Host Cell invasion

The Apicomplexa phylum is defined by the presence of an apical complex of organelles comprising two specific secretory granules called micronemes and rhoptries, which sequentially release their contents during invasion. Microneme proteins contribute to motility, attachment and invasion, while rhoptry proteins contribute to both invasion and subsequent manipulation of host cell functions after the parasites have established themselves in their host cells. Our research is focused on the formation of a structure (the moving junction) which is essential for host cell invasion in both Toxoplasma and Plasmodium, and which depends on the cooperation between microneme and rhoptry proteins. We are also interested on the mechanism of secretion of rhoptries, which remains a major conundrum in the field.

Schematic of T. gondii tachyzoite invading a host cell. Details in the inset show how, in the MJ, AMA1 is exposed on the parasite surface and interacts with a short extracellular domain of RON2 incorporated into the membrane of the host cell. The complex of RON2, RON4, RON5 and RON8 localize to the host cytosol and cooperate to recruit adaptor proteins (ALIX, CD2AP, CIN85, TSG101) through multiple specific interaction motifs that physically link the RONs complex to the cortical actin cytoskeleton. This results in the stabilization of the junction between the parasite and the host cortical actin providing a substantial cellular anchor for the AMA1/RON2 bridge at the surface, which is necessary to sustain the parasite invasive force.

Rhoptry secretion

The ability of Apicomplexa to cause disease depends on the coordinated secretion of specialized secretory organelles. The rhoptries are particularly important, because they act as the apicomplexan equivalent of bacterial secretion systems. They inject parasite proteins directly in the cytoplasm of host cells not only for invasion but also to hijack host functions crucial to establish and maintain infection. However, in contrast to bacteria where the secretion machinery has been resolved in details at the atomic scale, how these eukaryotic parasites secrete and inject rhoptry effectors into cells is still an enigma. We aim to dissect the mechanistic steps and the molecular components that assemble the rhoptry secretion machine.

Phosphoinosites function in Toxoplasma

We uncovered original apicoplast-related functions for two lipid kinases in Toxoplasma. Functional characterization of PI3Kinase and the PIKfyve kinase which produce PI(3)P and PI(3,5)P₂, respectively. These two phosphoinositides are classically associated with endolysosomal functions in mammalian cells and yeast, but are interestingly crucial for maintaining apicoplast homeostasis in the parasites. We use genetic and cellular approaches to elucidate how PI3P and PI(3,5)P₂ exert their function on apicoplast biogenesis.

Contribution of the apicoplast to the metabolism and survival of T. gondii in the context of acute and chronic toxoplasmosis.

Toxoplasma gondii is a parasitic protist infecting a wide variety of warm-blooded animals and about one third of the human population. Although it remains essentially asymptomatic in immunocompetent individuals, this parasite can cause a life-threatening disease called toxoplasmosis in fetuses, newborns, and individuals with weakened immune systems. Our group studies how these obligate intracellular parasites multiply and persist in the host. We are targeting essential cellular processes, which are thus sometimes conserved among eukaryotes, but bearing enough differences to make them potential therapeutic targets in the parasites.

Research project #1. Elucidating the unusual function of TgATG8 in maintaining apicoplast homeostasis.

Autophagy is a catabolic pathway that is highly conserved among eukaryotes and permits the degradation of cellular material. During the autophagic process, cytoplasmic components are sequestered in double-membrane vesicles called autophagosomes, and degraded after fusion with a degradative compartment. Autophagy is involved in multiple survival-promoting processes. It not only facilitates the maintenance of cell homeostasis by degrading long-lived proteins and damaged organelles, but it also plays a role in cell differentiation and cell development. The roles of autophagy and the autophagic machinery itself are poorly documented in protozoan parasites, especially in medically important apicomplexan parasites.
Over the recent years, we have been investigating autophagy in T. gondii tachyzoites, a highly invasive and fast replicating stage of the parasite responsible for the acute phase of toxoplasmosis. We have shown that autophagosomes can be induced in T. gondii in response to stress, in particular in extracellular tachyzoites (Fig. 1A). This suggests the presence of a functional canonical autophagic pathway in this parasite. This pathway is likely important for surviving stress-generating environments, like when the parasites are under the immune pressure from the host, but seems not essential for intracellular in vitro growth in permissive conditions. Paradoxically, we have also demonstrated that several members of the autophagic machinery are necessary for parasite growth. In fact, the TgATG8 protein, which is a bona fide autophagosomal marker in many eukaryotic cells, also associates with a peculiar organelle during the intracellular development of the parasites, the apicoplast (Fig. 1B). The apicoplast is a non-photosynthetic plastid which is vital to the parasite's survival. It has been acquired by the ancestor of apicomplexan parasites through a double endosymbiosis event. Consequently, its outermost membrane might bear properties similar to phagosomal membranes, which also appear to be able to recruit ATG8 in other eukaryotic systems. The precise function of TgATG8 at the apicoplast is currently unknown, but it highlights essential, yet non-canonical, roles for the autophagic machinery in Apicomplexa.


