Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

The clever strategies used by intracellular parasites to hijack host gene expression


Intracellular pathogens need to develop sophisticated mechanisms to survive and thrive in the hostile environment within host cells. Unicellular, eukaryotic parasites from the Apicomplexa phylum have become masters of manipulating their host cells, exploiting signaling, and metabolic pathways to hijack host gene expression to their own advantage. These intracellular parasites have developed a wide range of strategies that affect transcriptional machineries and epigenetic events in the host cell nucleus. In recent years, many laboratories have risen to the challenge of studying the epigenetics of host-pathogen interactions with the hope that unraveling the complexity of the mechanisms involved will provide important insights into parasitism and provide clues to fight infection. In this review, we survey some of these many strategies that Apicomplexan parasites employ to hijack their hosts, including inducing epigenetic enzymes, secreting epigenators into host cells, sequestering host signaling proteins, and co-opting non-coding RNAs to change gene and protein expression. We cite selected examples from the literature on Apicomplexa parasites (including Toxoplasma, Theileria, and Cryptosporidium) to highlight the success of these parasitic processes. We marvel at the effectiveness of the strategies that these pathogens have evolved and wonder what mysteries lie ahead in exploring the epigenetics of host–parasite interactions.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Seeber F, Steinfelder S (2016) Recent advances in understanding apicomplexan parasites. F1000Res 5:1369

  2. 2.

    Cowman AF, Healer J, Marapana D, Marsh K (2016) Malaria: biology and disease. Cell. 167(3):610–624

  3. 3.

    Pasternak ND, Dzikowski R (2009) PfEMP1: an antigen that plays a key role in the pathogenicity and immune evasion of the malaria parasite Plasmodium falciparum. Int J Biochem Cell Biol 41(7):1463–1466

  4. 4.

    Hviid L, Jensen ATR (2015) PfEMP1 – a parasite protein family of key importance in Plasmodium falciparum malaria immunity and pathogenesis. Adv Parasitol 88:51–84

  5. 5.

    Hunter CA, Sibley LD (2012) Modulation of innate immunity by Toxoplasma gondii virulence effectors. Nat Rev Microbiol 10(11):766–778

  6. 6.

    Tretina K, Gotia HT, Mann DJ, Silva JC (2015) Theileria-transformed bovine leukocytes have cancer hallmarks. Trends Parasitol 31(7):306–314

  7. 7.

    Dobbelaere DA, Küenzi P (2004) The strategies of the Theileria parasite: a new twist in host–pathogen interactions. Curr Opin Immunol 16(4):524–530

  8. 8.

    Morisaki JH, Heuser JE, Sibley LD (1995) Invasion of Toxoplasma gondii occurs by active penetration of the host cell. J Cell Sci 108(Pt 6):2457–2464

  9. 9.

    Hakimi M-A, Bougdour A (2015) Toxoplasma’s ways of manipulating the host transcriptome via secreted effectors. Curr Opin Microbiol 26:24–31

  10. 10.

    Hakimi M-A, Olias P, Sibley LD (2017) Toxoplasma effectors targeting host signaling and transcription. Clin Microbiol Rev 30(3):615–645

  11. 11.

    Soldati D, Dubremetz JF, Lebrun M (2001) Microneme proteins: structural and functional requirements to promote adhesion and invasion by the apicomplexan parasite Toxoplasma gondii. Int J Parasitol 31(12):1293–1302

  12. 12.

    Cheeseman K, Weitzman JB (2015) Host-parasite interactions: an intimate epigenetic relationship. Cell Microbiol 17(8):1121–1132

  13. 13.

    Heussler VT, Rottenberg S, Schwab R, Küenzi P, Fernandez PC, McKellar S, Shiels B, Chen ZJ, Orth K, Wallach D, Dobbelaere DA (2002) Hijacking of host cell IKK signalosomes by the transforming parasite Theileria. Science. 298(5595):1033–1036

  14. 14.

    Certad G, Viscogliosi E, Chabé M, Cacciò SM (2017) Pathogenic mechanisms of Cryptosporidium and Giardia. Trends Parasitol 33(7):561–576

  15. 15.

