Journal of Otolaryngology and Ophthalmology of Shandong University ›› 2022, Vol. 36 ›› Issue (5): 70-76.doi: 10.6040/j.issn.1673-3770.0.2022.076

Previous Articles    

Research progress on the pathogenesis and control of ocular toxoplasmosis

ZHANG YuOverview,QU YiGuidance   

  1. Department of Geriatrics, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
  • Published:2022-09-20

Abstract: Ocular toxoplasmosis is a unilateral necrotizing retinochoroiditis caused by intraocular infection with Toxoplasma gondii. When people are infected with T.gondii, tachyzoites can cross the blood-retinal barrier and infect most nucleated cells to directly cause tissue damage. At the same time, they can also cause a series of excessive cellular immune responses to further aggravate tissue damage and cause visual impairment. Finally, tachyzoites can create an equilibrium between parasite invasion and host resistance, thus forming tissue cysts in the host. Aside from the traditional drug treatment of pyrimethamine and sulfadiazine in clinical practice, new combined treatment programs and anti-T.gondii compounds have also been studied and applied to achieve precise treatment and reduce the toxic and side effects of systemic drugs. This article focuses on reviewing the pathogenesis and control of ocular toxoplasmosis, together with the current clinical predicaments, so as to provide a theoretical basis for the diagnosis and treatment of this disease in the future.

Key words: Ocular toxoplasmosis, Clinical features, Cellular immunity, Treatment strategies, Drug target

CLC Number: 

  • R774.1
[1] Petersen E, Kijlstra A, Stanford M. Epidemiology of ocular toxoplasmosis[J]. Ocul Immunol Inflamm, 2012, 20(2): 68-75. doi:10.3109/09273948.2012.661115.
[2] Patel NS, Vavvas DG. Ocular toxoplasmosis: a review of current literature[J]. Int Ophthalmol Clin, 2022, 62(2): 231-250. doi:10.1097/IIO.0000000000000419.
[3] Fabiani S, Caroselli C, Menchini M, et al. Ocular toxoplasmosis, an overview focusing on clinical aspects[J]. Acta Trop, 2022, 225: 106180. doi:10.1016/j.actatropica.2021.106180.
[4] 刘莉莉, 招志毅. 弓形虫眼病的诊断与治疗[J]. 医学信息, 2021, 34(9): 54-57. doi:10.3969/j.issn.1006-1959.2021.09.014. LIU Lili, ZHAO Zhiyi. Diagnosis and treatment of toxoplasmosis[J]. Journal of Medical Information, 2021, 34(9): 54-57. doi:10.3969/j.issn.1006-1959.2021.09.014.
[5] Pichi F, Veronese C, Lembo A, et al. New appraisals of Kyrieleis plaques: a multimodal imaging study[J]. Br J Ophthalmol, 2017, 101(3): 316-321. doi:10.1136/bjophthalmol-2015-308246.
[6] Yannuzzi NA, Gal-Or O, Motulsky E, et al. Multimodal imaging of punctate outer retinal toxoplasmosis[J]. Ophthalmic Surg Lasers Imaging Retina, 2019, 50(5): 281-287. doi:10.3928/23258160-20190503-04.
[7] Oliver GF, Ferreira LB, Vieira BR, et al. Posterior segment findings by spectral-domain optical coherence tomography and clinical associations in active toxoplasmic retinochoroiditis[J]. Sci Rep, 2022, 12(1): 1156. doi:10.1038/s41598-022-05070-9.
[8] Jones EJ, Korcsmaros T, Carding SR. Mechanisms and pathways of Toxoplasma gondii transepithelial migration[J]. Tissue Barriers, 2017, 5(1): e1273865. doi:10.1080/21688370.2016.1273865.
[9] Runkle EA, Antonetti DA. The blood-retinal barrier: structure and functional significance[J]. Methods Mol Biol, 2011, 686: 133-148. doi:10.1007/978-1-60761-938-3_5.
