Head-to-head comparisons of Toxoplasma gondii and its near relative Hammondia hammondi reveal dramatic differences in the host response and effectors with species-specific functions


Autoři: Zhee Sheen Wong aff001;  Sarah L. Sokol-Borrelli aff001;  Philip Olias aff002;  J. P. Dubey aff003;  Jon P. Boyle aff001
Působiště autorů: Department of Biological Sciences, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America aff001;  University of Bern, Bern, Switzerland aff002;  Animal Parasitic Diseases Laboratory, Beltsville Agricultural Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, Maryland, United States of America aff003
Vyšlo v časopise: Head-to-head comparisons of Toxoplasma gondii and its near relative Hammondia hammondi reveal dramatic differences in the host response and effectors with species-specific functions. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1008528
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008528

Souhrn

Toxoplasma gondii and Hammondia hammondi are closely-related coccidian intracellular parasites that differ in their ability to cause disease in animal and (likely) humans. The role of the host response in these phenotypic differences is not known and to address this we performed a transcriptomic analysis of a monocyte cell line (THP-1) infected with these two parasite species. The pathways altered by infection were shared between species ~95% the time, but the magnitude of the host response to H. hammondi was significantly higher compared to T. gondii. Accompanying this divergent host response was an equally divergent impact on the cell cycle of the host cell. In contrast to T. gondii, H. hammondi infection induces cell cycle arrest via pathways linked to DNA-damage responses and cellular senescence and robust secretion of multiple chemokines that are known to be a part of the senescence associated secretory phenotype (SASP). Remarkably, prior T. gondii infection or treatment with T. gondii-conditioned media suppressed responses to H. hammondi infection, and promoted the replication of H. hammondi in recipient cells. Suppression of inflammatory responses to H. hammondi was found to be mediated by the T. gondii effector IST, and this finding was consistent with reduced functionality of the H. hammondi IST ortholog compared to its T. gondii counterpart. Taken together our data suggest that T. gondii manipulation of the host cell is capable of suppressing previously unknown stress and/or DNA-damage induced responses that occur during infection with H. hammondi, and that one important impact of this T. gondii mediated suppression is to promote parasite replication.

Klíčová slova:

Cell cycle and cell division – DNA damage – Host cells – Parasite replication – Parasitic cell cycles – Parasitic diseases – Sporozoites – Toxoplasma gondii


Zdroje

1. Blader IJ, Manger ID, Boothroyd JC. Microarray analysis reveals previously unknown changes in Toxoplasma gondii-infected human cells. J Biol Chem. 2001;276(26):24223–31. doi: 10.1074/jbc.M100951200 11294868.

2. Melo MB, Nguyen Q.P., Cordeiro C., Hassan M.A., Yang N., McKell R., Rosowski E.E., Julien L., Butty V., Dardé D.A., Fitzgerald K., Young L.H., Saeij J.P.J. Transcriptional analysis of murine macrophages infected with different Toxoplasma strains identified novel regulation of host signaling pathways. Plos Pathogens. 2013:1003779.

3. Hunter CA, Sibley LD. Modulation of innate immunity by Toxoplasma gondii virulence effectors. Nature reviews Microbiology. 2012;10(11):766–78. Epub 2012/10/17. doi: 10.1038/nrmicro2858 23070557; PubMed Central PMCID: PMC3689224.

4. Hakimi MA, Olias P, Sibley LD. Toxoplasma Effectors Targeting Host Signaling and Transcription. Clinical microbiology reviews. 2017;30(3):615–45. doi: 10.1128/CMR.00005-17 28404792; PubMed Central PMCID: PMC5475222.

5. Zhou XW, Kafsack BF, Cole RN, Beckett P, Shen RF, Carruthers VB. The opportunistic pathogen Toxoplasma gondii deploys a diverse legion of invasion and survival proteins. J Biol Chem. 2005;280(40):34233–44. doi: 10.1074/jbc.M504160200 16002397.