    Clough B, Frickel E-M (2017) The Toxoplasma parasitophorous vacuole: an evolving host–parasite frontier. Trends Parasitol 33(6):473–488

  16. 16.

    Robert McMaster W, Morrison CJ, Kobor MS (2016) Epigenetics: a new model for intracellular parasite–host cell regulation. Trends Parasitol 32(7):515–521

  17. 17.

    Silmon de Monerri NC, Kim K (2014) Pathogens hijack the epigenome. Am J Pathol 184(4):897–911

  18. 18.

    Kouzarides T (2007) Chromatin modifications and their function. Cell. 128(4):693–705

  19. 19.

    Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25(10):1010–1022

  20. 20.

    Huang H, Weng H, Chen J (2019) The biogenesis and precise control of RNA m6A methylation. Trends Genet 36(1):44–52

  21. 21.

    Baumgarten S, Bryant JM, Sinha A, Reyser T, Preiser PR, Dedon PC, Scherf A (2019) Transcriptome-wide dynamics of extensive m6A mRNA methylation during Plasmodium falciparum blood-stage development. Nat Microbiol 4(12):2246–2259

  22. 22.

    Hattman S (2005) DNA-[adenine] methylation in lower eukaryotes. Biochem. 70(5):550–558

  23. 23.

    Tessarz P, Kouzarides T (2014) Histone core modifications regulating nucleosome structure and dynamics. Nat Rev Mol Cell Biol 15(11):703–708

  24. 24.

    Sindikubwabo F, Ding S, Hussain T, Ortet P, Barakat M et al (2017) Modifications at K31 on the lateral surface of histone H4 contribute to genome structure and expression in apicomplexan parasites. Elife. 6. pii: e29391

  25. 25.

    Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21(3):381–395

  26. 26.

    Carlson SM, Gozani O (2016) Nonhistone lysine methylation in the regulation of cancer pathways. Cold Spring Harb Perspect Med 6(11):a026435

  27. 27.

    Dillon SC, Zhang X, Trievel RC, Cheng X (2005) The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol 6(8):227

  28. 28.

    Wu Z, Connolly J, Biggar KK (2017) Beyond histones - the expanding roles of protein lysine methylation. FEBS J 284(17):2732–2744

  29. 29.

    Wei J-W, Huang K, Yang C, Kang C-S (2017) Non-coding RNAs as regulators in epigenetics. Oncol Rep 37(1):3–9

  30. 30.

    Bierne H, Cossart P (2012) When bacteria target the nucleus: the emerging family of nucleomodulins. Cell Microbiol 14(5):622–633

  31. 31.

    Weitzman MD, Weitzman JB (2014) What’s the damage? The impact of pathogens on pathways that maintain host genome integrity. Cell Host Microbe 15(3):283–294

  32. 32.

    Somerville RPTT, Adamson RE, Brown CGDD, Hall FR (1998) Metastasis of Theileria annulata macroschizont-infected cells in scid mice is mediated by matrix metalloproteinases. Parasitology. 116(3):S0031182097002151

  33. 33.

    Cock-Rada AM, Medjkane S, Janski N, Yousfi N, Perichon M, Chaussepied M, Chluba J, Langsley G, Weitzman JB (2012) SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9. Cancer Res 72(3):810–820

  34. 34.

    Bougdour A, Durandau E, Brenier-Pinchart MP, Ortet P, Barakat M, Kieffer S, Curt-Varesano A, Curt-Bertini RL, Bastien O, Coute Y, Pelloux H, Hakimi MA (2013) Host cell subversion by Toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression. Cell Host Microbe 13(4):489–500

  35. 35.

    Braun L, Brenier-Pinchart M-P, Hammoudi P-M, Cannella D, Kieffer-Jaquinod S et al (2019) The Toxoplasma effector TEEGR promotes parasite persistence by modulating NF-κB signalling via EZH2. Nat Microbiol 4(7):1208–1220

  36. 36.

    Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of Zeste protein. Genes Dev 16(22):2893–2905

  37. 37.

    Bierne H, Tham TN, Batsche E, Dumay A, Leguillou M, Kernéis-Golsteyn S, Regnault B, Seeler JS, Muchardt C, Feunteun J, Cossart P (2009) Human BAHD1 promotes heterochromatic gene silencing. Proc Natl Acad Sci U S A 106(33):13826–13831

  38. 38.