[10] Nogueira AR, Leve F, Morgado-Diaz J, et al. Effect of Toxoplasma gondii infection on the junctional complex of retinal pigment epithelial cells[J]. Parasitology, 2016, 143(5): 568-575. doi:10.1017/S0031182015001973.
[11] Ramírez-Flores CJ, Cruz-Mirón R, Arroyo R, et al. Characterization of metalloproteases and serine proteases of Toxoplasma gondii tachyzoites and their effect on epithelial cells[J]. Parasitol Res, 2019, 118(1): 289-306. doi:10.1007/s00436-018-6163-5.
[12] Holtkamp GM, Kijlstra A, Peek R, et al. Retinal pigment epithelium-immune system interactions: cytokine production and cytokine-induced changes[J]. Prog Retin Eye Res, 2001, 20(1): 29-48. doi:10.1016/s1350-9462(00)00017-3.
[13] Lie S, Rochet E, Segerdell E, et al. Immunological molecular responses of human retinal pigment epithelial cells to infection with Toxoplasma gondii[J]. Front Immunol, 2019, 10: 708. doi:10.3389/fimmu.2019.00708.
[14] Song HB, Jun HO, Kim JH, et al. Disruption of outer blood-retinal barrier by Toxoplasma gondii-infected monocytes is mediated by paracrinely activated FAK signaling[J]. PLoS One, 2017, 12(4): e0175159. doi:10.1371/journal.pone.0175159.
[15] Ramírez-Flores CJ, Cruz-Mirón R, Lagunas-Cortés N, et al. Toxoplasma gondii excreted/secreted proteases disrupt intercellular junction proteins in epithelial cell monolayers to facilitate tachyzoites paracellular migration[J]. Cell Microbiol, 2021, 23(3): e13283. doi:10.1111/cmi.13283.
[16] Barragan A, Brossier F, Sibley LD. Transepithelial migration of Toxoplasma gondii involves an interaction of intercellular adhesion molecule 1(ICAM-1)with the parasite adhesin MIC2[J]. Cell Microbiol, 2005, 7(4): 561-568. doi:10.1111/j.1462-5822.2005.00486.x.
[17] Furtado JM, Bharadwaj AS, Chipps TJ, et al. Toxoplasma gondii tachyzoites cross retinal endothelium assisted by intercellular adhesion molecule-1 in vitro[J]. Immunol Cell Biol, 2012, 90(9): 912-915. doi:10.1038/icb.2012.21.
[18] Smith JR, David LL, Appukuttan B, et al. Angiogenic and immunologic proteins identified by deep proteomic profiling of human retinal and choroidal vascular endothelial cells: potential targets for new biologic drugs[J]. Am J Ophthalmol, 2018, 193: 197-229. doi:10.1016/j.ajo.2018.03.020.
[19] Poncet AF, Blanchard N, Marion S. Toxoplasma and dendritic cells: an intimate relationship that deserves further scrutiny[J]. Trends Parasitol, 2019, 35(11): 870-886. doi:10.1016/
[20] Bharadwaj AS, Schewitz-Bowers LP, Wei L, et al. Intercellular adhesion molecule 1 mediates migration of Th1 and Th17 cells across human retinal vascular endothelium[J]. Invest Ophthalmol Vis Sci, 2013, 54(10): 6917-6925. doi:10.1167/iovs.13-12058.
[21] Kalogeropoulos D, Kalogeropoulos C, Sakkas H, et al. Pathophysiological aspects of ocular toxoplasmosis: host-parasite interactions[J]. Ocul Immunol Inflamm, 2021: 1-10. doi:10.1080/09273948.2021.1922706.
[22] Belfort RN, Isenberg J, Fernandes BF, et al. Evaluating the presence of Toxoplasma gondii in peripheral blood of patients with diverse forms of uveitis[J]. Int Ophthalmol, 2017, 37(1): 19-23. doi:10.1007/s10792-016-0221-8.
[23] Weidner JM, Kanatani S, Hernández-Castañeda MA, et al. Rapid cytoskeleton remodelling in dendritic cells following invasion by Toxoplasma gondii coincides with the onset of a hypermigratory phenotype[J]. Cell Microbiol, 2013, 15(10): 1735-1752. doi:10.1111/cmi.12145.
