PROJET LatentToxoDiag

A new diagnostic toolbox for serodetection of persistent parasites for better management of toxoplasmosis in human medicine.

Ce projet est porté par l’INSERM – CNRS – CHU Grenoble Alpes – Université Grenoble Alpes.

CONTEXT

Les TETs sont des tumeurs rares intrathoraciques qui se développent au dépend du médiastin antérieur. Ces tumeurs surviennent vers l’âge de 50ans, sans Toxoplasma gondii, a significant parasitic threat, poses major health and economic challenges worldwide. Typically asymptomatic in healthy individuals, it can cause serious neurological and eye diseases, and other infections in those with compromised immune systems. Pregnant women with toxoplasmosis face risks of miscarriages, and it can lead to severe conditions like mental disabilities, hydrocephalus, and blindness in newborns. The acute phase involves rapidly multiplying tachyzoites, which the immune response transforms into bradyzoites, causing cysts in nervous and muscle tissues and leading to chronic toxoplasmosis. In weakened immune systems, these can revert to tachyzoites, resulting in severe illnesses like encephalitis in AIDS patients or recurrent eye issues. Moreover, bradyzoite persistence in the brain is associated with increased mental health disorder risks. Current serological tests, focused on IgG and IgM antibodies against tachyzoite antigens, are ineffective in detecting the cyst form. They overlook antigens from the dormant bradyzoite stage, key to chronic disease progression. The environmentally resistant sporozoite stage in oocysts is crucial in Toxoplasma’s epidemiology, yet specific antigens for it are absent. Identifying these antigens could be crucial for serological diagnosis, helping estimate prevalence, transmission routes, and infection rates in populations.

OBJECTIVES

Our first goal is to monitor the level of antibodies against biomarkers that are only found in bradyzoites, specifically BCLA (Farhat et al. 2020; Dard C. et al. 2021) and BSM (Robert GM, et al. manuscript), – in serum samples from different groups: (i) patients with serological reactivation due to cancer treatments or after transplantation, (ii) patients with confirmed ocular toxoplasmosis and (iii) serum samples from the Lyon cohort with cases of maternal and congenital Toxoplasma infections. Secondly, we are investigating the possible association between chronic Toxoplasma infections and neuropsychiatric disorders such as schizophrenia and bipolar disorder using the BCLA/BSM markers. The sexual stages of Toxoplasma develop naturally in the intestine of cats, a developmental step that is essential for transmission to humans. However, until now there has been no in vitro system for cultivating the sexual stages and producing oocysts in vitro without infecting cats. Our third goal is to develop a system that allows the sexual development of Toxoplasma to unfold in vitro.

RESULTS

1.  We have made a groundbreaking achievement by successfully producing the pre-gametes of Toxoplasma in vitro without infecting cats (Antunes et al. Nature, in press). This is a first step towards understanding the transmission of this zoonosis and identifying new serological markers that can be used to detect sexual stages and their final outcome oocysts.
2. We have identified a novel marker, the Bradyzoite Serological Marker (BSM – Robert GM, et al. manuscript), that in concert with BCLA (Dard C. et al. 2021) were presented as pivotal markers for tracking the progression of the infection. This new study of the team provides new reference standards for studying the pathophysiology of chronic toxoplasmosis in humans, particularly for cyst carriage, which has been poorly described so far.
3. We have begun testing the serum bank of the FondaMental Foundation on cohorts of patients with bipolar disorder or schizophrenia, with results expected in the course of 2024.

RECENT PUBLICATIONS

1. Dard C, Swale C, Brenier-Pinchart MP, Farhat DC, Bellini, V Robert MG, Cannella D, Pelloux H, Tardieux I and Hakimi MA. BCLA is a Toxoplasma biomarker for high confidence serodetection of chronic infection and guidance for predictive medicine.  BMC Biol. 2021 Feb 9;19(1):25.

2. Farhat DC, Swale C, Dard C, Cannella D, Ortet P, Barakat M, Sindikubwabo F, Belmudes L, De Bock PJ, Couté Y, Bougdour A and Hakimi MA. A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment. Nature Microbiology.  2020 5(4):570-583.

3. Robert MG, Swale C, Bellini V, Cannella D, Braun L, Bougdour A, Corrao C, Belmudes L, Couté Y, Pelloux H, Brenier-Pinchart MP and Hakimi MA. Serological Detection of Toxoplasmosis Dormancy by Cyst- and Bradyzoite-specific Biomarkers. Manuscript in preparation.

4. Antunes AV, Shahinas M, Swale C, Farhat DC, Ramakrishnan C, Bruley C, Cannella D, Robert MG, Corrao C, Coute Y, Hehl AB, Bougdour A, Coppens I and Hakimi MA.  In vitro production of cat-restricted Toxoplasma pre-sexual stages. Nature (in press).