The apicoplast is important for the viability and persistence of 1 Toxoplasma gondii bradyzoites 2

16 Toxoplasma gondii is responsible for toxoplasmosis, a disease that can be serious when contracted 17 during pregnancy, but can also be a threat for immunocompromised individuals. Acute infection is 18 associated with the tachyzoite form that spreads rapidly within the host. However, under stress 19 conditions, some parasites can differentiate into cyst-forming bradyzoites, residing mainly in the 20 central nervous system, retina and muscle. Because this latent form of the parasite is resistant to 21 all currently available treatments, and is central to persistence and transmission of the parasite, 22 new specific therapeutic strategies targeting this developmental stage need to be discovered. 23 T. gondii contains a plastid of endosymbiotic origin called the apicoplast, which is an appealing 24 drug target because it is essential for tachyzoite viability and contains several key metabolic 25 pathways that are largely absent from the mammalian host. Its function in bradyzoites, however, is 26 unknown. Our objective was thus to study the contribution of the apicoplast to the viability and 27 persistence of bradyzoites during chronic toxoplasmosis.

[1]  A. Hehl,et al.  Importance of aspartyl protease 5 in the establishment of the intracellular niche during acute and chronic infection of Toxoplasma gondii , 2022, Molecular microbiology.

[2]  D. Soldati-Favre,et al.  A Signaling Factor Linked to Toxoplasma gondii Guanylate Cyclase Complex Controls Invasion and Egress during Acute and Chronic Infection , 2022, mBio.

[3]  Yaara Oren Standing on the shoulders of microbes: How cancer biologists are expanding their view of hard‐to‐kill persister cells , 2022, Molecular systems biology.

[4]  Cyrille Y. Botté,et al.  Toxoplasma metabolic flexibility in different growth conditions , 2022, Trends in parasitology.

[5]  T. Steinfeldt,et al.  In vitro maturation of Toxoplasma gondii bradyzoites in human myotubes and their metabolomic characterization , 2022, Nature Communications.

[6]  Sébastien Besteiro,et al.  The pathogenicity and virulence of Toxoplasma gondii , 2021, Virulence.

[7]  O. Silvie,et al.  A toolbox for conditional control of gene expression in apicomplexan parasites , 2021, Molecular microbiology.

[8]  S. Prigge,et al.  Critical role for isoprenoids in apicoplast biogenesis by malaria parasites , 2021, bioRxiv.

[9]  J. Lambert,et al.  Primary brain cell infection by Toxoplasma gondii reveals the extent and dynamics of parasite differentiation and its impact on neuron biology , 2021, bioRxiv.

[10]  I. Coppens,et al.  Toxoplasma TgATG9 is critical for autophagy and long-term persistence in tissue cysts , 2020, bioRxiv.

[11]  Sébastien Besteiro,et al.  The Bradyzoite: A Key Developmental Stage for the Persistence and Pathogenesis of Toxoplasmosis , 2020, Pathogens.

[12]  Masahiro Yamamoto,et al.  Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection , 2019, Experimental & Molecular Medicine.

[13]  L. Weiss,et al.  Toxoplasma gondii: Bradyzoite Differentiation In Vitro and In Vivo. , 2019, Methods in molecular biology.

[14]  S. Ralph,et al.  Delayed Death by Plastid Inhibition in Apicomplexan Parasites. , 2019, Trends in parasitology.

[15]  S. Quake,et al.  A single-parasite transcriptional atlas of Toxoplasma Gondii reveals novel control of antigen expression , 2019, bioRxiv.

[16]  R. Liblau,et al.  Robust Control of a Brain-Persisting Parasite through MHC I Presentation by Infected Neurons. , 2019, Cell reports.

[17]  G. Watson,et al.  Systematic review and meta-analysis of variation in Toxoplasma gondii cyst burden in the murine model. , 2019, Experimental parasitology.

[18]  Seeber,et al.  Metabolic interactions between Toxoplasma gondii and its host , 2018, F1000Research.

[19]  Kentaro Kato,et al.  Identification of compounds that suppress Toxoplasma gondii tachyzoites and bradyzoites , 2017, PloS one.

