Toxoplasma gondii-Driven Cytokine Dysregulation as a Differentiating Biomarker Between Schizophrenia and Depression
DOI:
https://doi.org/10.57235/jetish.v5i2.9011Keywords:
Depression, immune biomarkers, neuroinflammation, schizophrenia, Toxoplasma gondiiAbstract
Schizophrenia and depression are among the most prevalent psychiatric disorders, and both have been mechanistically linked to systemic and neuroinflammatory processes. Infection with the protozoan parasite Toxoplasma gondii has been proposed as a potential trigger of these inflammatory pathways, yet direct comparisons of proinflammatory cytokine profiles between the two disorders in the context of T. gondii infection remain scarce. Consequently, it is still unclear whether schizophrenia and depression share a common toxoplasmosis-associated inflammatory signature or instead display distinct immunological fingerprints. This systematic review aimed to characterize the proinflammatory cytokine biomarker patterns—particularly IL-6, IFN-γ, and TNF-α—among T. gondii-infected patients with schizophrenia and depression. Conducted in accordance with the PRISMA 2020 guidelines and the PICO framework, the review searched PubMed Central, PubMed, ScienceDirect, and Scopus for original English-language studies published between 2021 and 2025. Of 454 records initially retrieved and screened for eligibility using Mendeley Reference Manager, five studies satisfied all inclusion criteria. The synthesis revealed that toxoplasmosis-associated schizophrenia was characterized by elevated MCP-1, RANTES, GRO-α, IP-10, and IL-8, along with reduced MIP-1α, MIP-1β, and IL-8, whereas toxoplasmosis-associated depression was primarily characterized by increased IL-6 and TNF-α. These divergent cytokine patterns suggest that chronic T. gondii infection induces disorder-specific immune dysregulation rather than a uniform inflammatory response. Such distinct profiles may hold promise as biomarkers for differentiating infection-related psychiatric subtypes and could inform the development of more targeted, immunomodulatory therapeutic strategies for affected patients
Downloads
References
Abramova, O., Zorkina, Y., Goncharov, D., Abbazova, E., Baranets, M., Berdalin, A., Ushakova, V., Zakurazhnaya, V., Morozova, I., Ochneva, A., Pavlov, K., Andreyuk, D., Kostyuk, G., & Morozova, A. (2025). Association of Neurobiological and Immune Serum Biomarkers with Toxoplasma gondii Infection in Patients with Schizophrenia. Parasitology Research, 124(53), 1–18. https://doi.org/10.1007/S00436-025-08498-W
Ali, N. A. H., & Al-Hadraawy, S. K. (2024). Immune Response Dynamics and Chemokine Profile from MCP-1 and MIP-1α in Toxoplasma gondii Infection. Journal of Angiotherapy, 8(3), 1–5. https://doi.org/10.25163/angiotherapy.839645
Andreou, D., Steen, N. E., Mørch-Johnsen, L., Jørgensen, K. N., Wortinger, L. A., Barth, C., Szabo, A., O’Connell, K. S., Lekva, T., Hjell, G., Johansen, I. T., Ormerod, M. B. E. G., Haukvik, U. K., Aukrust, P., Djurovic, S., Yolken, R. H., Andreassen, O. A., Ueland, T., & Agartz, I. (2024). Toxoplasma gondii Infection Associated with Inflammasome Activation and Neuronal Injury. Scientific Reports, 14(5327), 1–9. https://doi.org/10.1038/S41598-024-55887-9
Barrios, L. C., Pinheiro, A. P. D. S., Gibaldi, D., Silva, A. A., Silva, P. M. R. e, Roffê, E., Santiago, H. da C., Gazzinelli, R. T., Mineo, J. R., Silva, N. M., & Lannes-Vieira, J. (2021). Behavioral Alterations in Long-Term Toxoplasma gondii Infection of C57BL/6 Mice are Associated with Neuroinflammation and Disruption of the Blood Brain Barrier. PLoS ONE, 16, 1–30. https://doi.org/10.1371/journal.pone.0258199
