Mohamed-Ali HAKIMI

Information

Scientific interests and projects

Toxoplasma gondii is a prevalent single-celled eukaryotic parasite causing toxoplasmosis, a food-borne zoonotic disease, with life-threatening potentials in cases of immunesuppressed individuals and of unborn fetuses. As an obligate intracellular parasite, T. gondii deploys sophisticated mechanisms to profoundly modify the host cells to acquire nutrients and to promote parasite persistence. Our project considers the "host-parasite" association as a whole, aiming at filling current gaps of knowledge in the comprehensive understanding of the biology of Toxoplasma gondii and the etiology of Toxoplasmosis. Our long-term goal is to reveal the molecular mechanisms by which T. gondii is orchestrating immune evasion and lifelong persistence in a great range of hosts. Capitalizing on past achievements, we aim at exploring three lines of investigation:

1- We investigate how this single-cell parasite is able to co-opt specific host cell signaling pathways (e.g. MAPK or p53) upon invasion. Along the way, we uncovered a novel subfamily of T. gondii effector proteins that are singularly exported beyond the vacuolecontaining parasites and reach the host cell nucleus to reshape the host (epi)genetic program. We aim to study their modus operandi and particularly their possible implications in immune evasion and parasite persistence.

2- We are also studying the 'epigenetic' mechanisms involved in the regulation of the developmental transition between acute and chronic stages of infection. We thus identified serological markers for Toxoplasma chronic infection in Humans. Our team also uncovers a way to epigenetically reprogram the life cycle and therefore to study the parasite’s sexual development in vitro, as an alternative to the requirement of cat infections.

3- Current drugs for treating toxoplasmosis have been used for decades and have limitations such as the appearance of side-effects, low-to-medium drug efficacy and administration routes. Importantly, there are no drugs that clear chronic infection. Along the way, we discovered new anti-parasitic compounds that efficiently prevent acute toxoplasmosis, but also malaria and Cryptosporidiosis.

Top 5 publications of the last 5 years

1. Swale C, Bougdour A, Gnahoui-David A, Tottey J, Georgeault S, Laurent F, Palencia A and Hakimi MA@ Metal-Captured Inhibition of pre-mRNA Processing Activity by CPSF3 controls very efficiently Cryptosporidium Infection. Science Translational Medicine. 2019 Nov 6;11(517). pii: eaax7161. 10.1126/scitranslmed.aax7161

2. Braun L, Brenier-Pinchart MP, Hammoudi PM, Cannella D, Kieffer-Jaquinod S, Vollaire J, Josserand V, Touquet B, Coute Y, Tardieux I, Bougdour A, and Hakimi MA@ The Toxoplasma effector TEEGR promotes parasite persistence by modulating NF-kB signalling via EZH2. Nature Microbiology. 2019 Jul;4(7):1208-1220. doi: 10.1038/s41564-019-0431-8

3. Sindikubwabo F, Ding S, Hussain T, Ortet P, Barakat M, Baumgarten S, Cannella D, Palencia A, Bougdour A, Belmudes L, Couté Y, Tardieux I, Botté CY, Scherf A, and Hakimi MA@ Modifications at K31 on the lateral surface of histone H4 contribute to genome structure and expression in apicomplexan parasites. Elife. 2017 Nov 4;6. pii: e29391. 10.7554/eLife.29391

4. Palencia A, Bougdour A, Brenier-Pinchart MP, Touquet B, Bertini RL, Sensi C, Gay G, Vollaire J, Josserand V, Easom E, Freund YR, Pelloux H, Rosenthal PJ, Cusack S, and Hakimi MA@. Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis. EMBO Mol Med. 2017 Mar;9(3):385-394. 10.15252/emmm.201607370

5. Gay G, Braun L, Brenier-Pinchart MP, Vollaire J, Josserand V, Bertini RL, Varesano A, Touquet B, De Bock PJ, Coute Y, Tardieux I, Bougdour A, and Hakimi MA@ Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses. J Exp Med. 2016 213(9):1779-98. doi: 10.1084/jem.20160340