Toxoplasma gondii, a plea for a thorough investigation of its oncogenic potential

Abstract

It is estimated that 30 % of the world's population harbours the parasite Toxoplasma gondii, particularly in the brain. Beyond its implication in potentially severe opportunistic or congenital infections, this persistence has long been considered as without consequence. However, certain data in animals and humans suggest that this carriage may be linked to various neuropsychiatric or neurodegenerative disorders. The hypothesis of a potential cerebral oncogenicity of the parasite is also emerging. In this personal view, we will present the epidemiological arguments in favour of an association between toxoplasmosis and cerebral malignancy, before considering the points that could underlie a potential causal link. More specifically, we will focus on the brain as the preferred location for T. gondii persistence and the propensity of this parasite to interfere with the apoptosis and cell cycle signalling pathways of their host cell.

Keywords: Apoptosis; Brain; Cancer; Cell cycle; Toxoplasma.

Fig. 1

Schematic representation of the tumoral process. The tumoral process is characterized by the progressive acquisition by normal cells of characteristics that allow them to become cancerous. It is favoured by the occurrence of genetic or epigenetic alterations affecting 3 types of genes: (i) Pro-oncogenes which play a major role in cell proliferation, differentiation and survival, and which uncontrolled activation leads to the formation of tumoral cells, (ii) Tumour suppressor genes whose main function is to counter cell proliferation to allow DNA repair, and cell apoptosis in case it has failed. The mutation of these genes leads to their inactivation thus signalling non-proliferation. For example, p53 protein is coded by a gene of the tumour suppressor family, which is found mutated in approximately 50 % of human cancers. (iii) The alteration of genes maintaining the human genome integrity code for repair systems of damaged DNA (BRCA1, rad50, MLH-1) leads to an increased susceptibility to cancers because of genetic instability. Among the characteristics of cancer cells are the ability to resist cell death and proliferate, to promote vascularization and invasion, or to resist destruction by immunity. Created with Biorender.

Fig. 2

Schematic representation of the mechanisms of inhibition of apoptosis byToxoplasma gondii. Apoptosis can be triggered by intrinsic or extrinsic stimuli. The extrinsic pathway requires the binding of extracellular ligands to their membrane receptors such as Fas, which induces the activation of the initiating caspases 8 and 10. These caspases in turn activate effector caspases such as caspase 3. The intrinsic pathway is regulated by the balance between pro (Bim, Bid, Bad, Bax and Bak) and anti-apoptotic (Bcl-2, Bcl-XL, Mcl-1 or Bfl-1) proteins of the Bcl-2 family and involves mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome C which binds to the cytoplasmic protein APAF-1 to form the apoptosome that activates the initiator caspase 9. In parallel, T and NK cells can also induce apoptosis through the perforin/granzyme pathway. The influence of Toxoplasma gondii can be exerted, depending on the cell type, the parasite strain and infection stage, (i) on the intrinsic pathway via the decrease in cytochrome c release, apoptosome formation and caspase 9 activation, or via the NF-κB pathway and modification of the balance between pro- and anti-apoptotic proteins, (ii) on the extrinsic pathway via inhibition of caspase 8 activation, (iii) or on the perforin/granzyme pathway. Created with Biorender.

Fig. 3

Influence ofToxoplasma gondiion the cell cycle of the host cell. The cell cycle consists of four successive phases G1, S (DNA replication), G2 and M (mitosis). Its progression is finely regulated by the action of cyclins and their associated cyclin-dependent kinases. T. gondii exerts a positive effect on host cell cycle initiation via induction of cyclin E by TEEGR, but this stimulation is followed by a blockage of the transition from G2 to M phase. Created with Biorender.