Benkarim, O., Paquola, C., Park, B. Y., Kebets, V., Hong, S. J., Vos de Wael, R., Zhang, S., Yeo, B. T. T., Eickenberg, M., Ge, T., Poline, J. B., Bernhardt, B. C., & Bzdok, D. (2022). Population Heterogeneity in Clinical Cohorts Affects the Predictive Accuracy of Brain Imaging. In PLoS Biology (Vol. 20, Issue 4). https://doi.org/10.1371/journal.pbio.3001627
Bisetegn, H., Debash, H., Ebrahim, H., Mahmood, N., Gedefie, A., Tilahun, M., Alemayehu, E., Mohammed, O., & Feleke, D. G. (2023). Global Seroprevalence of Toxoplasma gondii Infection among Patients with Mental and Neurological Disorders: A Systematic Review and Meta‐Analysis. Health Science Reports, 6(6), 1–15. https://doi.org/10.1002/hsr2.1319
Bishop, J. R., Zhang, L., & Lizano, P. (2022). Inflammation Subtypes and Translating Inflammation-Related Genetic Findings in Schizophrenia and Related Psychoses: A Perspective on Pathways for Treatment Stratification and Novel Therapies. Harvard Review of Psychiatry, 30(1), 59–70. https://doi.org/10.1097/HRP.0000000000000321
Chang, J., Jiang, T., Shan, X., Zhang, M., Li, Y., Qi, X., Bian, Y., & Zhao, L. (2024). Pro-Inflammatory Cytokines in Stress-Induced Depression: Novel Insights into Mechanisms and Promising Therapeutic Strategies. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 131, 1–18. https://doi.org/10.1016/j.pnpbp.2023.110931
Chirico, F. (2023). Cross-Sectional Studies in Occupational Health Research: An Overview of Strengths and Limitations. Italian Journal of Psychology and Occupational Health, 3(3), 86–93. https://doi.org/10.69088/2023/CRSS2
Comai, S., Manchia, M., Bosia, M., Miola, A., Poletti, S., Benedetti, F., Nasini, S., Ferri, R., Rujescu, D., Leboyer, M., Licinio, J., Baune, B. T., & Serretti, A. (2025). Moving Toward Precision and Personalized Treatment Strategies in Psychiatry. International Journal of Neuropsychopharmacology, 28(5), 1–13. https://doi.org/10.1093/ijnp/pyaf025
Eberhard, J. N., Shallberg, L. A., Winn, A., Chandrasekaran, S., Giuliano, C. J., Merritt, E. F., Willis, E., Konradt, C., Christian, D. A., Aldridge, D. L., Bunkofske, M. E., Jacquet, M., Dzierszinski, F., Katifori, E., Lourido, S., Koshy, A. A., & Hunter, C. A. (2025). Immune Targeting and Host-Protective Effects of the Latent Stage of Toxoplasma gondii. Nature Microbiology, 10(4), 992–1005. https://doi.org/10.1038/s41564-025-01967-z
Everett, A., & Elsheikha, H. M. (2025). Neuroinflammation and Schizophrenia: The Role of Toxoplasma gondii Infection and Astrocytic Dysfunction. Journal of Neuroimmunology, 403, 1–8. https://doi.org/10.1016/j.jneuroim.2025.578588
Fernandes, S. M., Dias, A. R., & Miranda-Scippa, Â. (2021). Association between Exposure to Toxoplasmosis and Major Psychiatric Disorders: A Systematic Review. Brazilian Journal of Psychiatry, 43(4), 438–445. https://doi.org/10.1590/1516-4446-2020-0904
Flegr, J., & Horáček, J. (2020). Negative Effects of Latent Toxoplasmosis on Mental Health. Frontiers in Psychiatry, 10, 1–8. https://doi.org/10.3389/fpsyt.2019.01012
Friesema, I. H. M., Hofhuis, A., Hoek-Van Deursen, D., Jansz, A. R., Ott, A., Hellemond, J. J. Van, Giessen, J. Van Der, Kortbeek, L. M., & Opsteegh, M. (2023). Risk Factors for Acute Toxoplasmosis in the Netherlands. Epidemiology and Infection, 151(e95), 1–6. https://doi.org/10.1017/S0950268823000808
Gajewski, P. D., Bröde, P., Claus, M., Golka, K., Hengstler, J. G., Reinders, J., Watzl, C., Wascher, E., & Getzmann, S. (2025). Changes of Cognitive Functions and Proinflammatory Cytokines Across the Lifespan in Latent Toxoplasma gondii Infection. Brain, Behavior, & Immunity - Health, 49, 1–16. https://doi.org/10.1016/j.bbih.2025.101105
Gorji, A. (2022). Neuroinflammation : The Pathogenic Mechanism of Neurological Disorders. International Journal of Molecular Sciences, 23(10), 1–5.
