma Infection

Author(s): Aline Cristina Abreu Moreira-Souza and Robson Coutinho-Silva*

Volume 21, Issue 3, 2021

Published on: 11 December, 2020

Page: [205 - 212] Pages: 8

DOI: 10.2174/1568026621999201211202533

Price: $65

Abstract

Toxoplasmosis is a neglected disease caused by infection by the protozoan Toxoplasma gondii. One-third of the global population is expected to be by infected T. gondii. In Europe and North America, most infections do not induce disease, except in the context of immunosuppression. However, in endemic regions such Central and South America, infections induce severe ocular and potentially lethal disease, even in immunocompetent individuals.

The immune response against T. gondii infection involves components of innate immunity even in the chronic phase of the disease, including dangerous signal molecules such as extracellular nucleotides.

Purinergic signaling pathways include ionotropic and metabotropic receptors activated by extracellular nucleotides that are divided into P2X, P2Y, and A1 receptor families. The activation of purinergic signaling impacts biological systems by modulating immune responses to intracellular pathogens such as T. gondii. Ten years ago, purinergic signaling in the T. gondii infection was reported for the first time. In this review, we update and summarize the main findings regarding the role of purinergic signaling in T. gondii infection; these include in vitro findings: the microbicidal effect of P2Y and P2X7 activation phagocytic cells and parasite control by P2X7 activation in non-phagocytic cells; and in vivo findings: the promotion of early pro-inflammatory events that protect the host in acute and chronic models.

Keywords: Toxoplasma gondii, P2X7 receptor, Purinergic receptors, IL-1β, Innate immunity, Chronic models.