Figure 1. A) TgATG8 labels autophagosomal structures in starved extracellular parasites. B) In dividing intracellular parasites (mother and daughter cells are labelled with inner membrane complex –IMC- staining), TgATG8 associates with the apicoplast. Scale bar= 5µM.

Overall, the presence of a pathway that is i) conserved in the phylum Apicomplexa, ii) potentially essential for the survival of these pathogens iii) containing potentially druggable targets that could bear significant differences with their host’s counterparts, provides the rationale for further studies in the cellular functions of autophagy in these parasites.

This research project aims at:
- elucidating the physiological roles of parasite autophagy in the context of acute and chronic toxoplasmosis (collaboration with the lab ofVern Carruthers, Univ. Michigan, USA)
- identifying novel parasite-specific functions for the autophagy-related machinery at the apicoplast
- discovering drugs that specifically inhibit TgATG8 function at the apicoplast (collaboration with the lab of  Feng Tan, Wenzhou Medical University, China)

Funding:
Over recent years, financial support for this project has been provided by the CNRS, the “Fondation pour la Recherche Médicale” and the “Agence Nationale de la Recherche”.

Research project #2. Contribution of the apicoplast to Toxoplasma persistence.

Acute infection of intermediate hosts by T. gondii is associated with the rapid replication and spread of the tachyzoite forms within the body. This infection phase is often readily contained by the immune system. However, the parasites can differentiate into slowly growing bradyzoites, establishing within tissue cysts, primarily in the central nervous system and muscle. Although there are effective medicines available against tachyzoites, the persistent chronic form of the pathogen remains in the host throughout its life and can convert repeatedly back into tachyzoites, and hence lead to a severe pathology (i.e. encephalitis or retinitis) in the event of a weakened immune system. These bradyzoites forms are thus central to the pathology, yet there are no effective drugs against them so far.
In bradyzoites, where apicoplast function has been largely overlooked, we wish to determine the importance of the organelle for survival and persistence of this parasite stage. We are using stage-specific conditional knock-down or knock-out approaches to deplete apicoplast proteins in bradyzoites (Fig. 2).

 
Figure 2.  Stage-specific depletion of an apicoplast marker (green) in in vitro-differentiated bradyzoites (arrowhead, cyst labelled by the Dolichos biflorus lectin –DBL, red-).

 

This research project aims at:
- generating genetic tools to investigate the function of essential genes in bradyzoites
- elucidating the contribution of the apicoplast to the persistence and reactivation of bradyzoites in vitro and in vivo (collaboration with the lab of Nicolas Blanchard, Université de Toulouse, France)

 

Other research projects.

We are also interested in other aspects of the cell biology of Toxoplasma, including specific aspects of the cell division process, the cytoskeleton, and apicoplast homeostasis.

 

During its life cycle, P. falciparum regulates diverse biological mechanisms by reversible protein phosphorylation, via the enzymatic activities of kinases and phosphatases (PPs). In particular, red blood cell egress and invasion take place within less than a minute and rely on a rapid burst of protein discharge from several apical organelles, including exonemes, micronemes and rhoptries. To orchestrate these finely tuned events, the parasite uses complex signaling pathways relying mainly on cyclic nucleotides, namely cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), and calcium as signaling molecules. These signals activate their dedicated kinases, i.e. PfPKG, PfPKA and calcium-dependent protein kinases (CDPKs) that will in turn phosphorylate their respective substrates thought to be direct or indirect effectors required for these steps to proceed. Importantly, the signals allowing egress and invasion to take place are conserved in the related apicomplexan parasite T. gondii, as are the primary kinase effectors (TgPKG, TgPKA and TgCDPKs), suggesting that the phospho-signaling pathways controlling these essential steps are largely conserved in Apicomplexa.