    Lebreton A, Lakisic G, Job V, Fritsch L, Tham TN et al (2011) A bacterial protein targets the BAHD1 chromatin complex to stimulate type III interferon response. Science 331(6022):1319–1321

  39. 39.

    Gay G, Braun L, Brenier-Pinchart M-P, Vollaire J, Josserand V et al (2016) Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ–mediated host defenses. J Exp Med 213(9):1779–1798

  40. 40.

    Olias P, Etheridge RD, Zhang Y, Holtzman MJ, Sibley LD (2016) Toxoplasma effector recruits the Mi-2/NuRD complex to repress STAT1 transcription and block IFN-γ-dependent gene expression. Cell Host Microbe 20(1):72–82

  41. 41.

    Denslow SA, Wade PA (2007) The human Mi-2/NuRD complex and gene regulation. Oncogene. 26(37):5433–5438

  42. 42.

    Tong JK, Hassig CA, Schnitzler GR, Kingston RE, Schreiber SL (1998) Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature. 395(6705):917–921

  43. 43.

    Braun L, Brenier-Pinchart MP, Yogavel M, Curt-Varesano A, Curt-Bertini RL, Hussain T, Kieffer-Jaquinod S, Coute Y, Pelloux H, Tardieux I, Sharma A, Belrhali H, Bougdour A, Hakimi MA (2013) A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation. J Exp Med 210(10):2071–2086

  44. 44.

    Pellegrini E, Palencia A, Braun L, Kapp U, Bougdour A, Belrhali H, Bowler MW, Hakimi MA (2017) Structural basis for the subversion of MAP kinase signaling by an intrinsically disordered parasite secreted agonist. Structure. 25(1):16–26

  45. 45.

    Dessauge F, Lizundia R, Baumgartner M, Chaussepied M, Langsley G (2005) Taking the Myc is bad for Theileria. Trends Parasitol 21(8):377–385

  46. 46.

    Marsolier J, Perichon M, DeBarry JD, Villoutreix BO, Chluba J, Lopez T, Garrido C, Zhou XZ, Lu KP, Fritsch L, Ait-Si-Ali S, Mhadhbi M, Medjkane S, Weitzman JB (2015) Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation. Nature. 520(7547):378–382

  47. 47.

    Marsolier J, Perichon M, Weitzman JB, Medjkane S (2019) Secreted parasite Pin1 isomerase stabilizes host PKM2 to reprogram host cell metabolism. Commun Biol 2(1):152

  48. 48.

    Zurawski DV, Mumy KL, Faherty CS, McCormick BA, Maurelli AT (2009) Shigella flexneri type III secretion system effectors OspB and OspF target the nucleus to downregulate the host inflammatory response via interactions with retinoblastoma protein. Mol Microbiol 71(2):350–368

  49. 49.

    Bierne H, Hamon M, Cossart P (2012) Epigenetics and bacterial infections. Cold Spring Harb Perspect Med 2(12):a010272–a010272

  50. 50.

    Rolando M, Sanulli S, Rusniok C, Gomez-Valero L, Bertholet C, Sahr T, Margueron R, Buchrieser C (2013) Legionella pneumophila effector RomA uniquely modifies host chromatin to repress gene expression and promote intracellular bacterial replication. Cell Host Microbe 13(4):395–405

  51. 51.

    Pennini ME, Perrinet S, Dautry-Varsat A, Subtil A (2010) Histone methylation by NUE, a novel nuclear effector of the intracellular pathogen Chlamydia trachomatis. PLoS Pathog 6(7):1–12

  52. 52.

    Ming Z, Gong A-Y, Wang Y, Zhang X-T, Li M et al (2018) Involvement of Cryptosporidium parvum Cdg7_FLc_1000 RNA in the attenuation of intestinal epithelial cell migration via trans-suppression of host cell SMPD3. J Infect Dis 217(1):122–133

  53. 53.

    Ming Z, Gong AY, Wang Y, Zhang XT, Li M, Li Y, Pang J, Dong S, Strauss-Soukup JK, Chen XM (2018) Trans-suppression of host CDH3 and LOXL4 genes during Cryptosporidium parvum infection involves nuclear delivery of parasite Cdg7_FLc_1000 RNA. Int J Parasitol 48(6):423–431

  54. 54.

