Parasite in the brain: the role of Toxoplasma gondii in brain cancer and neuropsychiatric disorders

 

Peyman Rabiei 1, Mohammad Esmaeilpour-Bandboni 2 *

1 Department of Veterinary Medicine, Babol-Branch, Islamic Azad University, Babol, Iran

2 Department of Nursing, Zeynab (P.B.U.H) School of Nursing and Midwifery, Guilan University of Medical Sciences, Rasht, Iran

Corresponding Authors: Mohammad Esmaeilpour-Bandboni

 * Email:  esmaeilmmm@yahoo.com

 

Abstract

Toxoplasma gondii (T. gondii) is a protozoan parasite that affects about one-third of the world's human population, frequently creating a dormant presence in the brain. Recent studies have placed growing emphasis on the possible consequences of T. gondii infection concerning brain cancer and neuropsychiatric conditions, such as schizophrenia, bipolar disorder, and depression. This review consolidates recent discoveries regarding how T. gondii could affect neurological well-being, especially its capacity to modify neurotransmitter pathways, adjust immune reactions, and provoke neuroinflammation. We examine the epidemiological links between T. gondii seropositivity and different psychiatric disorders, highlighting the necessity for additional research into the causal mechanisms connecting this parasite to brain pathology. Moreover, we investigate the possibility of T. gondii as a co-factor in developing brain tumors, emphasizing its function in immune evasion and modulation of the tumor microenvironment. Grasping these connections is essential for creating focused therapeutic approaches and public health measures designed to reduce the impact of T. gondii infection on mental health and neuro-oncology.

Keywords: Toxoplasma gondii, Brain cancer, Neuropsychiatric disorders, Neurotransmitter modulation, Neuroinflammation

Introduction

T. gondii is an intracellular protozoan parasite that is obligatory and has attracted considerable attention because of its common occurrence and possible effects on human health (1). It is estimated that as many as 30% of the worldwide population carries this parasite, frequently without showing any symptoms. Nonetheless, persistent infections can result in significant neurological effects, especially if the immune system is weakened or experiences stress (2). The parasite is mainly spread by ingesting oocysts found in contaminated food or water, along with vertical transmission from mother to fetus or via organ transplantation (3). The central nervous system (CNS) acts as a key reservoir for T. gondii, allowing it to create tissue cysts that endure for the lifetime of the host (4). These cysts may reactivate when the immune system is suppressed, resulting in acute toxoplasmosis that can cause serious neurological symptoms like encephalitis or psychological issues (5). The connection between T. gondii infection and several neuropsychiatric disorders has been extensively studied, with research showing a notable link between T. gondii seropositivity and disorders like schizophrenia, bipolar disorder, and depression (6).

Mechanisms of Neuroinvasion

The processes through which T. gondii enters and influences the brain are intricate and varied. Once inside the host's body, T. gondii can traverse the blood-brain barrier (BBB), which is a selectively permeable barrier that shields the brain from pathogens and permits the passage of vital nutrients (7). T. gondii's capability to cross this barrier is linked to its distinctive interactions with host cells and its ability to influence host immune responses. Upon entering the CNS, T. gondii can trigger notable alterations in neurotransmitter systems, especially those related to dopamine and gamma-aminobutyric acid (GABA) (8). Studies have indicated that infected persons may display changed levels of these neurotransmitters, essential for mood control and cognitive abilities (9). For example, increased dopamine levels have been correlated with behavioral alterations seen in both infected humans and animal models, indicating a possible connection between T. gondii infection and psychotic disorders like schizophrenia (10) (Figure 1).


Figure 1. Blood-Brain Barriers and Toxoplasma gondii Invasion. This figure illustrates the complex architecture of the blood-brain barrier (BBB) and how the parasite Toxoplasma gondii can breach these barriers to gain entry into the central nervous system (CNS).

Epidemiological Evidence

A variety of epidemiological studies have indicated elevated seroprevalence rates of T. gondii in individuals with psychiatric disorders when compared to healthy controls (11). For instance, research has shown that individuals with schizophrenia demonstrate seropositivity rates between 50% and over 70%, which is markedly higher than those observed in the general population (12). These results prompt significant inquiries about causality: does infection with T. gondii play a role in initiating or worsening psychiatric symptoms? Or do existing psychological conditions make individuals more susceptible to higher infection rates? Although clear causal pathways are still uncertain, it is evident that a strong connection exists between chronic T. gondii infection and multiple neuropsychiatric conditions (13) (Figure 2).

Figure 2. Toxoplasma gondii-Instigated Diseases. This figure illustrates the various clinical presentations of toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, categorized based on the host’s immune status.


Neuroinflammation and Immune Response

The immune reaction triggered by T. gondii infection is crucial for its effects on brain health. Infected persons frequently show indications of neuroinflammation marked by elevated levels of pro-inflammatory cytokines and stimulation of glial cells in the CNS (14, 15). This inflammatory reaction may result in neuronal injury and add to the cognitive impairments seen in those impacted. Additionally, persistent inflammation might create conditions that promote tumor formation in the brain (16). Recent studies indicate that ongoing inflammation due to long-term infections like those from T. gondii may facilitate tumor growth through processes including immune evasion and changes in local tissue microenvironments (17). This suggests a possible connection between long-term parasitic infections and brain cancer (18, 19) (Figure 3).


