IRP APICOLIPIDADAPTFrench-Australian International Research Project in Biology
Apicoplast in malaria
Zoom basal caps and rigs Full Resolution midlate division 3
The CNRS-INSERM IRP ApicoLipid (Apicomplexan parasites lipid and membrane biogenesis) is managed by Dr Cyrille Botté (IAB CNRS UMR5309 INSERM U1209, Université Grenoble Alpes) in collaboration with Professor Geoff McFadden (School of Biosciences, University of Melbourne). Our IRP was initiated through a long term and fruitful collaboration between our two laboratories initially supported by a CNRS International Scientific Project (PICS 2013-2017) and through our IRP in 2018. Our consortium aims to better understand the role propagation and pathogenicity of infectious agents causing malaria and toxoplasmosis to identify novel drug targets.
Missions and research themes
Apicomplexan parasites are unicellular eukaryotes responsible for major human infectious and chronic diseases such as malaria and toxoplasmosis, which cause massive social and economic burden. Malaria is caused by Plasmodium spp., via the bite of Anopheles mosquitoes in tropical and sub-tropical areas. Plasmodium infects ±200 million people every year and is responsible for the death of ±450,000, mainly children under the age of 8. Toxoplasma gondii is the causative agent of toxoplasmosis, a global chronic disease that affects ±1/3 of the world population. T. gondii is a lethal threat for the foetus of primo-infected pregnant women and for any immunocompromised patients (HIV, leukemia, chemotherapies, organ transplant…). To date, there is no efficient vaccine against these parasites, and parasite are rapidly developing resistance to most marketed molecules, especially for malaria. Thus, there is a pressing need for the identification of new targets and efficient drugs.
Apicomplexa are obligate intracellular parasites of humans, which means that they have to invade a host cell to survive and propagate. Current evidences strongly support lipid synthesis and membrane biogenesis as crucial pathways for parasite propagation in humans and therefore represent pertinent drug targets.
Our consortium focuses on understanding how this group of infectious parasites can acquire the lipid required for their survival. Our IRP combines a strong expertise, long lasting collaboration and complementary expertise to decipher the complex metabolic pathways sustaining parasite survival in the human hhost. We use a combination of novel genetic edition of the parasite (CrispR-Cas9-based), mass spectrometry-based lipidomics and fluxomics approaches developed in the metabolomic platform developed on the French side (Dr Botté, GEMELI Université Grenoble Alpes) as well as full life cycle analysis of the parasite lipid synthesis via the unique insectarium and mice facility of the Australian partner (Prof McFadden University of Melbourne). Through our interaction, we showed that the parasite can actively scavenge the human host lipid resources, but can also synthesize lipids de novo via a relict non-photosynthetic plastid (i.e. the apicoplast). Importantly, we showed that the parasite has to combine lipids from both host and de novo sources to survive. Recently we also showed that the parasite is also capable to metabolically reprogram both pathways upon the physiological and nutritional environment of their host. We currently focus on understanding how the parasite can sense and adapt to the host and how this is happening in the malaria mosquito vector. Together with our partners (Prof McConville Bio21 University of Melbourne, Dr Christopher Tonkin WEHI Melbourne), we form a taskforce to decipher parasite lipid biology, find the parasite weaknesses that could potentially benefit malaria and toxoplasmosis patients worldwide.
MAIN PROJECT OF RESEARCH THEMES
- Understand the pathways of lipid channeling, recycling and combination between the host and the parasite
- Determine the specificity of lipid synthesis throughout the whole parasite life cycle
- Contribute to the global knowledge of the intracellular development, lipid synthesis, membrane biogenesis, nutrient acquisition of apicomplexa parasite within their host
- Identify novel drug targets against malaria and toxoplasmosis
- Teach and promote novel techniques developed by the consortium: metabolomics/lipidomics/fluxomics; malaria liver and mosquito analysis, molecular approaches in malaria and toxoplasmosis
- Promote the environment young researcher (PhD, Postdoc, technicians…) to develop their skills and career
- Promote French and Australian research and knowledge
institutions and laboratories involved
- Cyrille Botté , DR CNRS, UMR5309 Institut pour l’Avancée des Biosciences (IAB), INSERM U1209, Université Grenoble Alpes
- Prof McFadden, School of Biosciences, University of Melbourne
- Prof Malcolm McConville, Bio21 Institute, University of Melbourne
- Dr Christopher Tonkin, Walter Eliza Health Institute (WEHI) Melbourne
some key publications
Amiar+ S, Katris+ NJ, Berry L, Dass S, Shears MJ, Brunet C, Touquet B, Hakimi MA, McFadden GI, Yamaryo-Botté Y*, Botté CY*. Division and adaptation to host nutritional environment of apicomplexan parasites depend on apicoplast lipid metabolic plasticity and host organelles remodelling, (2020) Cell Rep. 2020 Mar 17;30(11):3778-3792.e9. doi: 10.1016/j.celrep.2020.02.072.
Yang L, Uboldi AD, Seizova S, Wilde ML, Coffey MJ, Katris NJ, Yamaryo-Botté Y, Kocan M, Bathgate RAD, Stewart RJ, McConville MJ, Thompson PE, Botté CY, Tonkin CJ. J Biol Chem. An apically located hybrid guanylate cyclase-ATPase is critical for the initiation of Ca2+ signaling and motility in Toxoplasma gondii. J Biol Chem 2019 May 31;294(22):8959-8972. doi: 10.1074/jbc.RA118.005491
Uboldi AD, Wilde ML, McRae EA, Stewart RJ, Dagley LF, Yang L, Katris NJ, Hapuarachchi SV, Coffey MJ, Lehane AM, Botte CY, Waller RF, Webb AI, McConville MJ, Tonkin CJ. Protein kinase A negatively regulates Ca2+ signalling in Toxoplasma gondii. PLoS Biol. 2018 Sep 12;16(9):e2005642. doi: 10.1371/journal.pbio.2005642.
Shears MJ, MacRae JI, Goodman DG, Mollard VSU, Botté CY *, McFadden GI*. (2017). Characterization of the Plasmodium falciparum and P. berghei glycerol-3-phosphate acyltranferase involved in FASII fatty acid utilization in the malaria parasite apicoplast. Cellular Microbiology 19(1). PMCID:PMC5213128.
Amiar S, MacRae JI, Callahan DL, vanDooren GG, Shears MJ, Dubois D, Cesbron-Delauw MF, Maréchal E, McConville MJ, McFadden GI, Yamaryo-Botté Y*, BOTTÉ CY *. The Toxoplasma gondii apicoplast is responsible for bulk phospholipid synthesis mainly via a plant-like glycerol 3-phosphate acyltransferase for lysophosphatidic acid precursor assembly. Plos Pathogens 2016 Aug 4;12(8):e1005765. doi: 10.1371/journal.ppat.1005765
BOTTÉ CY*, Yamaryo-Botté Y, Rupasinghe TW, Mullin KA, MacRae JI, Spurck TP, Kalanon M, Shears MJ, Coppel RL, Crellin PK, Maréchal E, McConville MJ, McFadden GI*. Atypical lipid composition in the purified relict plastid (apicoplast) of malaria parasites. (*co-corresponding) Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7506-11.
Signature of the LIA APICOLIPID CNRS INSERM at the Australian Science Academy, with CNRS CEO Antoine Petit
Metabolomic day I IAB February 2020
Metabolomic day I IAB February 2020
Journal of lipid Research takeover