[24] Smith JR, Chipps TJ, Ilias H, et al. Expression and regulation of activated leukocyte cell adhesion molecule in human retinal vascular endothelial cells[J]. Exp Eye Res, 2012, 104: 89-93. doi:10.1016/j.exer.2012.08.006.
[25] Furtado JM, Bharadwaj AS, Ashander LM, et al. Migration of Toxoplasma gondii-infected dendritic cells across human retinal vascular endothelium[J]. Invest Ophthalmol Vis Sci, 2012, 53(11): 6856-6862. doi:10.1167/iovs.12-10384.
[26] Song HB, Jung BK, Kim JH, et al. Investigation of tissue cysts in the Retina in a mouse model of ocular toxoplasmosis: distribution and interaction with glial cells[J]. Parasitol Res, 2018, 117(8): 2597-2605. doi:10.1007/s00436-018-5950-3.
[27] Lahmar I, Pfaff AW, Marcellin L, et al. Müller cell activation and photoreceptor depletion in a mice model of congenital ocular toxoplasmosis[J]. Exp Parasitol, 2014, 144: 22-26. doi:10.1016/j.exppara.2014.06.006.
[28] Reichenbach A, Bringmann A. Glia of the human Retina[J]. Glia, 2020, 68(4): 768-796. doi:10.1002/glia.23727.
[29] Rochet E, Appukuttan B, Ma YF, et al. Expression of long non-coding RNAs by human retinal Müller glial cells infected with clonal and exotic virulent Toxoplasma gondii[J]. Noncoding RNA, 2019, 5(4): E48. doi:10.3390/ncrna5040048.
[30] Knight BC, Kissane S, Falciani F, et al. Expression analysis of immune response genes of Müller cells infected with Toxoplasma gondii[J]. J Neuroimmunol, 2006, 179(1/2): 126-131. doi:10.1016/j.jneuroim.2006.06.002.
[31] Smith JR, Ashander LM, Ma YF, et al. Model systems for studying mechanisms of ocular toxoplasmosis[J]. Methods Mol Biol, 2020, 2071: 297-321. doi:10.1007/978-1-4939-9857-9_17.
[32] Gao FF, Quan JH, Choi IW, et al. FAF1 downregulation by Toxoplasma gondii enables host IRF3 mobilization and promotes parasite growth[J]. J Cell Mol Med, 2021, 25(19): 9460-9472. doi:10.1111/jcmm.16889.
[33] Quan JH, Ismail HAHA, Cha GH, et al. VEGF production is regulated by the AKT/ERK1/2 signaling pathway and controls the proliferation of Toxoplasma gondii in ARPE-19 cells[J]. Front Cell Infect Microbiol, 2020, 10: 184. doi:10.3389/fcimb.2020.00184.
[34] Tedesco RC, Smith RL, Corte-Real S, et al. Ocular toxoplasmosis: the role of retinal pigment epithelium migration in infection[J]. Parasitol Res, 2004, 92(6): 467-472. doi:10.1007/s00436-003-1031-2.
[35] Nagineni CN, Detrick B, Hooks JJ. Toxoplasma gondii infection induces gene expression and secretion of interleukin 1(IL-1), IL-6, granulocyte-macrophage colony-stimulating factor, and intercellular adhesion molecule 1 by human retinal pigment epithelial cells[J]. Infect Immun, 2000, 68(1): 407-410. doi:10.1128/IAI.68.1.407-410.2000.
[36] Spekker-Bosker K, Ufermann CM, Oldenburg M, et al. Interplay between IDO1 and iNOS in human retinal pigment epithelial cells[J]. Med Microbiol Immunol, 2019, 208(6): 811-824. doi:10.1007/s00430-019-00627-4.
