Identification of a Master Regulator of Differentiation in Toxoplasma

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2020 Jan 21

PMID 31955846

Citations 118

Authors

Benjamin S Waldman

Dominic Schwarz

Marc H Wadsworth 2nd

Jeroen P Saeij

Alex K Shalek

Sebastian Lourido

Affiliations

Soon will be listed here.

Abstract

Toxoplasma gondii chronically infects a quarter of the world's population, and its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent. Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies. The molecular basis of this differentiation is unknown, despite being efficiently triggered by stresses in culture. Through Cas9-mediated screening and single-cell profiling, we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice. BFD1 accumulates during stress and its synthetic expression is sufficient to drive differentiation. Consistent with its function as a transcription factor, BFD1 binds the promoters of many stage-specific genes and represents a counterpoint to the ApiAP2 factors that dominate our current view of parasite gene regulation. BFD1 provides a genetic switch to study and control Toxoplasma differentiation and will inform prevention and treatment of chronic infections.

Citing Articles

Iron-mediated post-transcriptional regulation in Toxoplasma gondii.

Sloan M, Scott A, Aghabi D, Mrvova L, Harding C PLoS Pathog. 2025; 21(2):e1012857.

PMID: 39899594 PMC: 11801735. DOI: 10.1371/journal.ppat.1012857.

Pathological mechanisms of glial cell activation and neurodegenerative and neuropsychiatric disorders caused by infection.

Yang Z, Chen J, Zhang C, Peng H Front Microbiol. 2024; 15:1512233.

PMID: 39723133 PMC: 11668811. DOI: 10.3389/fmicb.2024.1512233.

A Novel Nuclear Protein Complex Controlling the Expression of Developmentally Regulated Genes in Toxoplasma Gondii.

Xue L, Zhang J, Zhang L, Fan F, Yin X, Tian H Adv Sci (Weinh). 2024; 12(7):e2412000.

PMID: 39716984 PMC: 11831446. DOI: 10.1002/advs.202412000.

A bioinformatic approach for the prediction and functional classification of Toxoplasma gondii long non-coding RNAs.

Vanagas L, Cristaldi C, La Bella G, Ganuza A, Angel S, Alonso A Sci Rep. 2024; 14(1):27687.

PMID: 39533086 PMC: 11557611. DOI: 10.1038/s41598-024-79204-6.

Dissecting host-microbe interactions with modern functional genomics.

Russell B, Verma M, Maier N, Jost M Curr Opin Microbiol. 2024; 82:102554.

PMID: 39368241 PMC: 11609025. DOI: 10.1016/j.mib.2024.102554.

References

Oldenhove G, Bouladoux N, Wohlfert E, Hall J, Chou D, Dos Santos L . Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity. 2009; 31(5):772-86. PMC: 2814877. DOI: 10.1016/j.immuni.2009.10.001. View

Hughes T, Wadsworth 2nd M, Gierahn T, Do T, Weiss D, Andrade P . Second-Strand Synthesis-Based Massively Parallel scRNA-Seq Reveals Cellular States and Molecular Features of Human Inflammatory Skin Pathologies. Immunity. 2020; 53(4):878-894.e7. PMC: 7562821. DOI: 10.1016/j.immuni.2020.09.015. View

Gissot M, Briquet S, Refour P, Boschet C, Vaquero C . PfMyb1, a Plasmodium falciparum transcription factor, is required for intra-erythrocytic growth and controls key genes for cell cycle regulation. J Mol Biol. 2005; 346(1):29-42. DOI: 10.1016/j.jmb.2004.11.045. View

Dzierszinski F, Nishi M, Ouko L, Roos D . Dynamics of Toxoplasma gondii differentiation. Eukaryot Cell. 2004; 3(4):992-1003. PMC: 500887. DOI: 10.1128/EC.3.4.992-1003.2004. View

Kent R, Modrzynska K, Cameron R, Philip N, Billker O, Waters A . Inducible developmental reprogramming redefines commitment to sexual development in the malaria parasite Plasmodium berghei. Nat Microbiol. 2018; 3(11):1206-1213. PMC: 6317699. DOI: 10.1038/s41564-018-0223-6. View