6. Bradley PJ, Ward C, Cheng SJ, Alexander DL, Coller S, Coombs GH, et al. Proteomic analysis of rhoptry organelles reveals many novel constituents for host-parasite interactions in Toxoplasma gondii. The Journal of Biological Chemistry. 2005;280:34245–58. doi: 10.1074/jbc.M504158200 16002398

7. Yamamoto M, Standley DM, Takashima S, Saiga H, Okuyama M, Kayama H, et al. A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3. Journal of Experimental Medicine. 2009;206:2747–60. doi: 10.1084/jem.20091703 19901082

8. Ong YC, Reese ML, Boothroyd JC. Toxoplasma rhoptry protein 16 (ROP16) subverts host function by direct tyrosine phosphorylation of STAT6. The Journal of Biological Chemistry. 2010;285:28731–40. doi: 10.1074/jbc.M110.112359 20624917

9. Rosowski EE, Lu D, Julien L, Rodda L, Gaiser RA, Jensen KD, et al. Strain-specific activation of NF-kappaB pathway by GRA15, a novel Toxoplasma gondii dense granule protein. Journal of Experimental Medicine. 2011;208:195–212. doi: 10.1084/jem.20100717 21199955

10. Bougdour A, Durandau E, Brenier-Pinchart MP, Ortet P, Barakat M, Kieffer-Jaquinod S, et al. Host cell subversion by Toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression. Cell Host Microbe. 2013;13:489–500. doi: 10.1016/j.chom.2013.03.002 23601110

11. Braun L, Brenier-Pinchart MP, Curt-Varesano A, Curt-Bertini RL, Hussain T, Kieffer-Jaquinod S, et al. A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation. Journal of Experimental Medicine. 2013;210:2071–86. doi: 10.1084/jem.20130103 24043761

12. He H, Brenier-Pinchart MP, Braun L, Kraut A, Touquet B, Coute Y, et al. Characterization of a Toxoplasma effector uncovers an alternative GSK3/β-catenin-regulatory pathway of inflammation. eLife. 2018;7:e39887. doi: 10.7554/eLife.39887 30320549

13. Shastri AJ, Marino ND, Franco M, Lodoen MB, Boothroyd JC. GRA25 is a novel virulence factor of Toxoplasma gondii and influences the host immune response. Infect Immun. 2014;82(6):2595–605. doi: 10.1128/IAI.01339-13 24711568; PubMed Central PMCID: PMC4019154.

14. Gay G, Braun L, Brenier-Pinchart MP, Vollaire J, Josserand V, Bertini R, et al. Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ–mediated host defenses. Journal of Experimental Medicine. 2016;213:1779. doi: 10.1084/jem.20160340 27503074

15. Olias P, Etheridge RD, Zhang Y, Holtzman MJ, Sibley LD. Toxoplasma effector recruits the Mi-2/NuRD complex to repress STAT1 transcription and block IFN-γ-dependent gene expression. Cell Host Microbe. 2016;20:72–82. doi: 10.1016/j.chom.2016.06.006 27414498

16. Franco M, Shastri AJ, Boothroyd JC. Infection by Toxoplasma gondii specifically induces host c-Myc and the genes this pivoral transcription factor regulates. Eukaryotic Cell. 2014;13:483–93. doi: 10.1128/EC.00316-13 24532536

17. Franco M, Panas MW, Marino ND, Lee MC, Buchholz KR, Kelly FD, et al. A novel secreted protein, MYR1, is central to Toxoplasma's manipulation of host cells. mBio. 2016;7:e02231–022315. doi: 10.1128/mBio.02231-15 26838724

18. Ander SE, Rudzki EN, Arora N, Sadovsky Y, Coyne CB, Boyle JP. Human Placental Syncytiotrophoblasts Restrict Toxoplasma gondii Attachment and Replication and Respond to Infection by Producing Immunomodulatory Chemokines. MBio. 2018;9(1). doi: 10.1128/mBio.01678-17 29317509; PubMed Central PMCID: PMC5760739.

19. Frenkel JK, Dubey J.P. Hammondia hammondi gen. nov., sp. nov., from domestic cats, a new coccidian related to Toxoplasma and Sarcocytis. Zeitschrift fu¨r Parasitenkunde. 1975;46:3–12.

20. Dubey JP, Sreekumar C. Redescription of Hammondia hammondi and its differentiation from Toxoplasma gondii. International Journal for Parasitology. 2003;33:1437–53. doi: 10.1016/s0020-7519(03)00141-3 14572507

21. Wallace GD. Observations on a feline coccidium with some characteristics of Toxoplasma and Sarcocystis. Z Parasitenkd. 1975;46(3):167–78. Epub 1975/06/27. doi: 10.1007/BF00389874 807050.

22. Walzer KA, Adomako-Ankomah Y, Dam RA, Herrmann DC, Schares G, Dubey JP, et al. Hammondia hammondi, an avirulent relative of Toxoplasma gondii, has functional orthologs of known T. gondii virulence genes. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:7446–51. doi: 10.1073/pnas.1304322110 23589877

23. Sokol SL, Primack AS, Nair SC, Wong ZS, Tembo M, Verma SK, et al. Dissection of the in vitro developmental program of Hammondia hammondi reveals a link between stress sensitivity and life cycle flexibility in Toxoplasma gondii. Elife. 2018;7. Epub 2018/05/23. doi: 10.7554/eLife.36491 29785929; PubMed Central PMCID: PMC5963921.

