The apicomplexan parasites Plasmodium and Toxoplasma gondii, causative agents of malaria and toxoplasmosis respectively, continue to present a public health menace and to weigh heavily on the socio-economic development in certain regions. Once inside host cells, these parasites set up a highly coordinated gene expression programs to promote their growth/differentiation. Concomitantly, diverse biological processes including post translational modifications (in particular reversible protein phosphorylations) of expressed proteins and their trafficking are initiated to keep their functions in fine-tuning with the progress of parasites life cycles. Our current research is focusing on three main research topics. In the first topic, we investigate the regulatory complexes that govern the expression of virulence factors in Toxoplasma gondii. We aim at understanding the role of the ApiAP2 family of transcription factors and epigenetic regulation of gene expression. We are particularly interested in discovering how transcription factors act in complex to regulate the gene expression program essential for proliferation and differentiation of this parasite. In the second topic, we examine reversible phosphorylation processes with particular emphasis on issues related to phosphatases and their regulation. Currently, our studies are mainly dedicated to explore the function and regulation of Plasmodium/Toxoplasma protein phosphatase type 1 or PP1, an essential ser/thr phosphatase for the (sur)vival of any eukaryotic cell. The third research topic aims to elucidate the molecular mechanisms that regulate the secretion of essential virulent parasitic factors contained in dense granules, a trafficking pathway which remained fully unexplored. By using reverse genetics, advance proteomics approaches, super-resolution microscopy and live imaging, we aim to identify the key regulatory mechanisms of this pathway in T. gondii and search for conserved mechanisms in P. falciparum.
The final goal of our basic research is to provide a better understanding of the molecular events contributing to the life cycles progression of these parasites and, ultimately, to control malaria and toxoplasmosis by translating the new fundamental knowledge into the development of therapeutic strategies.
Main recent publications of the team
TgAP2IX-5 is a key transcriptional regulator of the asexual cell cycle division in Toxoplasma gondii. Asma S. Khelifa, Cecilia Guillen Sanchez, Kevin M. Lesage, Ludovic Huot, Thomas Mouveaux, Pierre Pericard, Nicolas Barois, Helene Touzet, Guillemette Marot, Emmanuel Roger & Mathieu Gissot. Nature Communications volume 12, Article number: 116 (2021).
The UPR sensor IRE1α promotes dendritic cell responses to control Toxoplasma gondii infection Anaïs F Poncet, Victor Bosteels, Eik Hoffmann, Sylia Chehade, Sofie Rennen, Ludovic Huot, Véronique Peucelle, Sandra Maréchal, Jamal Khalife, Nicolas Blanchard, Sophie Janssens, Sabrina Marion. EMBO Rep (2021)22:e49617.
The Multifaceted Role of Protein Phosphatase 1 in Plasmodium Jamal Khalife, Aline Fréville, Bénédicte Gnangnon, Christine Pierrot. Trends in Parasitology, Volume 37, Issue 2, February 2021, Pages 154-164.
Essential role of GEXP15, a specific Protein Phosphatase type 1 partner, in Plasmodium berghei in asexual erythrocytic proliferation and transmission Thomas Hollin, Caroline De Witte, Aline Fréville, Ida Chiara Guerrera, Cerina Chhuon, Jean-Michel Saliou, Fabien Herbert, Christine Pierrot, Jamal Khalife. Plos Pathogens, 2019
Identification of novel quinazoline derivatives as potent antiplasmodial agents Anne Bouchut, Dante Rotili, Christine Pierrot, Sergio Valente, Sophia Lafitte, Johan Schultz, Urban Hoglund, Roberta Mazzone, Alessia Lucidi, Giancarlo Fabrizi, Dany Pechalrieu, Paola B.Arimondo, Tina S.Skinner-Adams, Ming Jang Chua, Kathy T.Andrews, Antonello Mai, Jamal Khalife. European Journal of Medicinal Chemistry, Volume 161, 1 January 2019, Pages 277-291