Immunology of Toxoplasma gondii infection I. A basic approach
Keywords:
Toxoplasma gondii, Toxoplasmosis; Immune Response; Natural Immunity; Adaptive Immunity; Immune Evasion.Abstract
Toxoplasma gondii is a widespread intracellular protozoan that affects around one-third of the World´s human population. The clinical expression of toxoplasmosis is closely related to the host immunocompetence. Whereas most immunocompetent persons are asymptomatic after primary acquired infection, immunocompromised patients may develop an array of severe clinical manifestations. In relation to numerous aspects of toxoplasmosis, including the immunity to T. gondii infection and related topics, the knowledge is scarce or controversial. In line with it, this Opinion aims to provide a concise and comprehensive overview of the host immune responses to this parasite. T. gondii induces a vigorous innate and adaptive immune response characterized by a strong T cell immunity. CD4 and CD8 T cells are protagonists in the control of acute infection and are essential for preventing cyst reactivation during chronic latent infection. This parasite can evade and modulate host innate and adaptive immune responses, and establish long-term niches in immune-privileged areas like the brain and retina. As this paper underlines, T. gondii infection reveals a delicate balance between protective immunity and immunopathology. In the interest of more efficient medical practice, the peculiarities of this sui generis host-parasite interaction must be deeply known by professionals involved in its diagnosis, treatment, and control.
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References
1. Dubey J. History of the discovery of the life cycle of Toxoplasma gondii. Int J Parasitol 2009; 39:877-82. DOI: https://doi.org/10.1016/j.ijpara.2009.01.005
2. Chen Z, Cheng S, Chen X, Zhang Z and Du Y. New advances in immune mechanism. Front Immunol. 15:1403025. DOI: https://doi:10.3389/fimmu.2024.1403025
3. Nayeri T, Sarvi S, Moosazadeh M, Amouei A, Hosseininejad Z, Daryani A. The global seroprevalence of anti-Toxo, preparaciónplasma gondii antibodies in women who had spontaneous abortion: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2020;14:e0008103. DOI: https://doi.org/10.1371/journal.pntd.0008103
4. Dard C, Fricker-Hidalgo H, Brenier-Pinchart M, Pelloux H. Relevance of and New Developments in Serology for Toxoplasmosis. Trends in Parasitol 2016;32(6):492-506. DOI: https://doi.org/10.1016/j.pt.2016.04.001
5. Ahmadpour E, Daryani A, Sharif M, Sarvi S, Aarabi M, Mizani A, et al. Toxoplasmosis Inimmunocompromised Patients in Iran: A Systematic Review and Meta-Analysis. J Infect Dev Ctries. 2014;8(12):1503-10. DOI: https://doi:10.3855/jidc.4796
6. Durdu CE, Bohîlțea RE. Toxoplasmosis and Pregnancy: Current Approaches for Favourable Fetal Outcome. Romanian Journal of Preventive Medicine. 2023; 2(3):12-21. DOI: https://doi.org/10.3390/rjpm2030012
7. Montoya J, Liesenfeld O. Toxoplasmosis. Lancet 2004; 363:1965-76. DOI: https://doi.org/10.1016/S0140-6736(04)16412-X
8. Muñoz M, Liesenfeld O, Heimesaat M. Immunology of Toxoplasma gondii. Immunol Rev 2011; 240:85. DOI: https://doi.org/10.1111/j.1600-065X.2010.00992.x
9. Erazo Flores BJ, Knoll LJ. Toxoplasma gondii at the Host Interface: Immune Modulation and Translational Strategies for Infection Control. Vaccines 2025; 13:819. DOI:
https://doi.org/10.3390/vaccines13080819
10. Howe DK, Sibley LD. Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease. J Infect Dis 1995; 172:1561-6. DOI: https://doi:10.1093/infdis/172.6.1561
11. Saeij JPJ, Boyle JP, Boothroyd JC. Differences among the Three Major Strains of Toxoplasma gondii and Their Specific Interactions with the Infected Host. Trends Parasitol 2005; 21:476-81. DOI: https://doi:10.1016/j.pt.2005.08.001
12. Jensen KDC, Camejo A, Melo MB, Cordeiro C, Julien L, Grotenbreg GM, et al. Toxoplasma gondii Superinfection and Virulence during Secondary Infection Correlate with the Exact ROP5/ROP18 Allelic Combination. mBio 2015; 6:e02280-14. DOI: https://doi.10.1128/mBio.02280-14
13. Niedelman W, Gold DA, Rosowski EE, Sprokholt JK, Lim D, Arenas AF, et al. The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response. PLOS Pathog 2012; 8:e1002784. DOI: https://10.1371/journal.ppat.1002784
14. Etheridge RD, Alaganan A, Tang K, Lou HJ, Turk BE, Sibley LD. The Toxoplasma Pseudokinase ROP5 Forms Complexes with ROP18 and ROP17 Kinases That Synergize to Control Acute Virulence in Mice. Cell Host Microbe 2014; 15:537-50. DOI: https://10.1016/j.chom.2014.04.002
15. Grigg ME, Ganatra J, Boothroyd JC, Margolis TP. Unusual abundance of atypical strains associated with human ocular toxoplasmosis. J Infect Dis 2001; 184:633-9. DOI: https://doi.10.1086/322800
16. Genova BMD, Wilson SK, Dubey JP, Knoll LJ. Intestinal Delta-6-Desaturase Activity Determines Host Range for Toxoplasma Sexual Reproduction. PLoS Biol 2019; 17:e3000364. DOI: https://10.1371/journal.pbio.3000364
17. Bhandage AK, Barragan A. Calling in the Ca(V)alry-Toxoplasma gondii Hijacks GABAergic Signaling and Voltage-Dependent Calcium Channel Signaling for Trojan horse- Mediated Dissemination. Front Cell Infect Microbiol 2019; 9:61. DOI: https://doi:10.3389/fcimb.2019.00061
18. Schlüter D, Barragan A. Advances and Challenges in Understanding Cerebral Toxoplasmosis. Front Immunol. 2019; 10. DOI: https://doi.org/10.3389/fimmu.2019.00242
19. Robbins JR, Zeldovich VB, Poukchanski A, Boothroyd JC, Bakardjiev AI. Tissue Barriers of the Human Placenta to Infection with Toxoplasma gondii. Infect Immun 2012; 80:418-28. DOI: https://doi:10.1128/IAI.05899-11
20. Hu X, Binns D, Reese ML. The Coccidian Parasites Toxoplasma and Neospora Dysregulate Mammalian Lipid Droplet Biogenesis. J Biol Chem 2017; 292:11009-20. DOI: https://doi:10.1074/jbc.M116.768176
21. Kemp LE, Yamamoto M, Soldati-Favre D. Subversion of Host Cellular Functions by the Apicomplexan Parasites. FEMS Microbiol Rev 2013; 37:607-31. DOI: https://doi:10.1111/1574-6976.12013
22. Hakimi MA, Bougdour A. Toxoplasma’s Ways of Manipulating the Host Transcriptome via Secreted Effectors. Curr Opin Microbiol 2015; 26:24-31. DOI: https://doi.org/10.1016/j.mib.2015.04.003
23. Lima TS, Lodoen MB. Mechanisms of Human Innate Immune Evasion by Toxoplasma gondii. Front Cell Infect Microbiol 2019; 9:103. DOI: https://doi.org/10.3389/fcimb.2019.00103
24. Fonte L, Rodriguez L, Domenech I, Ginori M, Oliva K, Tamayo N, et al. Conocimientos y percepciones en relación con toxoplasmosis de residentes y especialistas de ginecología y obstetricia de La Habana, 2025. Acta Médica 2026. [access 09/5/2026]; 27:e985. Available at:
https://revactamedica.sld.cu/index.php/act/article/view/985