24. Walzer KA, Wier GM, Dam RA, Srinivasan AR, Borges AL, English ED, et al. Hammondia hammondi harbors functional orthologs of the host-modulating effectors GRA15 and ROP16 but is distinguished from Toxoplasma gondii by a unique transcriptional profile. Eukaryot Cell. 2014;13(12):1507–18. doi: 10.1128/EC.00215-14 25280815; PubMed Central PMCID: PMC4248688.

25. Munday BL, Dubey JP. Serological cross-reactivity between Hammondia hammondi and Toxoplasma gondii in experimentally inoculated sheep. Aust Vet J. 1986;63(10):344–5. doi: 10.1111/j.1751-0813.1986.tb02886.x 3541885

26. Schares G, Ziller M, Herrmann DC, Globokar MV, Pantchev N, Conraths FJ. Seasonility in the proportions of domestic cats shedding Toxoplasma gondii or Hammondia hammondi oocysts is associated with climatic factors. International Journal for Parasitology. 2015;46:263–73.

27. Tsuchiya S, Yamabe M, Yamaguchi Y, Kobayashi Y, Konno T, Tada K. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). International journal of cancer. 1980;26(2):171–6. doi: 10.1002/ijc.2910260208 6970727.

28. Love M, Anders S, Huber W. Estimate variance-mean dependence in count data from high-throughput sequencing assays and test for differential expression based on a model using the negative binomial distribution. Genome Biology. 2014;15:550. doi: 10.1186/s13059-014-0550-8 25516281

29. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gilette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:15545–50. doi: 10.1073/pnas.0506580102 16199517

30. Gazzinelli RT, Xu Y, Hieny S, Cheever A, Sher A. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. Journal of Immunology. 1992;149:175–80.

31. Suzuki Y, Orellana MA, Schreiber RD, Remington JS. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988;240:516–8. doi: 10.1126/science.3128869 3128869

32. Yap GS, Sher A. Effector cells of both nonhemopoietic and hemopoietic origin are required for interferon (IFN)-gamma- and tumor necrosis factor (TNF)-alpha-dependent host resistance to the intracellular pathogen, Toxoplasma gondii. Journal of Experimental Medicine. 1999;189:1083–92. doi: 10.1084/jem.189.7.1083 10190899

33. Brunet J, Pfaff AW, Abidi A, Unoki M, Nakamura Y, Guinard M, et al. Toxoplasma gondii exploits UHRF1 and induces host cell cycle arrest at G2 to enable its proliferation. Cellular Microbiology. 2008;10:908–20. doi: 10.1111/j.1462-5822.2007.01093.x 18005238

34. Molestina RE, El-Guendy N, Sinai AP. Infection with Toxoplasma gondii results in dysregulation of the host cell cycle. Cellular Microbiology. 2008;10:1153–65. doi: 10.1111/j.1462-5822.2008.01117.x 18182087

35. Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L, et al. GADD45 induction of a G2/M cell cycle checkpoint. Proceedings of the National Academy of Sciences of the United States of America. 1999;96:3706–11. doi: 10.1073/pnas.96.7.3706 10097101

36. Salvador JM, Brown-Clay JD, Fornace AJ Jr. Gadd45 in stress signaling, cell cycle control, and apoptosis. Adv Exp Med Biol. 2013;793:1–19. Epub 2013/10/10. doi: 10.1007/978-1-4614-8289-5_1 24104470.

37. Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science. 1997;277:1501–5. doi: 10.1126/science.277.5331.1501 9278512

38. Grant GD, Brooks L, Zhang X, Mahoney MJ, Martyanov V, Wood TA, et al. Identification of cell cycle-regulated genes periodically expressed in U2OS cells and their regulation by FOXM1 and E2F transcription factors. Molecular Biology of the Cell. 2013;24:3634–50. doi: 10.1091/mbc.E13-05-0264 24109597

39. Fischer M, Grossmann P, Padi M, DeCaprio JA. Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks. Nucleic Acids Research. 2016;44:6070–86. doi: 10.1093/nar/gkw523 27280975

40. Fridman AL, Tainsky MA. Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene. 2008;9:5975–87.

41. Chen J, Huang X, Halicka D, Brodsky S, Avram A, Eskander J, et al. Contribution of p16INKa and p21CIP1 pathways to induction of premature senescence of human endothelial cells: permissive role of p53. American Journal of Physiology Heart and Circulatory Physiology. 2006;290:H1575–86. doi: 10.1152/ajpheart.00364.2005 16243918