[37] Nagineni CN, Detrick B, Hooks JJ. Transforming growth factor-beta expression in human retinal pigment epithelial cells is enhanced by Toxoplasma gondii: a possible role in the immunopathogenesis of retinochoroiditis[J]. Clin Exp Immunol, 2002, 128(2): 372-378. doi:10.1046/j.1365-2249.2002.01815.x.
[38] Lie S, Vieira BR, Arruda S, et al. Molecular basis of the retinal pigment epithelial changes that characterize the ocular lesion in toxoplasmosis[J]. Microorganisms, 2019, 7(10): E405. doi:10.3390/microorganisms7100405.
[39] Ashander LM, Lie S, Ma YF, et al. Neutrophil activities in human ocular toxoplasmosis: an in vitro study with human cells[J]. Invest Ophthalmol Vis Sci, 2019, 60(14): 4652-4660. doi:10.1167/iovs.19-28306.
[40] Raouf-Rahmati A, Ansar AR, Rezaee SA, et al. Local and systemic gene expression levels of IL-10, IL-17 and TGF-β in active ocular toxoplasmosis in humans[J]. Cytokine, 2021, 146: 155643. doi:10.1016/j.cyto.2021.155643.
[41] LIS A, Wiley M, Vaughan J, et al. The activin receptor, activin-like kinase 4, mediates Toxoplasma gondii activation of hypoxia inducible factor-1[J]. Front Cell Infect Microbiol, 2019, 9: 36. doi:10.3389/fcimb.2019.00036.
[42] Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states[J]. Br J Pharmacol, 2016, 173(4): 649-665. doi:10.1111/bph.13139.
[43] Wang LT, Liu Q, Zhang YL, et al. Establishment of BV2 microglia polarization model and its effect on Toxoplasma gondii proliferation[J]. Res Vet Sci, 2019, 125: 382-389. doi:10.1016/j.rvsc.2019.08.002.
[44] Hwang YS, Shin JH, Yang JP, et al. Characteristics of infection immunity regulated by Toxoplasma gondii to maintain chronic infection in the brain[J]. Front Immunol, 2018, 9: 158. doi:10.3389/fimmu.2018.00158.
[45] Liu JF, Huang SG, Lu FL. Galectin-3 and galectin-9 may differently regulate the expressions of microglial M1/M2 markers and T helper 1/Th2 cytokines in the brains of genetically susceptible C57BL/6 and resistant BALB/c mice following peroral infection with Toxoplasma gondii[J]. Front Immunol, 2018, 9: 1648. doi:10.3389/fimmu.2018.01648.
[46] Wang MH, Wong WT. Microglia-Müller cell interactions in the Retina[J]. Adv Exp Med Biol, 2014, 801: 333-338. doi:10.1007/978-1-4614-3209-8_42.
[47] Conedera FM, Pousa AMQ, Mercader N, et al. Retinal microglia signaling affects Müller cell behavior in the zebrafish following laser injury induction[J]. Glia, 2019, 67(6): 1150-1166. doi:10.1002/glia.23601.
[48] Fernandes Felix JP, Cavalcanti Lira RP, Grupenmacher AT, et al. Long-term results of trimethoprim-sulfamethoxazole versus placebo to reduce the risk of recurrent Toxoplasma gondii retinochoroiditis[J]. Am J Ophthalmol, 2020, 213: 195-202. doi:10.1016/j.ajo.2019.12.025.
[49] Feliciano-Alfonso JE, Muñoz-Ortiz J, Marín-Noriega MA, et al. Safety and efficacy of different antibiotic regimens in patients with ocular toxoplasmosis: systematic review and meta-analysis[J]. Syst Rev, 2021, 10(1): 206. doi:10.1186/s13643-021-01758-7.
[50] Casoy J, Nascimento H, Silva LMP, et al. Effectiveness of treatments for ocular toxoplasmosis[J]. Ocul Immunol Inflamm, 2020, 28(2): 249-255. doi:10.1080/09273948.2019.1569242.
[51] Ozgonul C, Besirli CG. Recent developments in the diagnosis and treatment of ocular toxoplasmosis[J]. Ophthalmic Res, 2017, 57(1): 1-12. doi:10.1159/000449169.