25. Dunay IR, Diefenbach A. Group 1 Innate Lymphoid Cells in Toxoplasma gondii Infection. Parasite Immunol 2018; 40:e12516. DOI: https://doi.org/10.1111/pim.12516
26. Park E, Patel S, Wang Q, Andhey P, Zaitsev K, Porter S, et al. Toxoplasma gondii Infection Drives Conversion of NK Cells into ILC1-like Cells. eLife 2019; 8:e47605. DOI: https://10.7554/eLife.47605
27. Sasai M, Yamamoto M. Innate, Adaptive, and Cell-Autonomous Immunity against Toxoplasma gondii Infection. Exp Mol Med 2019; 51:1-10. DOI: https://doi:10.1038/s12276-019-0353-9
28. Kawai T, Akira S. The Role of Pattern-Recognition Receptors in Innate Immunity: Update on Toll-like Receptors. Nat Immunol 2010; 11:373-84. DOI: https://doi:10.1038/ni.1863
29. Sher A, Tosh K, Jankovic D. Innate Recognition of Toxoplasma gondii in Humans Involves a Mechanism Distinct from That Utilized by Rodents. Cell Mol Immunol 2017; 14:36-42. DOI: https://doi.org/10.1038/cmi.2016.12
30. Sasai M, Yamamoto M. Pathogen recognition receptors: ligands and signaling pathways by Toll-like receptors. Int Rev Immunol 2013; 32:116-33. DOI: https://doi.org/10.3109/08830185.2013.774391
31. Andrade WA, Souza MdC, Ramos-Martinez E, Nagpal K, Dutra MS, Melo MB, et al. Combined Action of Nucleic Acid-Sensing Toll-like Receptors and TLR11/TLR12 Heterodimers Imparts Resistance to Toxoplasma gondii in Mice. Cell Host Microbe 2013; 13:42-53. DOI: https://doi.org/10.1016/j.chom.2012.12.003
32. Mahmoudzadeh S, Nozad Charoudeh H, Marques CS, Bahadory S, Ahmadpour E. The Role of IL-12 in Stimulating NK Cells against Toxoplasma gondii Infection: A Mini-Review. Parasitol Res 2021; 120:2303-9. DOI: https://doi.org/10.1002/iid3.1329
33. Cai G, Kastelein R, Hunter CA. Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii. Infect Immun 2000; 68:6932-38. DOI: https://doi:10.1128/IAI.68.12.6932-6938.2000
34. Wallet P, Benaoudia S, Mosnier A, Lagrange B, Martin A, Lindgren H, et al. IFN-γ Extends the Immune Functions of Guanylate Binding Proteins to Inflammasome-Independent Antibacterial Activities during Francisella Novicida Infection. PLoS Pathog 2017; 13:e1006630. DOI: https://doi.org/10.1371/journal.ppat.1006630
35. Tretina K, Park ES, Maminska A, MacMicking JD. Interferon-Induced Guanylate-Binding Proteins: Guardians of Host Defense in Health and Disease. J Exp Med 2019; 216:482-500. DOI: https://doi.org/10.1084/jem.20182031
36. Zhao YO, Khaminets A, Hunn JP, Howard JC. Disruption of the Toxoplasma gondii Parasitophorous Vacuole by IFN gamma-Inducible Immunity-Related GTPases (IRG Proteins) Triggers Necrotic Cell Death. PLoS Pathog 2009; 5:e1000288. DOI: https://doi.org/10.1371/journal.ppat.1000288
37. Praefcke GJK. Regulation of Innate Immune Functions by Guanylate-Binding Proteins. Int J Med Microbiol. 2018, 308, 237–245. DOI: https://doi.10.1016/j.ijmm.2017.10.013
38. Khan IA, Matsuura T, Fonseka S, Kasper LH. Production of Nitric Oxide (NO) Is Not Essential for Protection against Acute Toxoplasma gondii Infection in IRF-1-/- Mice. J Immunol 1996. [access 09/5/2026]; 156:636-43. Available at: https://popline.org/node/468342
39. Dincel GC, Atmaca HT. Nitric Oxide Production Increases during Toxoplasma gondii Encephalitis in Mice. Exp Parasitol 2015; 156:104-12. DOI: https://doi.org/10.1016/j.exppara.2015.06.009