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Graphical Abstract

[1]
Pappas, G.; Roussos, N.; Falagas, M.E. Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. Int. J. Parasitol., 2009, 39(12), 1385-1394.
[http://dx.doi.org/10.1016/j.ijpara.2009.04.003] [PMID: 19433092]
[2]
Dubey, J.P. Toxoplasmosis - a waterborne zoonosis. Vet. Parasitol., 2004, 126(1-2), 57-72.
[http://dx.doi.org/10.1016/j.vetpar.2004.09.005] [PMID: 15567579]
[3]
Innes, E.A. A brief history and overview of Toxoplasma gondii. Zoonoses Public Health, 2010, 57(1), 1-7.
[http://dx.doi.org/10.1111/j.1863-2378.2009.01276.x] [PMID: 19744303]
[4]
Robert-Gangneux, F.; Dardé, M.L. Epidemiology of and diagnostic strategies for toxoplasmosis. Clin. Microbiol. Rev., 2012, 25(2), 264-296.
[http://dx.doi.org/10.1128/CMR.05013-11] [PMID: 22491772]
[5]
Khan, A.; Jordan, C.; Muccioli, C.; Vallochi, A.L.; Rizzo, L.V.; Belfort, R., Jr; Vitor, R.W.; Silveira, C.; Sibley, L.D. Genetic divergence of toxoplasma gondii strains associated with ocular toxoplasmosis, brazil. Emerg. Infect. Dis., 2006, 12(6), 942-949.
[http://dx.doi.org/10.3201/eid1206.060025] [PMID: 16707050]
[6]
Yarovinsky, F. Innate immunity to Toxoplasma gondii infection. Nat. Rev. Immunol., 2014, 14(2), 109-121.
[http://dx.doi.org/10.1038/nri3598] [PMID: 24457485]
[7]
Sibley, L.D. Toxoplasma gondii: perfecting an intracellular life style. Traffic, 2003, 4(9), 581-586.
[http://dx.doi.org/10.1034/j.1600-0854.2003.00117.x] [PMID: 12911812]
[8]
Burnstock, G. Purine and pyrimidine receptors. Cell. Mol. Life Sci., 2007, 64(12), 1471-1483.
[http://dx.doi.org/10.1007/s00018-007-6497-0] [PMID: 17375261]
[9]
Abbracchio, M.P.; Burnstock, G.; Boeynaems, J.M.; Barnard, E.A.; Boyer, J.L.; Kennedy, C.; Knight, G.E.; Fumagalli, M.; Gachet, C.; Jacobson, K.A.; Weisman, G.A. International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol. Rev., 2006, 58(3), 281-341.
[http://dx.doi.org/10.1124/pr.58.3.3] [PMID: 16968944]
[10]
Savio, L.E.B.; de Andrade Mello, P.; da Silva, C.G.; Coutinho-Silva, R. The p2x7 receptor in inflammatory diseases: angel or demon? Front. Pharmacol., 2018, 9, 52.
[http://dx.doi.org/10.3389/fphar.2018.00052] [PMID: 29467654]
[11]
Corrêa, G.; Marques da Silva, C.; de Abreu Moreira-Souza, A.C.; Vommaro, R.C.; Coutinho-Silva, R. Activation of the P2X(7) receptor triggers the elimination of Toxoplasma gondii tachyzoites from infected macrophages. Microbes Infect., 2010, 12(6), 497-504.
[http://dx.doi.org/10.1016/j.micinf.2010.03.004] [PMID: 20298798]
[12]
Jones, T.C.; Hirsch, J.G. The interaction between Toxoplasma gondii and mammalian cells. II. The absence of lysosomal fusion with phagocytic vacuoles containing living parasites. J. Exp. Med., 1972, 136(5), 1173-1194.
[http://dx.doi.org/10.1084/jem.136.5.1173] [PMID: 4343243]
[13]
Sibley, L.D.; Weidner, E.; Krahenbuhl, J.L. Phagosome acidification blocked by intracellular Toxoplasma gondii. Nature, 1985, 315(6018), 416-419.
[http://dx.doi.org/10.1038/315416a0] [PMID: 2860567]
[14]
Lees, M.P.; Fuller, S.J.; McLeod, R.; Boulter, N.R.; Miller, C.M.; Zakrzewski, A.M.; Mui, E.J.; Witola, W.H.; Coyne, J.J.; Hargrave, A.C.; Jamieson, S.E.; Blackwell, J.M.; Wiley, J.S.; Smith, N.C. P2X7 receptor-mediated killing of an intracellular parasite, Toxoplasma gondii, by human and murine macrophages. J. Immunol., 2010, 184(12), 7040-7046.
[http://dx.doi.org/10.4049/jimmunol.1000012] [PMID: 20488797]
[15]
Saunders, B.M.; Fernando, S.L.; Sluyter, R.; Britton, W.J.; Wiley, J.S. A loss-of-function polymorphism in the human P2X7 receptor abolishes ATP-mediated killing of mycobacteria. J. Immunol., 2003, 171(10), 5442-5446.
[http://dx.doi.org/10.4049/jimmunol.171.10.5442] [PMID: 14607949]
[16]
Fernando, S.L.; Saunders, B.M.; Sluyter, R.; Skarratt, K.K.; Wiley, J.S.; Britton, W.J. Gene dosage determines the negative effects of polymorphic alleles of the P2X7 receptor on adenosine triphosphate-mediated killing of mycobacteria by human macrophages. J. Infect. Dis., 2005, 192(1), 149-155.
[http://dx.doi.org/10.1086/430622] [PMID: 15942904]
[17]