Grada, S., Mihu, A. G., Petrescu, C., Suciu, O., Marincu, I., Lupu, M. A., & Olariu, T. R. (2022). Toxoplasma gondii Infection in Patients with Psychiatric Disorders from Western Romania. Medicina, 58(2), 1–7. https://doi.org/10.3390/MEDICINA58020208
Guo, T., Chen, L., Luan, L., Yang, M., Zhang, X., & Yang, H. (2024). Variations in Inflammatory Regulators in Male Patients with Chronic Schizophrenia Associated with Psychopathology and Cognitive Deficits. BMC Psychiatry, 24(811), 1–11. https://doi.org/10.1186/s12888-024-06288-9
Haddaway, N. R., Page, M. J., Pritchard, C. C., & McGuinness, L. A. (2022). PRISMA2020: An R package and Shiny App for Producing PRISMA 2020-Compliant Flow Diagrams, with Interactivity for Optimised Digital Transparency and Open Synthesis. In Campbell Systematic Reviews. John Wiley & Sons, Ltd. https://doi.org/https://doi.org/10.1002/cl2.1230
Harsanyi, S., Kupcova, I., Danisovic, L., & Klein, M. (2023). Selected Biomarkers of Depression : What are the Effects of Cytokines and Inflammation? International Journal of Molecular Sciences, 24(1), 1–25.
Hasegawa, T., Oka, T., & Demehri, S. (2022). Alarmin Cytokines as Central Regulators of Cutaneous Immunity. Frontiers in Immunology, 13, 1–13. https://doi.org/10.3389/fimmu.2022.876515
Hassamal, S. (2023). Chronic Stress, Neuroinflammation, and Depression: An Overview of Pathophysiological Mechanisms and Emerging Anti-Inflammatories. Frontiers in Psychiatry, 14, 1–18. https://doi.org/10.3389/fpsyt.2023.1130989
Jańczak, D., Stryjek, R., Maj, A. K., Olszewski, J., & Szaluś-Jordanow, O. (2025). PCR Detection, Genotyping, and Differentiation of Toxoplasma gondii from Hammondia hammondi Excreted in the Feces of Cats in Poland Between 2020 and 2024. Pathogens, 14(5), 1–20. https://doi.org/10.3390/pathogens14050444
Kip, E., & Parr-Brownlie, L. C. (2023). Healthy Lifestyles and Wellbeing Reduce Neuroinflammation and Prevent Neurodegenerative and Psychiatric Disorders. Frontiers in Neuroscience, 17, 1–18. https://doi.org/10.3389/fnins.2023.1092537
Li, X., Zhou, W., & Yi, Z. (2022). A Glimpse of Gender Differences in Schizophrenia. General Psychiatry, 35(4), 1–3. https://doi.org/10.1136/gpsych-2022-100823
Liu, R., Liu, L., Ren, S., Wei, C., Wang, Y., Li, D., & Zhang, W. (2023). The Role of IL-33 in Depression: A Systematic Review and Meta-Analysis. Frontiers in Psychiatry, 14, 1–12. https://doi.org/10.3389/fpsyt.2023.1242367
Lopes, C. S., Carvalho, R. J. V., da Silva, T. L., Barros, H. L. S., Costa, L. V. S., Mota, D. C. A. M., Barbosa, B. F., Vieira, L. S., de Araújo, T. M., Costa, A. R., Awoyinka, R. O., Mineo, T. W. P., Diniz, A. L. D., & Mineo, J. R. (2025). Pregnant Women Chronically Infected by Toxoplasma gondii with Depressive Disorder: Differential Modulation of Pro-Inflammatory and Anti-Inflammatory Cytokines. Pathogens, 14(330), 1–15. https://doi.org/10.3390/PATHOGENS14040330
Lv, H., Guo, M., Guo, C., & He, K. (2024). The Interrelationships between Cytokines and Schizophrenia : A Systematic Review. International Journal of Molecular Sciences, 25(15), 1–20.