[20]  B. Maco,et al.  Myosin-dependent cell-cell communication controls synchronicity of division in acute and chronic stages of Toxoplasma gondii , 2017, Nature Communications.

[21]  M. Igarashi,et al.  Lactate dehydrogenase in Toxoplasma gondii controls virulence, bradyzoite differentiation, and chronic infection , 2017, PloS one.

[22]  Constance A. M. Finney,et al.  Toxoplasma gondii: One Organism, Multiple Models. , 2017, Trends in parasitology.

[23]  A. Sinai,et al.  Novel Approaches Reveal that Toxoplasma gondii Bradyzoites within Tissue Cysts Are Dynamic and Replicating Entities In Vivo , 2015, mBio.

[24]  Kelly J Pittman,et al.  Long-Term Relationships: the Complicated Interplay between the Host and the Developmental Stages of Toxoplasma gondii during Acute and Chronic Infections , 2015, Microbiology and Molecular Reviews.

[25]  M. Ferdig,et al.  Guanabenz Repurposed as an Antiparasitic with Activity against Acute and Latent Toxoplasmosis , 2015, Antimicrobial Agents and Chemotherapy.

[26]  D. Schlüter,et al.  Persistence of Toxoplasma gondii in the central nervous system: a fine‐tuned balance between the parasite, the brain and the immune system , 2015, Parasite immunology.

[27]  L. Knoll,et al.  Dual transcriptional profiling of mice and Toxoplasma gondii during acute and chronic infection , 2014, BMC Genomics.

[28]  N. Westwood,et al.  Efficient Genome Engineering of Toxoplasma gondii Using CRISPR/Cas9 , 2014, PloS one.

[29]  Ronald C. Taylor,et al.  The Toxoplasma gondii Cyst Wall Protein CST1 Is Critical for Cyst Wall Integrity and Promotes Bradyzoite Persistence , 2013, PLoS pathogens.

[30]  G. V. van Dooren,et al.  The algal past and parasite present of the apicoplast. , 2013, Annual review of microbiology.

[31]  N. Shastri,et al.  Location of the CD8 T Cell Epitope within the Antigenic Precursor Determines Immunogenicity and Protection against the Toxoplasma gondii Parasite , 2013, PLoS pathogens.

[32]  A. Sanecka,et al.  Use and abuse of dendritic cells by Toxoplasma gondii , 2012, Virulence.

[33]  R. Yolken,et al.  Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis , 2012, Proceedings of the National Academy of Sciences.

[34]  M. Mann,et al.  Novel Murine Dendritic Cell Lines: A Powerful Auxiliary Tool for Dendritic Cell Research , 2012, Front. Immun..

[35]  J. Mak,et al.  Significant Reduction of Brain Cysts Caused by Toxoplasma gondii after Treatment with Spiramycin Coadministered with Metronidazole in a Mouse Model of Chronic Toxoplasmosis , 2012, Antimicrobial Agents and Chemotherapy.

[36]  Michael S. Behnke,et al.  A Systematic Screen to Discover and Analyze Apicoplast Proteins Identifies a Conserved and Essential Protein Import Factor , 2011, PLoS pathogens.

[37]  David M. Rocke,et al.  Identification of Tissue Cyst Wall Components by Transcriptome Analysis of In Vivo and In Vitro Toxoplasma gondii Bradyzoites , 2011, Eukaryotic Cell.

[38]  G. McFadden,et al.  Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii , 2011, The Journal of experimental medicine.

[39]  L. Weiss,et al.  Type II Toxoplasma gondii KU80 Knockout Strains Enable Functional Analysis of Genes Required for Cyst Development and Latent Infection , 2011, Eukaryotic Cell.

[40]  Sini Skariah,et al.  Toxoplasma gondii: determinants of tachyzoite to bradyzoite conversion , 2010, Parasitology Research.

[41]  Karsten Fischer,et al.  The toxoplasma apicoplast phosphate translocator links cytosolic and apicoplast metabolism and is essential for parasite survival. , 2010, Cell host & microbe.

[42]  G. V. van Dooren,et al.  Genetic Evidence that an Endosymbiont-derived Endoplasmic Reticulum-associated Protein Degradation (ERAD) System Functions in Import of Apicoplast Proteins* , 2009, The Journal of Biological Chemistry.