Fernando, S.L.; Saunders, B.M.; Sluyter, R.; Skarratt, K.K.; Goldberg, H.; Marks, G.B.; Wiley, J.S.; Britton, W.J. A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis. Am. J. Respir. Crit. Care Med., 2007, 175(4), 360-366.
[http://dx.doi.org/10.1164/rccm.200607-970OC] [PMID: 17095747]
[18]
Sluyter, R.; Dalitz, J.G.; Wiley, J.S. P2X7 receptor polymorphism impairs extracellular adenosine 5′-triphosphate-induced interleukin-18 release from human monocytes. Genes Immun., 2004, 5(7), 588-591.
[http://dx.doi.org/10.1038/sj.gene.6364127] [PMID: 15306849]
[19]
Jamieson, S.E.; Peixoto-Rangel, A.L.; Hargrave, A.C.; Roubaix, L.A.; Mui, E.J.; Boulter, N.R.; Miller, E.N.; Fuller, S.J.; Wiley, J.S.; Castellucci, L.; Boyer, K.; Peixe, R.G.; Kirisits, M.J. Elias, Lde.S.; Coyne, J.J.; Correa-Oliveira, R.; Sautter, M.; Smith, N.C.; Lees, M.P.; Swisher, C.N.; Heydemann, P.; Noble, A.G.; Patel, D.; Bardo, D.; Burrowes, D.; McLone, D.; Roizen, N.; Withers, S.; Bahia-Oliveira, L.M.; McLeod, R.; Blackwell, J.M. Evidence for associations between the purinergic receptor P2X(7) (P2RX7) and toxoplasmosis. Genes Immun., 2010, 11(5), 374-383.
[http://dx.doi.org/10.1038/gene.2010.31] [PMID: 20535134]
[20]
Ferrari, D.; Pizzirani, C.; Adinolfi, E.; Lemoli, R.M.; Curti, A.; Idzko, M.; Panther, E.; Di Virgilio, F. The P2X7 receptor: a key player in IL-1 processing and release. J. Immunol., 2006, 176(7), 3877-3883.
[http://dx.doi.org/10.4049/jimmunol.176.7.3877] [PMID: 16547218]
[21]
Ferrari, D.; Chiozzi, P.; Falzoni, S.; Dal Susino, M.; Melchiorri, L.; Baricordi, O.R.; Di Virgilio, F. Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J. Immunol., 1997, 159(3), 1451-1458.
[PMID: 9233643]
[22]
Kelley, N.; Jeltema, D.; Duan, Y.; He, Y. The nlrp3 inflammasome: an overview of mechanisms of activation and regulation. Int. J. Mol. Sci., 2019, 20(13)E3328
[http://dx.doi.org/10.3390/ijms20133328] [PMID: 31284572]
[23]
Chaves, M.M.; Sinflorio, D.A.; Thorstenberg, M.L.; Martins, M.D.A.; Moreira-Souza, A.C.A.; Rangel, T.P.; Silva, C.L.M.; Bellio, M.; Canetti, C.; Coutinho-Silva, R. Non-canonical NLRP3 inflammasome activation and IL-1β signaling are necessary to L. amazonensis control mediated by P2X7 receptor and leukotriene B4. PLoS Pathog., 2019, 15(6)e1007887
[http://dx.doi.org/10.1371/journal.ppat.1007887] [PMID: 31233552]
[24]
Morandini, A.C.; Ramos-Junior, E.S.; Potempa, J.; Nguyen, K.A.; Oliveira, A.C.; Bellio, M.; Ojcius, D.M.; Scharfstein, J.; Coutinho-Silva, R. Porphyromonas gingivalis fimbriae dampen P2X7-dependent interleukin-1β secretion. J. Innate Immun., 2014, 6(6), 831-845.
[http://dx.doi.org/10.1159/000363338] [PMID: 24925032]
[25]
Moreira-Souza, A.C.A.; Almeida-da-Silva, C.L.C.; Rangel, T.P.; Rocha, G.D.C.; Bellio, M.; Zamboni, D.S.; Vommaro, R.C.; Coutinho-Silva, R. The p2x7 receptor mediates toxoplasma gondii control in macrophages through canonical nlrp3 inflammasome activation and reactive oxygen species production. Front. Immunol., 2017, 8, 1257.
[http://dx.doi.org/10.3389/fimmu.2017.01257] [PMID: 29075257]
[26]
Liesenfeld, O. Oral infection of C57BL/6 mice with Toxoplasma gondii: a new model of inflammatory bowel disease? J. Infect. Dis., 2002, 185(Suppl. 1), S96-S101.
[http://dx.doi.org/10.1086/338006] [PMID: 11865446]
[27]
Morampudi, V.; Braun, M.Y.; D’Souza, S. Modulation of early β-defensin-2 production as a mechanism developed by type I Toxoplasma gondii to evade human intestinal immunity. Infect. Immun., 2011, 79(5), 2043-2050.
[http://dx.doi.org/10.1128/IAI.01086-10] [PMID: 21383053]
[28]
Quan, J.H.; Huang, R.; Wang, Z.; Huang, S.; Choi, I.W.; Zhou, Y.; Lee, Y.H.; Chu, J.Q. P2X7 receptor mediates NLRP3-dependent IL-1β secretion and parasite proliferation in Toxoplasma gondii-infected human small intestinal epithelial cells. Parasit. Vectors, 2018, 11(1), 1.
[http://dx.doi.org/10.1186/s13071-017-2573-y] [PMID: 29291748]
[29]
Huang, S.W.; Walker, C.; Pennock, J.; Else, K.; Muller, W.; Daniels, M.J.; Pellegrini, C.; Brough, D.; Lopez-Castejon, G.; Cruickshank, S.M. P2X7 receptor-dependent tuning of gut epithelial responses to infection. Immunol. Cell Biol., 2017, 95(2), 178-188.