While extensive work has been performed to characterize the parasite kinases, the role of PPs has been poorly studied. In this context, we aim at fully characterizing P. falciparum PPs that play an important role during its intra-erythrocytic development, with a particular interest on the invasion and egress mechanisms. Our goal is to determine their biological function using reverse genetics and to characterize their partners and substrates. Furthermore, we aim to extend some of our conclusions to Apicomplexa more generally by describing the role of their orthologs in T. gondii. This comprehensive study will not only add some important insights on biological mechanisms essential to the parasites, but will also give a more holistic view on the functional relationships between protein kinases and PPs. This understanding is of great importance as both enzymes are emerging as potential targets for drug development.

Scheme of P. falciparum red blood cell cycle (adapted from Maier et al. 2009), with the function of the PPs studied in the lab highlighted.

GROUPE Maryse LEBRUN


LEBRUN Maryse
DR INSERM
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DUBREMETZ Jean-François
DR CNRS, Emérite 
jean-françois.dubremetz[arobase]umontpellier.fr



PENARETE VARGAS Diana
Research Assistant, UM
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GRAINDORGE Arnault
Maître de conférences (MC) UM
arnault.graindorge[arobase]umontpellier.fr



MENDONÇA COVA Marta
Post-Doctorante 
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SPARVOLI Daniela
Post-Doctorante 
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HECKENDORN Justine
Doctorante
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RUIVO Margarida
Doctorante
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NAJM Rania
Doctorante
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BIENVENU Marjorie
TCE CNRS 
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GROUPE Sébastien BEISTERO

BESTEIRO Sébastien
CR INSERM
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SANCHEZ Syrian
Doctorant 
syrian.sanchez[arobase]umontpellier.fr

Sarah.Z
Doctorante



GROUPE Mauld LAMARQUE

LAMARQUE  Mauld    
Maître de conférences (MC) UM
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SEVENO Marie
AI CNRS
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Maryse Lebrun Group:

Suarez C, Lentini G, Ramaswamy R, Maynadier M, Aquilini E, Berry-Sterkers L, Cipriano M, Chen AL, Bradley P, Striepen B, Boulanger MJ, Lebrun M. A lipid-binding protein mediates rhoptry discharge and invasion in Plasmodium falciparum and Toxoplasma gondii parasites. Nat Commun. 2019 Sep 6;10(1):4041.

Berry L, Chen CT, Francia ME, Guerin A, Graindorge A, Saliou JM, Grandmougin M, Wein S, Bechara C, Morlon-Guyot J, Bordat Y, Gubbels MJ, Lebrun M, Dubremetz JF, Daher W. Toxoplasma gondii chromosomal passenger complex is essential for the organization of a functional mitotic spindle: a prerequisite for productive endodyogeny. Cell Mol Life Sci, (2018) Jul 26.

Morlon-Guyot J, El Hajj H, Martin K, Fois A, Carrillo A, Berry L, Burchmore R, Meissner M, Lebrun M, Daher W. A proteomic analysis unravels novel CORVET and HOPS proteins involved in Toxoplasma gondii secretory organelles biogenesis. Cell Microbiol, (2018) 17:e12870.

Wengelnik K, Daher W, Lebrun M. Phosphoinositides and their functions in apicomplexan parasites. Int J Parasitol. (2018) Jun;48(7):493-504.

Lebrun M, Blanchard N. Host-microbe interactions: parasites. Volume 40 December 2017

Guérin A, El Hajj H, Penarete-Vargas D, Besteiro S, Lebrun M. RON4(L1) is a new member of the moving junction complex in Toxoplasma gondii. Sci Rep, (2017) Dec 20;7(1):17907.

Lentini G, El Hajj H, Papoin J, Fall G, Pfaff AW, Tawil N, Braun-Breton C, Lebrun M. Characterization of Toxoplasma DegP, a rhoptry serine protease crucial for lethal infection in mice. PLoS One, (2017) Dec 15;12(12):e0189556.

Frénal K, Dubremetz JF, Lebrun M, Soldati-Favre D. Gliding motility powers invasion and egress in Apicomplexa. Nat Rev Microbiol, (2017) Nov;15(11):645-660.

Guérin A, Corrales RM, Parker ML, Lamarque MH, Jacot D, El Hajj H, Soldati-Favre D, Boulanger MJ, Lebrun M. Efficient invasion by Toxoplasma depends on the subversion of host protein networks. Nat Microbiol, (2017) Oct;2(10):1358-1366.

Miliu A, Lebrun M, Braun-Breton C, Lamarque MH. Shelph2, a bacterial-like phosphatase of the malaria parasite Plasmodium falciparum, is dispensable during asexual blood stage. PLoS One, (2017) Oct 26;12(10):e0187073.