Ma, X. zhen, Chen, L. lei, Qu, L., Li, H., Wang, J., Song, N., & Xie, J. xia. (2024). Gut Microbiota-Induced CXCL1 Elevation Triggers Early Neuroinflammation in the Substantia Nigra of Parkinsonian Mice. Acta Pharmacologica Sinica, 45(1), 52–65. https://doi.org/10.1038/s41401-023-01147-x
Maulana, H., Mawarpury, M., & Fourianalistyawati, E. (2022). Prevalensi Depresi pada Wanita dengan Riwayat Keguguran: Studi Berbasis Data IFLS-5. Jurnal Psikologi Ulayat, 10(1), 23–38. https://doi.org/10.24854/jpu469
Miller, A. H., Berk, M., Bloch, G., Briquet-Laugier, V., Brouillon, C., Cuthbert, B. N., Dantzer, R., Davis, M. C., De Picker, L. J., Drevets, W. C., Eyre, H. A., Hack, L. M., Harrison, N. A., Krystal, A. D., Lombardo, G., Mondelli, V., Pariante, C. M., Pulvirenti, L., Salvadore, G., … Leboyer, M. (2025). Advancing Precision Psychiatry and Targeted Treatments: Insights from Immunopsychiatry. Brain, Behavior, and Immunity, 125, 319–329. https://doi.org/10.1016/j.bbi.2025.01.002
Moghaddami, R., Mahdipour, M., & Ahmadpour, E. (2024). Inflammatory Pathways of Toxoplasma gondii Infection in Pregnancy. Travel Medicine and Infectious Disease, 62(6), 1–9. https://doi.org/10.1016/j.tmaid.2024.102760
Moradi, F., Dashti, N., Farahvash, A., Baghaei Naeini, F., & Zarebavani, M. (2023). Curcumin Ameliorates Chronic Toxoplasma gondii Infection-Induced Affective Disorders through Modulation of Proinflammatory Cytokines and oxidative stress. Iranian Journal of Basic Medical Sciences, 26(4), 461–467. https://doi.org/10.22038/IJBMS.2023.68487.14937
Pawełczyk, A., Bednarska, M., Cortés, K. C., Glamkowska-Sady, M., Kowalska, J., Uszyńska-Kałuża, B., Radkowski, M., & Welc-Falęciak, R. (2022). Seronegative Infection with Toxoplasma gondii in Asymptomatic Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Patients and in Blood Donors. Journal of Clinical Medicine, 11(3), 1–10. https://doi.org/10.3390/jcm11030638
Perry, B. I., Upthegrove, R., Kappelmann, N., Jones, P. B., Burgess, S., & Khandaker, G. M. (2021). Associations of Immunological Proteins/Traits with Schizophrenia, Major Depression and Bipolar Disorder: A Bi-Directional Two-Sample Mendelian Randomization Study. Brain, Behavior, and Immunity, 97, 176–185. https://doi.org/10.1016/j.bbi.2021.07.009
Pino, L. E. B. del, & Zanón-Moreno, V. (2024). Systematic Review on the Relationship between Toxoplasmosis and Mental Disorders. Actas Espanolas de Psiquiatria, 52(2), 149–160. https://doi.org/10.62641/aep.v52i2.1658
Poursalar, A., Astaraki, P., Khalaf, A. K., Baharvand, P., Sepahvand, A., Fallahi, S., & Mahmoudvand, H. (2025). Epidemiological Aspects and Inflammatory Cytokine Profiles Associated with Toxoplasma gondii Infection in Suicide Attempters in Iran. BMC Infectious Diseases, 25(834), 1–12. https://doi.org/10.1186/S12879-025-11200-1
Rantala, M. J., Luoto, S., Borráz-León, J. I., & Krams, I. (2022). Schizophrenia: The New Etiological Synthesis. Neuroscience and Biobehavioral Reviews, 142, 1–21. https://doi.org/10.1016/j.neubiorev.2022.104894