[52] Kalogeropoulos D, Sakkas H, Mohammed B, et al. Ocular toxoplasmosis: a review of the current diagnostic and therapeutic approaches[J]. Int Ophthalmol, 2022, 42(1): 295-321. doi:10.1007/s10792-021-01994-9.
[53] Zhang YX, Lin X, Lu FL. Current treatment of ocular toxoplasmosis in immunocompetent patients: a network meta-analysis[J]. Acta Trop, 2018, 185: 52-62. doi:10.1016/j.actatropica.2018.04.026.
[54] Dunphy L, Palmer B, Chen FB, et al. Fulminant diffuse cerebral toxoplasmosis as the first manifestation of HIV infection[J]. BMJ Case Rep, 2021, 14(1): e237120. doi:10.1136/bcr-2020-237120.
[55] Khalili Pour E, Riazi-Esfahani H, Ebrahimiadib N, et al. Acquired immunodeficiency syndrome presented as atypical ocular toxoplasmosis[J]. Case Rep Ophthalmol Med, 2021, 2021: 5512408. doi:10.1155/2021/5512408.
[56] Smith NC, Goulart C, Hayward JA, et al. Control of human toxoplasmosis[J]. Int J Parasitol, 2021, 51(2/3): 95-121. doi:10.1016/j.ijpara.2020.11.001.
[57] Dunay IR, Gajurel K, Dhakal R, et al. Treatment of toxoplasmosis: historical perspective, animal models, and current clinical practice[J]. Clin Microbiol Rev, 2018, 31(4): e00057-e00017. doi:10.1128/CMR.00057-17.
[58] Khan K, Khan W. Congenital toxoplasmosis: an overview of the neurological and ocular manifestations[J]. Parasitol Int, 2018, 67(6): 715-721. doi:10.1016/j.parint.2018.07.004.
[59] Araujo-Silva CA, de Souza W, Martins-Duarte ES, et al. HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics[J]. Int J Parasitol Drugs Drug Resist, 2021, 15: 25-35. doi:10.1016/j.ijpddr.2020.12.003.
[60] Loeuillet C, Touquet B, Guichou JF, et al. A tiny change makes a big difference in the anti-parasitic activities of an HDAC inhibitor[J]. Int J Mol Sci, 2019, 20(12): E2973. doi:10.3390/ijms20122973.
[61] Hopper AT, Brockman A, Wise A, et al. Discovery of selective Toxoplasma gondii dihydrofolate reductase inhibitors for the treatment of toxoplasmosis[J]. J Med Chem, 2019, 62(3): 1562-1576. doi:10.1021/acs.jmedchem.8b01754.
[62] Welsch ME, Zhou J, Gao YQ, et al. Discovery of potent and selective leads against Toxoplasma gondii dihydrofolate reductase via structure-based design[J]. ACS Med Chem Lett, 2016, 7(12): 1124-1129. doi:10.1021/acsmedchemlett.6b00328.
[63] Hajj RE, Tawk L, Itani S, et al. Toxoplasmosis: current and emerging parasite druggable targets[J]. Microorganisms, 2021, 9(12): 2531. doi:10.3390/microorganisms9122531.
[64] Alday PH, Bruzual I, Nilsen A, et al. Genetic evidence for cytochrome b qi site inhibition by 4(1H)-quinolone-3-diarylethers and antimycin in Toxoplasma gondii[J]. Antimicrob Agents Chemother, 2017, 61(2): e01866-e01816. doi:10.1128/AAC.01866-16.
[65] MacLean AE, Bridges HR, Silva MF, et al. Complexome profile of Toxoplasma gondii mitochondria identifies divergent subunits of respiratory chain complexes including new subunits of cytochrome bc1 complex[J]. PLoS Pathog, 2021, 17(3): e1009301. doi:10.1371/journal.ppat.1009301.
[66] Hayward JA, van Dooren GG. Same same, but different: Uncovering unique features of the mitochondrial respiratory chain of api complexans[J]. Mol Biochem Parasitol, 2019, 232: 111204. doi:10.1016/j.molbiopara.2019.111204.