Nguyen HM, El Hajj H, El Hajj R, Tawil N, Berry L, Lebrun M, Bordat Y, Besteiro S. Toxoplasma gondii autophagy-related protein ATG9 is crucial for the survival of parasites in their host. Cell Microbiol, (2016) Jun (19) 6.

Berry L, Chen CT, Reininger L, Carvalho TG, El Hajj H, Morlon-Guyot J, Bordat Y, Lebrun M, Gubbels MJ, Doerig C, Daher W. The conserved apicomplexan Aurora kinase TgArk3 is involved in endodyogeny, duplication rate and parasite virulence. Cell Microbiol, (2016) Aug;18(8):1106-20.

Daher W, Morlon-Guyot J, Alayi TD, Tomavo S, Wengelnik K, Lebrun M. Identification of Toxoplasma TgPH1, a pleckstrin homology domain-containing protein that binds to the phosphoinositide PI(3,5)P2. Mol Biochem Parasitol, (2016) May;207(1):39-44.

Parker ML, Penarete-Vargas DM, Hamilton PT, Guérin A, Dubey JP, Perlman SJ, Spano F, Lebrun M*, Boulanger MJ*. Dissecting the interface between apicomplexan parasite and host cell: Insights from a divergent AMA-RON2 pair. PNAS, (2016) Jan 12;113(2):398-403. *equal contribution

Wang K, Peng ED, Huang AS, Xia D, Vermont SJ, Lentini G, Lebrun M, Wastling JM, Bradley PJ. Identification of Novel O-Linked Glycosylated Toxoplasma Proteins by Vicia villosa Lectin Chromatography. PLoS One, (2016) Mar 7;11(3):e0150561.

Delgadillo RF, Parker ML, Lebrun M, Boulanger MJ, Douguet D. Stability of the Plasmodium falciparum AMA1-RON2 Complex Is Governed by the Domain II (DII) Loop. PLoS One, (2016) Jan 5;11(1):e0144764.

Pihan E., Delgadillo RF., Tonkin ML., Pugnière M., Lebrun M., Boulanger MJ., Douguet D. Computational and biophysical approaches to protein-protein interaction inhibition of Plasmodium falciparum AMA1/RON2 complex. J Comput Aided Mol Des, (2015) Jun;29(6):525-39

Rugarabamu G., Marq JB., Guérin A., Lebrun M., Soldati-Favre D. Distinct contribution of Toxoplasma gondii rhomboid proteases 4 and 5 to micronemal protein protease 1 activity during invasion. Mol Microbiol, (2015). Jul;97(2):244-62.

Lentini G., Kong-Hap M., El Hajj H., Francia M., Claudet C., Striepen B., Dubremetz JF., Lebrun M. Identification and characterization of Toxoplasma SIP, a conserved apicomplexan cytoskeleton protein involved in maintaining the shape, motility and virulence of the parasite. Cell Microbiol, (2015) 17(1):62-78.

Morlon-Guyot J., Pastore S., Berry L., Lebrun M., Daher W. Toxoplasma gondii Vps11, a subunit of HOPS and CORVET tethering complexes, is essential for the biogenesis of secretory organelles. Cell Microbiol, (2015) 1157-1178.

Daher W., Morlon-Guyot J., Sheiner L., Lentini G., Berry L., Tawk L., Dubremetz JF., Wengelnik K., Striepen B., Lebrun M. Lipid kinases are essential for apicoplast homeostasis in Toxoplasma gondii. Cell Microbiol, (2015) 559-578.

Risco-Castillo V., Topçu Selma., Marinach C., Manzon G., Bigorgne A.E., Briquet S., Baudin X., Lebrun M., Dubremetz J.F., and Olivier Silvie. Malaria Sporozoites Traverse Host Cells within Transient Vacuoles. Cell Host & Microbes, (2015) Nov 11;18(5):593-603.

Lamarque MH., Roques M., Kong-Hap M., Tonkin ML., Rugarabamu G., Marq JB., Penarete-Vargas DM., Boulanger MJ., Soldati-Favre D., Lebrun M. Plasticity and redundancy among AMA-RON pairs ensure host cell entry of Toxoplasma parasites. Nat Commun, (2014) Jun 17;5:4098.

Morlon-Guyot J., Berry L., Chen CT., Gubbels MJ., Lebrun M., Daher W. The Toxoplasma gondii calcium-dependent protein kinase 7 is involved in early steps of parasite division and is crucial for parasite survival. Cell Microbiol, (2014) 95-114.