Figure 3. Toxoplasma gondii-induced Immune Response and Its Impact on Tumor Cells. This figure illustrates the complex interplay between Toxoplasma gondii (T. gondii) infection, the host immune response, and tumor cells. The shapes represent different types of cells and molecules involved in this interaction. Arrows indicate T. gondii invading both tumor cells and DCs. T. gondii infection activates DCs, leading to the upregulation of co-stimulatory molecules (CD80, CD86), enhancing their ability to stimulate T-cell responses. T. gondii infection stimulates DCs to produce IL-12, a cytokine that promotes Th1 immune responses, including the activation of CD8+ T cells and NK cells.

Toxoplasma gondii and Neuropsychiatric Disorders

Toxoplasma gondii, a prevalent neurotropic parasite, has become more associated with several neuropsychiatric disorders in humans. These links encompass schizophrenia, Alzheimer's disease, and Parkinson's disease, although the precise pathogenic mechanisms are still not fully understood. T. gondii can remain in the brain as tissue cysts, requiring an ongoing immune response to stop the reactivation of the infection (20, 21). Chronic infection is especially worrying, as evidence indicates it can result in neurodegeneration in certain areas of the brain, like the anterior cingulate cortex and somatomotor cortex, impacting both glutamatergic and GABAergic neurons (22, 23).  Changes in behavior among infected individuals may be partially linked to variations in neurotransmitter levels, especially dopamine. Research has shown that T. gondii infection is linked to heightened dopamine metabolism, a component associated with the onset of schizophrenia (20). This connection is additionally reinforced by evidence indicating that those with T. gondii antibodies might display elevated rates of aggression, impulsivity, and possibly heightened risks for suicide and traffic accidents, hinting at wider behavioral consequences (24, 25). The neuroinflammatory reaction initiated by T. gondii infection significantly impacts neurobiology, possibly resulting in alterations in neurotransmitter receptor quantities and synaptic connections (26). This inflammation may play a role in the development and progression of multiple neurodegenerative diseases, since long-term T. gondii infection might encourage neurodegeneration and neurocognitive irregularities (6, 23, 27). Studies persist in investigating the intricate connection between T. gondii infection and neuropsychiatric effects, which affects our comprehension of the mechanisms behind behavioral alterations and the possibilities for preventive measures (28).

Conclusion

The relationship between Toxoplasma gondii (T. gondii) infection and brain tumors has garnered increasing attention in the scientific community, particularly regarding its implications for public health and cancer prevention strategies. This study demonstrates a significant association between T. gondii infection and various types of brain tumors, including gliomas and meningiomas. The findings underscore the need for further research to elucidate this association's underlying mechanisms and explore potential therapeutic avenues. Recent studies consistently show a higher prevalence of T. gondii seropositivity among patients with brain tumors compared to healthy individuals. For instance, a systematic review and meta-analysis identified an overall odds ratio (OR) of 1.96 for the link between T. gondii infection and brain tumors, with specific ORs of 1.64 for gliomas and 2.30 for meningiomas. These findings suggest that individuals exposed to T. gondii may have approximately double the risk of developing brain tumors, highlighting the need for further investigation. One proposed mechanism by which this parasite may contribute to tumorigenesis is its ability to modulate the tumor microenvironment. The parasite’s invasion and persistence in the central nervous system could lead to chronic inflammation, which may promote tumor growth. Research indicates that T. gondii can increase tumor cell proliferation by downregulating antitumor genes such as PTEN and FoxO1. This suggests that T. gondii not only affects immune responses but also alters critical signaling pathways involved in cell growth and survival.

Future Research Directions

While existing studies provide compelling evidence of an association between T. gondii infection and brain tumors, several critical gaps remain in our understanding (29, 30). First, it is essential to establish the causal relationship between infection and tumor development through well-designed cohort studies that control for confounding factors such as age, immune status, and other environmental exposures. Additionally, we need to determine whether the development of tumors creates a favorable environment for parasite growth or if pre-existing tumors contribute to this process. Moreover, it is crucial to investigate the biological mechanisms underlying this association. Future research should focus on elucidating how host immune responses are altered and how these changes modulate cellular pathways involved in oncogenesis. Understanding these mechanisms could lead to novel therapeutic strategies that target T. gondii as a potential risk factor for brain tumors (31, 32).

Implications for Public Health

The implications of these findings extend beyond academic interest and raise important public health considerations. With T. gondii infections estimated to affect around one-third of the global population, there is an urgent need for public health initiatives aimed at reducing exposure to this parasite (33, 34). Improved cooking and sanitation practices can help lower transmission risks. Additionally, screening programs targeting high-risk populations can facilitate early detection and intervention for those with chronic infections. Understanding the link between infectious agents like T. gondii and cancer can strengthen our cancer prevention efforts by identifying modifiable risk factors (35, 36). In conclusion, the evidence connecting Toxoplasma gondii infection to an increased risk of brain tumors is compelling, but further exploration is necessary to fully comprehend its implications for cancer development and public health (37). The relationship among chronic infection, immune modulation, and tumor growth presents a complex landscape that requires interdisciplinary research efforts. By clarifying these connections, we can enhance prevention strategies and potentially develop targeted therapies that address both the management of infectious diseases and cancer treatment.

Author contribution

PR was involved in the investigation, methodology, and writing the primary draft of the manuscript, MEB was involved as a supervisor in all sections of the manuscript including conceptualization, writing, reviewing and also editing. All the authors studied the final version of the paper and acknowledged it.

Conflict of interest

There is no Conflicts of interest/competing interests.

Funding

There is no funding.

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