Sadek, A. S. M., & Mahmoud, R. H. (2026). From Parasite-Induced Immune Activation to Neuroinflammation and Behavioral Dysfunction: Convergent Mechanisms Across Protozoa and Helminths: A Review. Journal of Neuroinflammation, 23(129), 1–24. https://doi.org/10.1186/s12974-026-03804-4
Seizova, S., Ruparel, U., Garnham, A. L., Bader, S. M., Uboldi, A. D., Coffey, M. J., Whitehead, L. W., Rogers, K. L., & Tonkin, C. J. (2022). Transcriptional Modification of Host Cells Harboring Toxoplasma gondii Bradyzoites Prevents IFN Gamma-Mediated Cell Death. Cell Host and Microbe, 30(2), 232–247. https://doi.org/10.1016/j.chom.2021.11.012
Shi, W. Q., Bai, S. Y., Pan, M., Jin, Q. W., Liu, Z., Bo, X., & Huang, S. Y. (2025). Chronic Toxoplasmosis Induces Depression-Like Behaviors and Neuroinflammatory Responses in Mice. Acta Tropica, 264, 1–8. https://doi.org/10.1016/j.actatropica.2025.107568
Shnayder, N. A., Khasanova, A. K., Strelnik, A. I., Al-Zamil, M., Otmakhov, A. P., Neznanov, N. G., Shipulin, G. A., Petrova, M. M., Garganeeva, N. P., & Nasyrova, R. F. (2022). Cytokine Imbalance as a Biomarker of Treatment-Resistant Schizophrenia. International Journal of Molecular Sciences, 23(19), 1–23. https://doi.org/10.3390/ijms231911324
Silva, Z. M., Toledo, D. N. M., Pio, S., Machado, B. A. A., Santos, P. V. dos, Hó, F. G., Medina, Y. N., Cordeiro, P. H. de M., Perucci, L. O., Pinto, K. M. de C., & Talvani, A. (2024). Neuroserpin, IL-33 and IL-17A as Potential Markers of Mild Symptoms of Depressive Syndrome in Toxoplasma gondii-Infected Pregnant Women. Frontiers in Immunology, 15, 1–10. https://doi.org/10.3389/FIMMU.2024.1394456
Spezani, R., & Mandarim-de-Lacerda, C. A. (2026). Beyond Diabetes and Obesity: GLP-1 Receptor Agonists in Disrupting the Vicious Cycle of Metabolic Dysfunction and Neuroinflammation. Diabetes, Obesity and Metabolism, 28(3), 1622–1637. https://doi.org/10.1111/dom.70400
Szabo, A., O‘Connell, K. S., Ueland, T., Sheikh, M. A., Agartz, I., Andreou, D., Aukrust, P., Boye, B., Bøen, E., Drange, O. K., Elvsåshagen, T., Engh, J. A., Hope, S., Collier Høegh, M., Joa, I., Johnsen, E., Kroken, R. A., Vik Lagerberg, T., Lekva, T., … Djurovic, S. (2022). Increased Circulating IL-18 Levels in Severe Mental Disorders Indicate Systemic Inflammasome Activation. Brain, Behavior, and Immunity, 99(1), 299–306. https://doi.org/10.1016/j.bbi.2021.10.017
Thebault, A., Kooh, P., Cadavez, V., Gonzales-barron, U., & Villena, I. (2021). Risk Factors for Sporadic Toxoplasmosis: A Systematic Review and Meta-Analysis. Microbial Risk Analysis, 17, 1–12. https://doi.org/10.1016/j.mran.2020.100133
Tsuboi, H., Sakakibara, H., Minamida-Urata, Y., Tsujiguchi, H., Hara, A., Suzuki, K., Miyagi, S., Nakamura, M., Takazawa, C., Kannon, T., Zhao, J., Shimizu, Y., Shibata, A., Ogawa, A., Suzuki, F., Kambayashi, Y., Konoshita, T., Tajima, A., & Nakamura, H. (2024). Serum TNFα and IL-17A Levels may Predict Pncreased Depressive Symptoms: Findings from the Shika Study Cohort Project in Japan. BioPsychoSocial Medicine, 18(20), 1–11. https://doi.org/10.1186/s13030-024-00317-5
Tunç, K. C., & Erbaş, O. (2022). Mental Health Disorders Associated with Bartonella spp. and Toxoplasma gondii. Journal of Experimental and Basic Medical Sciences, 3(3), 259–263. https://doi.org/10.5606/jebms.2022.1037