[67] Nilsen A, Miley GP, Forquer IP, et al. Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers[J]. J Med Chem, 2014, 57(9): 3818-3834. doi:10.1021/jm500147k.
[68] Long SJ, Wang QL, Sibley LD. Analysis of noncanonical calcium-dependent protein kinases in Toxoplasma gondii by targeted gene deletion using CRISPR/Cas9[J]. Infect Immun, 2016, 84(5): 1262-1273. doi:10.1128/IAI.01173-15.
[69] Choi R, Hulverson MA, Huang WL, et al. Bumped Kinase Inhibitors as therapy for api complexan parasitic diseases: lessons learned[J]. Int J Parasitol, 2020, 50(5): 413-422. doi:10.1016/j.ijpara.2020.01.006.
[70] Cardew EM, Verlinde CLMJ, Pohl E. The calcium-dependent protein kinase 1 from Toxoplasma gondii as target for structure-based drug design[J]. Parasitology, 2018, 145(2): 210-218. doi:10.1017/S0031182017001901.
[1] Superior semicircular canal dehiscence(SSCD)syndrome occurs as a result of a bony defect of the skull base involving the superior semicircular canal, particularly at the arcuate eminence. The bony labyrinthine defect creates a direct communication between the dura and the labyrinthine membranous structure and acts as a mobile third window which may result in various auditory and vestibular manifestations. Tinnitus and autophony are the most common audiological manifestations. Dizziness and disequilibrium are the most common vestibular manifestations. Audiometric findings vary based on the severity of the disease. Low-frequency conductive hearing loss is a common finding. Bone conduction thresholds may be negative. A patient with SSCD will typically have a lower Vestibular Evoked Myogenic Potentials(VEMP)threshold response in the affected ear and may also have a larger than normal VEMP amplitude. High-resolution computed tomography(CT)scan of temporal bone plays an important role in confirming the diagnosis of SSCD. Pöschl and Stenver reformatted views are often recommended. Surgical treatment is reserved for patients presenting with debilitating vestibular and auditory manifestations that substantially interfere with their quality of life. There are two main surgical approaches(middle fossa, trans-mastoid)and several techniques(plugging, capping, resurfacing and combination). Presently, there is insufficient evidence to clearly determine which surgical approach or technique is superior. Surgical repair of SSCD through either the middle cranial fossa approach or trans-mastoid approach is highly effective for auditory and vestibular symptom improvement and is associated with a low risk of complications.. Superior semicircular canal dehiscence syndrome [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2020, 34(5): 89-96.
[2] Chuangli HAO,Wenjing GU. Recognizing the etiology of chronic cough in children of different ages [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2019, 33(1): 20-24.
[3] YAN Aihui, HAN Jiali. Clinical features and diagnosis of allergic rhinitis. [J]. JOURNAL OF SHANDONG UNIVERSITY (OTOLARYNGOLOGY AND OPHTHALMOLOGY), 2016, 30(4): 7-9.
[4] LI Zhi-wei, ZHANG Han. Murine model of ocular toxoplasmosis and feature of fundus [J]. JOURNAL OF SHANDONG UNIVERSITY (OTOLARYNGOLOGY AND OPHTHALMOLOGY), 2015, 29(2): 81-85.
[5] ZHOU Rong-jin, WANG Jun-guo. Myoepithelial carcinoma in the nasopharynx:a case repot and literature review [J]. JOURNAL OF SHANDONG UNIVERSITY (OTOLARYNGOLOGY AND OPHTHALMOLOGY), 2014, 28(4): 33-34.
[6] FANG Wang1, YANG Xian-zeng2, ZHANG Li1, LI Wen-lin1, ZHONG Hui1, CHEN Ling-yan1. Clinical features and related environmental factors of children′s myopia [J]. JOURNAL OF SHANDONG UNIVERSITY (OTOLARYNGOLOGY AND OPHTHALMOLOGY), 2012, 26(3): 75-78.
Full text



No Suggested Reading articles found!