Meers M, Bryson T, Henikoff J, Henikoff S . Improved CUT&RUN chromatin profiling tools. Elife. 2019; 8. PMC: 6598765. DOI: 10.7554/eLife.46314. View

Radke J, Donald R, Eibs A, Jerome M, Behnke M, Liberator P . Changes in the expression of human cell division autoantigen-1 influence Toxoplasma gondii growth and development. PLoS Pathog. 2006; 2(10):e105. PMC: 1626100. DOI: 10.1371/journal.ppat.0020105. View

Jeffers V, Tampaki Z, Kim K, Sullivan Jr W . A latent ability to persist: differentiation in Toxoplasma gondii. Cell Mol Life Sci. 2018; 75(13):2355-2373. PMC: 5988958. DOI: 10.1007/s00018-018-2808-x. View

Pittman K, Aliota M, Knoll L . Dual transcriptional profiling of mice and Toxoplasma gondii during acute and chronic infection. BMC Genomics. 2014; 15:806. PMC: 4177681. DOI: 10.1186/1471-2164-15-806. View

10.

Painter H, Campbell T, Llinas M . The Apicomplexan AP2 family: integral factors regulating Plasmodium development. Mol Biochem Parasitol. 2010; 176(1):1-7. PMC: 3026892. DOI: 10.1016/j.molbiopara.2010.11.014. View

11.

Matrajt M, Donald R, Singh U, Roos D . Identification and characterization of differentiation mutants in the protozoan parasite Toxoplasma gondii. Mol Microbiol. 2002; 44(3):735-47. DOI: 10.1046/j.1365-2958.2002.02904.x. View

12.

LARKIN M, Blackshields G, Brown N, Chenna R, McGettigan P, McWilliam H . Clustal W and Clustal X version 2.0. Bioinformatics. 2007; 23(21):2947-8. DOI: 10.1093/bioinformatics/btm404. View

13.

Cleary M, Singh U, Blader I, Brewer J, Boothroyd J . Toxoplasma gondii asexual development: identification of developmentally regulated genes and distinct patterns of gene expression. Eukaryot Cell. 2002; 1(3):329-40. PMC: 118016. DOI: 10.1128/EC.1.3.329-340.2002. View

14.

Ambawat S, Sharma P, Yadav N, Yadav R . MYB transcription factor genes as regulators for plant responses: an overview. Physiol Mol Biol Plants. 2014; 19(3):307-21. PMC: 3715649. DOI: 10.1007/s12298-013-0179-1. View

15.

Suvorova E, Croken M, Kratzer S, Ting L, de Felipe M, Balu B . Discovery of a splicing regulator required for cell cycle progression. PLoS Genet. 2013; 9(2):e1003305. PMC: 3578776. DOI: 10.1371/journal.pgen.1003305. View

16.

Macosko E, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M . Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell. 2015; 161(5):1202-1214. PMC: 4481139. DOI: 10.1016/j.cell.2015.05.002. View

17.

Manger I, Hehl A, Parmley S, Sibley L, Marra M, Hillier L . Expressed sequence tag analysis of the bradyzoite stage of Toxoplasma gondii: identification of developmentally regulated genes. Infect Immun. 1998; 66(4):1632-7. PMC: 108098. DOI: 10.1128/IAI.66.4.1632-1637.1998. View

18.

Skene P, Henikoff S . An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. Elife. 2017; 6. PMC: 5310842. DOI: 10.7554/eLife.21856. View

19.

Radke J, Striepen B, Guerini M, Jerome M, Roos D, WHITE M . Defining the cell cycle for the tachyzoite stage of Toxoplasma gondii. Mol Biochem Parasitol. 2001; 115(2):165-75. DOI: 10.1016/s0166-6851(01)00284-5. View

20.

Hulsen T, de Vlieg J, Alkema W . BioVenn - a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. BMC Genomics. 2008; 9:488. PMC: 2584113. DOI: 10.1186/1471-2164-9-488. View