40. Denkers EY, Gazzinelli RT. Regulation and Function of T-Cell-Mediated Immunity during Toxoplasma gondii Infection. Clin Microbiol Rev 1998; 11:569-88. DOI: https://doi:10.1128/CMR.11.4.569
41. Hunter CA, Sibley LD. Modulation of innate immunity by Toxoplasma gondii virulence effectors. Nat Rev Microbiol 2012; 10:766-78 DOI: https://doi:10.1038/nrmicro2858
42. Liu Q, Wang ZD, Huang SY, Zhu XQ. Diagnosis of Toxoplasmosis and Typing of Toxoplasma gondii. Parasites Vectors 2015; 8:292. DOI: https://doi:10.1186/s13071-015-0902-6
43. Khan IA, Ouellette C, Chen K, Moretto M. Toxoplasma: Immunity and Pathogenesis. Curr Clin Microbiol Rep 2019; 6:44-50. DOI: https://doi:10.1007/s40588-019-0114-5
44. Suzuki Y, Sa Q, Gehman M, Ochiai E. Interferon-Gamma- and Perforin-Mediated Immune Responses for Resistance in the Brain against Toxoplasma gondii. Expert Rev Mol Med 2011; 13:e31. DOI: https://doi.org/10.1017/s1462399411002018
45. Liesenfeld O, Kosek J, Remington J. Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii. J Exp Med 1996: 184:597-607. DOI: https://doi.10.1084/jem.184.2.597
46. Ferreira PTM, Oliveira-Scussel ACM, Sousa RAP, Gomes BQ, Félix JE, Silva RJ, et al. Macrophage Migration Inhibitory Factor Contributes to Drive Phenotypic and Functional Macrophages Activation in Response to Toxoplasma gondii Infection. Immunobiology 2023; 228:152357. DOI: https://doi:10.1016/j.foodchem.2017.11.114.
47. Suzuki Y, Orellana MA, Schreiber RD, Remington JS. Interferon-γ: The Major Mediator of Resistance Against Toxoplasma gondii. Science 1988; 240:516-18. DOI: https://doi.org/10.1126/science.3128869
48. Denkers EY. From Cells to Signaling Cascades: Manipulation of Innate Immunity by Toxoplasma gondii. FEMS Immunol Med Microbiol 2003; 39:193-203. DOI: https://doi.org/10.1016/s0928-8244(03)00279-7
49. Scharton-Kersten TM, Yap G, Magram J, Sher A. Inducible Nitric Oxide Is Essential for Host Control of Persistent but Not Acute Infection with the Intracellular Pathogen Toxoplasma gondii. J Exp Med 1997; 185:1261-74. DOI: https://doi:10.1084/jem.185.7.1261
50. Halonen SK, Weiss LM. Investigation into the Mechanism of Gamma Interferon-Mediated Inhibition of Toxoplasma gondii in Murine Astrocytes. Infect Immun 2000; 68:3426-30. DOI: https://doi.org/10.1128/iai.68.6.3426-3430.2000
51. Khan IA, Green WR, Kasper LH, Green KA, Schwartzman JD. Immune CD8+ T Cells Prevent Reactivation of Toxoplasma gondii Infection in the Immunocompromised Host. Infect Immun 1999; 67:5869-76. DOI: https://doi:10.1128/IAI.67.11.5869-5876.1999
52. Krishnamurthy S, Konstantinou EK, Young LH, Gold DA, Saeij JPJ. The Human Immune Response to Toxoplasma: Autophagy versus Cell Death. PLoS Pathog 2017; 13:e1006176. DOI: https://doi.org/10.1371/journal.ppat.1006176
53. Suzuki Y, Wang X, Jortner BS, Payne L, Ni Y, Michie SA, et al. Removal of Toxoplasma gondii Cysts from the Brain by Perforin-Mediated Activity of CD8+ T Cells. Am J Pathol 2010; 176:1607-13. DOI: https://doi:10.2353/ajpath.2010.090825
54. Khan IA, Ely KH, Kasper LH. Antigen-specific CD8+ T cell clone protects against acute Toxoplasma gondii infection in mice. J Immunol 1994; 152:1856–60. DOI: https://doi.org/10.4049/jimmunol.152.4.1856
55. Denkers EY, Yap G, Scharton-Kersten T. Perforin-mediated cytolysis plays a limited role in host resistance to Toxoplasma gondii. J Immunol 1997. [access 09/5/2026]; 159:1903-8. Available at: https://pubmed.ncbi.nlm.nih.gov/9257855/