[43]  P. Baldacci,et al.  Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites , 2009, The Journal of experimental medicine.

[44]  B. Humbel,et al.  A Novel Dynamin-Related Protein Has Been Recruited for Apicoplast Fission in Toxoplasma gondii , 2009, Current Biology.

[45]  M. Huynh,et al.  Tagging of Endogenous Genes in a Toxoplasma gondii Strain Lacking Ku80 , 2009, Eukaryotic Cell.

[46]  Peter J. Bradley,et al.  A Thioredoxin Family Protein of the Apicoplast Periphery Identifies Abundant Candidate Transport Vesicles in Toxoplasma gondii , 2008, Eukaryotic Cell.

[47]  J. Boothroyd,et al.  Analysis of gene expression during development: lessons from the Apicomplexa. , 2006, Microbes and infection.

[48]  D. Rice,et al.  Maternal Inheritance and Stage-Specific Variation of the Apicoplast in Toxoplasma gondii during Development in the Intermediate and Definitive Host , 2005, Eukaryotic Cell.

[49]  D. Roos,et al.  Dynamics of Toxoplasma gondii Differentiation , 2004, Eukaryotic Cell.

[50]  A. Nikolić,et al.  Efficacy of atovaquone combined with clindamycin against murine infection with a cystogenic (Me49) strain of Toxoplasma gondii. , 2002, The Journal of antimicrobial chemotherapy.

[51]  D. Soldati,et al.  Toxoplasma gondii myosin A and its light chain: a fast, single‐headed, plus‐end‐directed motor , 2002, The EMBO journal.

[52]  B. A. Fox,et al.  De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii , 2002, Nature.

[53]  S. Tomavo The differential expression of multiple isoenzyme forms during stage conversion of Toxoplasma gondii: an adaptive developmental strategy. , 2001, International journal for parasitology.

[54]  D. Lindsay,et al.  Structures of Toxoplasma gondiiTachyzoites, Bradyzoites, and Sporozoites and Biology and Development of Tissue Cysts , 1998, Clinical Microbiology Reviews.

[55]  D. Roos,et al.  Stage-specific expression of a selectable marker in Toxoplasma gondii permits selective inhibition of either tachyzoites or bradyzoites. , 1997, Molecular and biochemical parasitology.

[56]  S. Parmley,et al.  Toxoplasma gondii expresses two distinct lactate dehydrogenase homologous genes during its life cycle in intermediate hosts. , 1997, Gene.

[57]  K. Gull,et al.  A novel epitope tag system to study protein targeting and organelle biogenesis in Trypanosoma brucei. , 1996, Molecular and biochemical parasitology.

[58]  J. Boothroyd,et al.  Interconnection between organellar functions, development and drug resistance in the protozoan parasite, Toxoplasma gondii. , 1995, International journal for parasitology.

[59]  J. Dubremetz,et al.  Experimental induction of bradyzoite-specific antigen expression and cyst formation by the RH strain of Toxoplasma gondii in vitro. , 1994, Experimental parasitology.

[60]  D. Ferguson,et al.  An ultrastructural study of the effect of treatment with atovaquone in brains of mice chronically infected with the ME49 strain of Toxoplasma gondii. , 1994, International journal of experimental pathology.

[61]  J. Dubremetz,et al.  Toxoplasma gondii: kinetics of bradyzoite-tachyzoite interconversion in vitro. , 1993, Experimental parasitology.

[62]  L. David Sibley,et al.  Virulent strains of Toxoplasma gondii comprise a single clonal lineage , 1992, Nature.

[63]  J. Dubremetz,et al.  Characterization of bradyzoite-specific antigens of Toxoplasma gondii , 1991, Infection and immunity.

[64]  D. Soldati-Favre,et al.  Metabolic pathways in the apicoplast of apicomplexa. , 2010, International review of cell and molecular biology.

[65]  D. Ferguson,et al.  An ultrastructural study of the early development and tissue cyst formation of Toxoplasma gondii in the brains of mice , 2004, Parasitology Research.