Kong-Hap MA., Mouammine A., Daher W., Berry L., Lebrun M., Dubremetz JF., Besteiro S. Regulation of ATG8 membrane association by ATG4 in the parasitic protist Toxoplasma gondii. Autophagy, (2013) September ;9(9):1334-48

Tonkin ML., Crawford J., Lebrun ML., Boulanger MJ. Babesia divergens and Neospora caninum apical membrane antigen 1 structures reveal selectivity and plasticity in apicomplexan parasite host cell invasion. Protein Sci, (2011) Jan;22(1):114-27

De Napoli. M.G., N. de Miguel., Lebrun M., Moreno S.N.J., Angel S.O., Corvi M.M. N-terminal palmitoylation is required for Toxoplasma gondii HSP20 inner membrane complex localization. Biochimica and Biophysica Acta (BBA) - Molecular Cell Research, (2013) Jun;1833(6):1329-37.

Lebrun, M., Carruthers, V.B., Cesbron-Delauw, M.-F. Toxoplasma Secretory Proteins and their roles in Cell Invasion and Intracellular Survival. in Toxoplasma gondii: The Model Apicomplexan – Perspectives and Methods, Weiss and Kim (Eds), 2nd edition (2013) 265-315.

Dubremetz JF, Lebrun M. Virulence factors of Toxoplasma gondii. Microbes Infect, (2012) Dec;14(15):1403-10.

Lamarque MH, Papoin J, Finizio AL, Lentini G, Pfaff AW, Candolfi E, Dubremetz JF, Lebrun M. Identification of a new rhoptry neck complex RON9/RON10 in the Apicomplexa parasite Toxoplasma gondii. PLoS One, (2012);7(3):e32457.

Vulliez-Le Normand B, Tonkin ML, Lamarque MH, Langer S, Hoos S, Roques M, Saul FA, Faber BW, Bentley GA, Boulanger MJ, Lebrun M. Structural and functional insights into the malaria parasite moving junction complex. PLoS Pathog, (2012);8(6):e1002755.

Tawk, L., Dubremetz, J. F., Montcourrier, P., Chicanne, G., Merezegue, F., Richard, V., Payrastre, B., Meissner, M., Vial, H. J., Roy, C., Wengelnik, K., and Lebrun, M. Phosphatidylinositol 3-monophosphate is involved in Toxoplasma apicoplast biogenesis. PLoS Pathog, (2011) 7, e1001286

Besteiro S, Dubremetz JF, Lebrun M. The moving junction of apicomplexan parasites: a key structure for invasion. Cell Microbiol, (2011) Jun;13(6):797-805.

Lamarque M, Besteiro S, Papoin J, Roques M, Vulliez-Le Normand B, Morlon-Guyot J, Dubremetz JF, Fauquenoy S, Tomavo S, Faber BW, Kocken CH, Thomas AW, Boulanger MJ, Bentley GA, Lebrun M. The RON2-AMA1 interaction is a critical step in moving junction-dependent invasion by apicomplexan parasites. PLoS Pathog, (2011) Feb 10;7(2):e1001276.

Hajagos BE, Turetzky JM, Peng ED, Cheng SJ, Ryan CM, Souda P, Whitelegge JP, Lebrun M, Dubremetz JF, Bradley PJ. Molecular dissection of novel trafficking and processing of the Toxoplasma gondii rhoptry metalloprotease toxolysin-1. Traffic, (2012) Feb;13(2):292-304.

Tonkin ML, Roques M, Lamarque MH, Pugnière M, Douguet D, Crawford J, Lebrun M*, Boulanger MJ*. Host cell invasion by apicomplexan parasites: insights from the co-structure of AMA1 with a RON2 peptide. Science, (2011) Jul 22;333(6041):463-7. *equal contribution

Mévélec MN, Ducournau C, Bassuny Ismael A, Olivier M, Sèche E, Lebrun M, Bout D, Dimier-Poisson I. Mic1-3 Knockout Toxoplasma gondii is a good candidate for a vaccine against T. gondii-induced abortion in sheep. Vet Res, (2010) Jul-Aug;41(4):49.

Moiré N, Dion S, Lebrun M, Dubremetz JF, Dimier-Poisson I. Mic1-3KO tachyzoite a live attenuated vaccine candidate against toxoplasmosis derived from a type I strain shows features of type II strain. Exp Parasitol, (2009) Oct;123(2):111-7.