56. Cohen SB, Denkers EY. Border Maneuvers: Deployment of Mucosal Immune Defenses against Toxoplasma gondii. Mucosal Immunol 2014; 7:744-52. DOI: https://doi.org/10.1038/mi.2014.25
57. Israelski DM, Remington JS. Toxoplasmic Encephalitis in Patients with AIDS. Infect Dis Clin N Am 1988. [access 09/5/2026]; 2:429-46. Available at: https://www.id.theclinics.com/article/S0891-5520(20)30196-3/abstract
58. Belkaid Y, Sun CM, Bouladoux N. Parasites and Immunoregulatory T Cells. Curr Opin Immunol 2006; 18:406-12. DOI: https://doi.org/10.1016/j.coi.2006.05.014
59. Mahamed DA, Toussaint LE, Bynoe MS. CD73-Generated Adenosine Is Critical for Immune Regulation during Toxoplasma gondii Infection. Infect Immun 2015; 83:721-9. DOI: https://doi:10.1128/IAI.02536-14
60. Tedford E, McConkey G. Neurophysiological Changes Induced by Chronic Toxoplasma gondii Infection. Pathogens 2017; 6:19. DOI: https://doi:10.3390/pathogens6020019
61. Heimesaat MM, Escher U, Grunau A, Fiebiger U, Bereswill S. Peroral Low-Dose Toxoplasma gondii Infection of Human Microbiota-Associated Mice-A Subacute Ileitis Model to Unravel Pathogen–Host Interactions. Eur J Microbiol Immunol 2018; 8:53-61. DOI: https://doi.org/10.1556/1886.2018.00005
62. Lei H, Schmidt-Bleek K, Dienelt A, Reinke P, Volk HD. Regulatory T Cell-Mediated Anti-Inflammatory Effects Promote Successful Tissue Repair in Both Indirect and Direct Manners. Front Pharmacol 2015; 6:184. DOI: https://doi.org/10.3389/fphar.2015.00184
63. Wang J, Zhao X, Wan YY. Intricacies of TGF-β Signaling in Treg and Th17 Cell Biology. Cell Mol Immunol 2023; 20:1002-22. DOI: https://10.1038/s41423-023-01036-7
64. Fonte L, Acosta A, Sarmiento ME, Ginori M, García G, Norazmi MN. COVID-19 Lethality in Sub-Saharan Africa and Helminth Immune Modulation. Front Immunol 2020; 11:574910. DOI: https://doi:10.3389/fimmu.2020.574910
65. Schlüter D, Barragan A. Advances and Challenges in Understanding Cerebral Toxoplasmosis. Front. Immunol 2019; 10:242. DOI: https://doi.org/10.3389/fimmu.2019.00242
66. Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kühn R. In the Absence of Endogenous IL-10, Mice Acutely Infected with Toxoplasma gondii Succumb to a Lethal Immune Response Dependent on CD4+ T Cells and Accompanied by Overproduction of IL-12, IFN-Gamma and TNF-Alpha. J Immunol 1996; 157:798-805. DOI: https://doi.org/10.4049/jimmunol.157.9.4045
67. Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, et al. TGF-β Signaling in Health, Disease and Therapeutics. Signal Transduct Target Ther 2024; 9:1-40. DOI: https://doi.org/10.1038/s41392-024-01764-w
68. Zhou Q, Shi Y, Chen C, Wu F, Chen Z. A narrative review of the roles of indoleamine 2,3-dioxygenase and tryptophan-2,3-dioxygenase in liver diseases. Ann Trans Med 2021; 9:174. DOI: https://doi:10.21037/atm
69. Ito H, Hoshi M, Ohtaki H, Taguchi A, Ando K, Ishikawa T, et al. Ability of IDO to attenuate liver injury in alpha-galactosylceramide-induced hepatitis model. J Immunol 2010; 185:4554-60. DOI: https://doi:10.4049/jimmunol.0904173
70. Ricci-Azevedo R, Mendonça-Natividade FC, Santana AC, Alcoforado Diniz J., Roque-Barreira, MC. Microneme Proteins 1 and 4 From Toxoplasma gondii Induce IL-10 Production by Macrophages Through TLR4 Endocytosis. Front Immunol 2021; 12:655371. DOI: https://doi:10.3389/fimmu.2021.655371
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