Ullmann, J., Flegr, J., Nouzová, K., Včelák, J., & Kaňková, S. (2025). Chronic Inflammation in Pregnant Women with Latent Toxoplasmosis and Explanation of Discordant Results of Serological Tests for Toxoplasmosis. Folia Parasitologica, 72(021), 1–11. https://doi.org/10.14411/fp.2025.021
Ureña, N. M. L., Chaudhry, U., Bernal, R. C., Alsua, S. C., Messina, D., Evangelista, F., Betson, M., Lalle, M., Jokelainen, P., Mora, L. M. O., & García, G. Á. (2022). Contamination of Soil, Water, Fresh Produce, and Bivalve Mollusks with Toxoplasma gondii Oocysts: A Systematic Review. Microorganisms, 10(3), 1–38. https://doi.org/10.3390/microorganisms10030517
Vida, H., Sahar, M., Nikdouz, A., & Arezoo, H. (2025). Chemokines in Neurodegenerative Diseases. Immunology and Cell Biology, 103(3), 275–292. https://doi.org/10.1111/imcb.12843
Virus, M. A., Ehrhorn, E. G., Lui, L. A. M., & Davis, P. H. (2021). Neurological and Neurobehavioral Disorders Associated with Toxoplasma gondii Infection in Humans. Journal of Parasitology Research, 2021(1), 1–18. https://doi.org/10.1155/2021/6634807
Wang, Q., Zhong, Y., Chen, N., & Chen, J. (2023). From the Immune System to Mood Disorders Especially Induced by Toxoplasma gondii: CD4+ T Cell as a Bridge. Frontiers in Cellular and Infection Microbiology, 13, 1–16. https://doi.org/10.3389/FCIMB.2023.1078984
Xu, L., Yang, H., Chen, W., Yang, M., Zhang, J., Zhang, X., & Tang, X. (2025). Associations of Serum TNF-α, IL-8, and IL-18 Levels with the Clinical Symptoms in Acute Schizophrenia: A Cross-Sectional Study. BMC Psychiatry, 25(1096), 1–9. https://doi.org/10.1186/s12888-025-07549-x
Yu, H., Li, R., Liang, X., Yang, W.-M., Guo, L., Liu, L., Tan, Q. R., & Peng, Z. (2024). A Cross-Section Study of the Comparison of Plasma Inflammatory Cytokines and Short-Chain Fatty Acid in Patients with Depression and Schizophrenia. BMC Psychiatry, 24(834), 1–12.
Zhao, X., Zhu, W., Bu, Y., Li, J., Hao, Y., & Bi, Y. (2024). Effects of 6-Week Olanzapine Treatment on Serum IL-2, IL-4, IL-8, IL-10, and TNF-α Levels in Drug-Naive Individuals with First-Episode Schizophrenia. BMC Psychiatry, 24(703), 1–10. https://doi.org/10.1186/s12888-024-06163-7
Downloads
Published
Issue
Section
Citation Check
License
Copyright (c) 2026 Lathifatul Azka Nurul Aini, Dita Pratiwi Kusuma Wardani, Isna Hikmawati, Ikhsan Mujahid

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors are copyright holders and maintain author rights in accordance with the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) or comparable license. While holding these rights, authors grant the JETISH: Journal of Education Technology Information Social Sciences and Health (publisher of JETISH) a non-exclusive right to the first publication of their articles, including abstracts. This enables us to ensure full copyright protection and to disseminate the article to the widest possible readership in electronic format. Authors are themselves responsible for obtaining permission to reproduce copyright material from other sources.