    Wang Y, Gong A-Y, Ma S, Chen X, Strauss-Soukup JK, Chen X-M (2017) Delivery of parasite Cdg7_Flc_0990 RNA transcript into intestinal epithelial cells during Cryptosporidium parvum infection suppresses host cell gene transcription through epigenetic mechanisms. Cell Microbiol 19(11):e12760

  55. 55.

    Tachibana M, Sugimoto K, Fukushima T, Shinkai Y (2001) SET domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to Lysines 9 and 27 of Histone H3. J Biol Chem 276(27):25309–25317

  56. 56.

    Menard KL, Haskins BE, Denkers EY (2019) Impact of Toxoplasma gondii infection on host non-coding RNA responses. Front Cell Infect Microbiol 9:132

  57. 57.

    Marsolier J, Pineau S, Medjkane S, Perichon M, Yin Q, Flemington E, Weitzman MD, Weitzman JB (2013) OncomiR addiction is generated by a miR-155 feedback loop in Theileria-transformed leukocytes. PLoS Pathog 9(4):e1003222

  58. 58.

    Haidar M, Rchiad Z, Ansari HR, Ben-Rached F, Tajeri S et al (2018) miR-126-5p by direct targeting of JNK-interacting protein-2 (JIP-2) plays a key role in Theileria-infected macrophage virulence. PLoS Pathog 14(3):e1006942

  59. 59.

    Cai Y, Chen H, Mo X, Tang Y, Xu X, Zhang A, Lun Z, Lu F, Wang Y, Shen J (2014) Toxoplasma gondii inhibits apoptosis via a novel STAT3-miR-17-92-Bim pathway in macrophages. Cell Signal 26(6):1204–1212

  60. 60.

    Cannella D, Brenier-Pinchart MP, Braun L, vanRooyen JM, Bougdour A et al (2014) MiR-146a and miR-155 delineate a microRNA fingerprint associated with toxoplasma persistence in the host brain. Cell Rep 6(5):928–937

  61. 61.

    Husmann D, Gozani O (2019) Histone lysine methyltransferases in biology and disease. Nat Struct Mol Biol 26(10):880–889

  62. 62.

    Morera L, Lübbert M, Jung M (2016) Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics 8(1):57

  63. 63.

    Copeland RA (2018) Protein methyltransferase inhibitors as precision cancer therapeutics: a decade of discovery. Philos Trans R Soc Lond Ser B Biol Sci 373(1748). pii: 20170080

  64. 64.

    Shiels BR, McKellar S, Katzer F, Lyons K, Kinnaird J et al (2004) A Theileria annulata DNA binding protein localized to the host cell nucleus alters the phenotype of a bovine macrophage cell line. Eukaryot Cell 3(2):495–505

  65. 65.

    Xu T, Ping J, Yu Y, Yu F, Yu Y et al (2010) Revealing parasite influence in metabolic pathways in Apicomplexa infected patients. BMC Bioinformatics. 2010 Dec 14;11 Suppl 11:S13

Download references


JBW is a senior member of the Institut Universitaire de France (IUF). We thanks members of the Weitzman lab and members of the UMR7216 for helpful discussions.


The work in our lab is supported by the LabEx “Who Am I?” #ANR-11-LABX-0071, and the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its “Investments for the Future” program, the Agence Nationale de la Recherche (ANR PATHO-METHYLOME #ANR-15-CE12-0020), and the Plan Cancer “Epigénétique et cancer” 2015 (PARA-CAN #PARA-15-RCA).

Author information

Correspondence to Jonathan B. Weitzman.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is a contribution to the special issue on Infection-induced epigenetic changes and the pathogenesis of diseases - Guest Editor: Nicole Fischer

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Villares, M., Berthelet, J. & Weitzman, J.B. The clever strategies used by intracellular parasites to hijack host gene expression. Semin Immunopathol (2020).

Download citation


  • Epigenetics
  • Parasites
  • Lysine methylation
  • Host-parasite interactions
  • Epigenators
  • Apicomplexa