Toxoplasma gondii-Driven Cytokine Dysregulation as a Differentiating Biomarker Between Schizophrenia and Depression

Authors

DOI:

https://doi.org/10.57235/jetish.v5i2.9011

Keywords:

Depression, immune biomarkers, neuroinflammation, schizophrenia, Toxoplasma gondii

Abstract

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

Download data is not yet available.

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

2026-08-10

Citation Check