[http://dx.doi.org/10.1038/icb.2016.75] [PMID: 27559003]
[30]
Santana, P.T.; Martel, J.; Lai, H.C.; Perfettini, J.L.; Kanellopoulos, J.M.; Young, J.D.; Coutinho-Silva, R.; Ojcius, D.M. Is the inflammasome relevant for epithelial cell function? Microbes Infect., 2016, 18(2), 93-101.
[http://dx.doi.org/10.1016/j.micinf.2015.10.007] [PMID: 26546965]
[31]
Corrêa, G.; Almeida Lindenberg, C.; Moreira-Souza, A.C.; Savio, L.E.; Takiya, C.M.; Marques-da-Silva, C.; Vommaro, R.C.; Coutinho-Silva, R. Inflammatory early events associated to the role of P2X7 receptor in acute murine toxoplasmosis. Immunobiology, 2017, 222(4), 676-683.
[http://dx.doi.org/10.1016/j.imbio.2016.12.007] [PMID: 28069296]
[32]
Miller, C.M.; Zakrzewski, A.M.; Ikin, R.J.; Boulter, N.R.; Katrib, M.; Lees, M.P.; Fuller, S.J.; Wiley, J.S.; Smith, N.C. Dysregulation of the inflammatory response to the parasite, Toxoplasma gondii, in P2X7 receptor-deficient mice. Int. J. Parasitol., 2011, 41(3-4), 301-308.
[http://dx.doi.org/10.1016/j.ijpara.2010.10.001] [PMID: 21044631]
[33]
Miller, C.M.; Zakrzewski, A.M.; Robinson, D.P.; Fuller, S.J.; Walker, R.A.; Ikin, R.J.; Bao, S.J.; Grigg, M.E.; Wiley, J.S.; Smith, N.C. Lack of a Functioning P2X7 Receptor Leads to Increased Susceptibility to Toxoplasmic Ileitis. PLoS One, 2015, 10(6)e0129048
[http://dx.doi.org/10.1371/journal.pone.0129048] [PMID: 26053862]
[34]
Bottari, N.B.; Pillat, M.M.; Schetinger, M.R.C.; Reichert, K.P.; Machado, V.; Assmann, C.E.; Ulrich, H.; Dutra, A.; Morsch, V.M.; Vidal, T.; Da Cruz, I.B.M.; Melazzo, C.; Da Silva, A.S. Resveratrol-mediated reversal of changes in purinergic signaling and immune response induced by Toxoplasma gondii infection of neural progenitor cells. Purinergic Signal., 2019, 15(1), 77-84.
[http://dx.doi.org/10.1007/s11302-018-9634-3] [PMID: 30535987]
[35]
Bottari, N.B.; Reichert, K.P.; Fracasso, M.; Dutra, A.; Assmann, C.E.; Ulrich, H.; Schetinger, M.R.C.; Morsch, V.M.; Da Silva, A.S. Neuroprotective role of resveratrol mediated by purinergic signalling in cerebral cortex of mice infected by Toxoplasma gondii. Parasitol. Res., 2020, 119(9), 2897-2905.
[http://dx.doi.org/10.1007/s00436-020-06795-0] [PMID: 32677001]
[36]
Moreira-Souza, A.C.A.; Rangel, T.P.; Silva, S.R.B.D.; Figliuolo, V.R.; Savio, L.E.B.; Schmitz, F.; Takiya, C.M.; Wyse, A.T.S.; Vommaro, R.C.; Coutinho-Silva, R. Disruption of purinergic receptor p2x7 signaling increases susceptibility to cerebral toxoplasmosis. Am. J. Pathol., 2019, 189(4), 730-738.
[http://dx.doi.org/10.1016/j.ajpath.2019.01.001] [PMID: 30653952]
[37]
Tonin, A.A.; Da Silva, A.S.; Casali, E.A.; Silveira, S.S.; Moritz, C.E.; Camillo, G.; Flores, M.M.; Fighera, R.; Thomé, G.R.; Morsch, V.M.; Schetinger, M.R. Rue, Mde.L.; Vogel, F.S.; Lopes, S.T. Influence of infection by Toxoplasma gondii on purine levels and E-ADA activity in the brain of mice experimentally infected mice. Exp. Parasitol., 2014, 142, 51-58.
[http://dx.doi.org/10.1016/j.exppara.2014.04.008] [PMID: 24768956]
[38]
Ralevic, V.; Burnstock, G. Receptors for purines and pyrimidines. Pharmacol. Rev., 1998, 50(3), 413-492.
[PMID: 9755289]
[39]
Mahamed, D.A.; Mills, J.H.; Egan, C.E.; Denkers, E.Y.; Bynoe, M.S. CD73-generated adenosine facilitates Toxoplasma gondii differentiation to long-lived tissue cysts in the central nervous system. Proc. Natl. Acad. Sci. USA, 2012, 109(40), 16312-16317.
[http://dx.doi.org/10.1073/pnas.1205589109] [PMID: 22988118]
[40]
Moreira-Souza, A.C.; Marinho, Y.; Correa, G.; Santoro, G.F.; Coutinho, C.M.; Vommaro, R.C.; Coutinho-Silva, R. Pyrimidinergic receptor activation controls toxoplasma gondii infection in macrophages. PLoS One, 2015, 10(7)e0133502
[http://dx.doi.org/10.1371/journal.pone.0133502] [PMID: 26192447]
[41]
Lourido, S.; Shuman, J.; Zhang, C.; Shokat, K.M.; Hui, R.; Sibley, L.D. Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma. Nature, 2010, 465(7296), 359-362.
[http://dx.doi.org/10.1038/nature09022] [PMID: 20485436]

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