AB Ismael, D Hedhli, O Cérède, M Lebrun, I Dimier-Poisson, and MN Mévélec. Further analysis of protection induced by the MIC3 DNA vaccine against T. gondii: CD4 and CD8 T Cells are the major effectors of the MIC3 DNA vaccine-induced protection, both Lectin-like and EGF-like domains of MIC3 conferred protection. Vaccine, (2009) 14;27(22):2959-66

S Besteiro, A Michelin, J Poncet, JF Dubremetz, M Lebrun. Export of a Toxoplasma gondii rhoptry neck protein complex at the host cell membrane to form the moving junction during invasion. PloS Pathog, (2009) 5(2):e1000309. “Exceptional" by the Faculty of 1000”

Breinich, DJP. Ferguson2, BJ. Foth, GG. van Dooren, M Lebrun, DV. Quon, B Striepen, PJ. Bradley, F Frischknecht1, VB. Carruthers and Markus Meissner. An ancestral dynamin is required for the biogenesis of specialised secretory organelles in apicomplexan parasites. Current Biology, (2009) 19:277-86.

G Labesse, M Gelin, Y Bessin, M Lebrun, J Papoin, R Cerdan, S Arold, JF Dubremetz. ROP2 from Toxoplasma gondii: A virulence factor with a protein-kinase fold and no enzymatic activity. Structure, (2009) 17(1):139-46.

Sebastien Beistero Group:

Nguyen HM, Liu S, Daher W, Tan F, Besteiro S. (2018) Characterisation of two Toxoplasma PROPPINs homologous to Atg18/WIPI suggests they have evolved distinct specialised functions. PLoS One. Apr 16;13(4):e0195921.


Besteiro S. (2017) Autophagy in apicomplexan parasites. (2017) Curr Opin Microbiol. Dec;40:14-20.


Nguyen HM, Berry L, Sullivan WJ Jr, Besteiro S. (2017) Autophagy participates in the unfolded protein response in Toxoplasma gondii. FEMS Microbiol Lett. 15;364(15).


Di Cristina M, Dou Z, Lunghi M, Kannan G, Huynh MH, McGovern OL, Schultz TL, Schultz AJ, Miller AJ, Hayes BM, van der Linden W, Emiliani C, Bogyo M, Besteiro S, Coppens I, Carruthers VB. (2017) Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection. Nat Microbiol. Jun 19;2:17096.


Nguyen HM, El Hajj H, El Hajj R, Tawil N, Berry L, Lebrun M, Bordat Y, Besteiro S. (2017) Toxoplasma gondii autophagy-related protein ATG9 is crucial for the survival of parasites in their host. Cell Microbiol. 19(6).


Latré de Laté P, Pineda M, Harnett M, Harnett W, Besteiro S, Langsley G. (2017) Apicomplexan autophagy and modulation of autophagy in parasite-infected host cells. Biomed J. 40(1):23-30.


Harnett MM, Pineda MA, Latré de Laté P, Eason RJ, Besteiro S, Harnett W, Langsley G. (2017). From Christian de Duve to Yoshinori Ohsumi: More to autophagy than just dining at home. Biomed J. 40(1):9-22.


Lévêque MF, Nguyen HM, Besteiro S. (2016) Repurposing of conserved autophagy-related protein ATG8 in a divergent eukaryote. Commun Integr Biol. 9(4):e1197447.


Lévêque MF, Berry L, Cipriano MJ, Nguyen HM, Striepen B, Besteiro S. (2015) Autophagy-related protein ATG8 has a noncanonical function for Apicoplast inheritance in Toxoplasma gondii. MBio.;6(6):e01446-15.


Kong-Hap MA, Mouammine A, Daher W, Berry L, Lebrun M, Dubremetz JF, Besteiro S. (2013) Regulation of ATG8 membrane association by ATG4 in the parasitic protist Toxoplasma gondii. Autophagy. 9(9):1334-48


Besteiro S. (2012) Which roles for autophagy in Toxoplasma gondii and related apicomplexan parasites? Mol Biochem Parasitol. 184(1):1-8


Besteiro S. (2012) Role of Atg3 in the parasite Toxoplasma gondii : autophagy in an early branching eukaryote. Autophagy. 8 (3):435-7


Besteiro S, Brooks CF, Striepen B, Dubremetz JF. (2011) Autophagy protein Atg3 is essential for maintaining mitochondrial integrity and for normal intracellular development of Toxoplasma gondii tachyzoites. PLoS Pathog. 7(12):e100241