42. Spazzafumo L, Mensà E, Matacchione G, Galeazzi T, Zampini L, Recchioni R, et al. Age-related modulation of plasmatic beta-Galactosidase activity in health subjects and in patients affected by T2DM. Oncotarget. 2017;8:93338–48. doi: 10.18632/oncotarget.21848 29212153

43. Perrott KM, Wiley CD, Desprez P, Campisi J. Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. GeroScience. 2017;39:161–73. doi: 10.1007/s11357-017-9970-1 28378188

44. Dufour JH, Dziejman M, Liu MT, Leung JH, Lane TE, Luster AD. IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J Immunol. 2002;168(7):3195–204. Epub 2002/03/22. doi: 10.4049/jimmunol.168.7.3195 11907072.

45. Kim SK, Fouts AE, Boothroyd JC. Toxoplasma gondii dysregulates IFN-gamma-inducible gene expression in human fibroblasts: insights from a genome-wide transcriptional profiling. J Immunol. 2007;178(8):5154–65. doi: 10.4049/jimmunol.178.8.5154 17404298.

46. Nguyen Ba AN, Pogoutse A, Provart N, Moses AM. NLStradamus: a simple Hidden Markov Model for nuclear localization signal prediction. BMC bioinformatics. 2009;10:202. doi: 10.1186/1471-2105-10-202 19563654; PubMed Central PMCID: PMC2711084.

47. Saeij JP, Coller S, Boyle JP, Jerome ME, White MW, Boothroyd JC. Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature. 2007;445(7125):324–7. Epub 2006/12/22. doi: 10.1038/nature05395 17183270; PubMed Central PMCID: PMC2637441.

48. Reese ML, Zeiner GM, Saeij JP, Boothroyd JC, Boyle JP. Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence. Proc Natl Acad Sci U S A. 2011;108(23):9625–30. Epub 2011/03/26. doi: 10.1073/pnas.1015980108 21436047; PubMed Central PMCID: PMC3111280.

49. Saeij JP, Boyle JP, Coller S, Taylor S, Sibley LD, Brooke-Powell ET, et al. Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science. 2006;314(5806):1780–3. Epub 2006/12/16. doi: 10.1126/science.1133690 17170306; PubMed Central PMCID: PMC2646183.

50. Sokol SL, Wong ZS, Boyle JP, Dubey JP. Generation of Toxoplasma gondii and Hammondia hammondi Oocysts and Purification of Their Sporozoites for Downstream Manipulation. Methods Mol Biol. 2020;2071:81–98. Epub 2019/11/24. doi: 10.1007/978-1-4939-9857-9_4 31758447.

51. Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nature Genetics. 2002;30:285–9. doi: 10.1038/ng837 11836499

52. Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death and Differentiation. 2018;25:114–32. doi: 10.1038/cdd.2017.172 29125603

53. Braun L, Brenier-Pinchart MP, Hammoudi PM, Cannella D, Kieffer-Jaquinod S, Vollaire J, et al. The Toxoplasma effector TEEGR promotes parasite persistence by modulating NF-kappaB signalling via EZH2. Nat Microbiol. 2019;4(7):1208–20. Epub 2019/05/01. doi: 10.1038/s41564-019-0431-8 31036909; PubMed Central PMCID: PMC6591128.

54. Panas MW, Naor A, Cygan AM, Boothroyd JC. Toxoplasma controls host cyclin E expression through the use of a novel MYR-1 dependent effector protein, HCE1. mBio. 2019: doi: 10.1128/mBio.00674-19 31040242

55. Norose K, Kikumura A, Luster AD, Hunter CA, Harris TH. CXCL10 is required to maintain T-cell population and to control parasite replication during chronic ocular toxoplasmosis. Investigative Opthalmology & Visual Science. 2011;52:389–98.

56. Riahi H, Darde ML, Bouteille B, Leboutet MJ, Pestre-Alexandre M. Hammondia hammondi cysts in cell cultures. The Journal of parasitology. 1995;81(5):821–4. 7472890.

57. Channon JY, Miselis KA, Minns LA, Dutta C, Kasper LH. Toxoplasma gondii induces granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor secretion by human fibroblasts: implications for neutrophil apoptosis. Infect Immun. 2002;70(11):6048–57. doi: 10.1128/iai.70.11.6048-6057.2002 12379681; PubMed Central PMCID: PMC130285.

58. Rozenfeld C, Martinez R, Figueiredo RT, Bozza MT, Lima FR, Pires AL, et al. Soluble factors released by Toxoplasma gondii-infected astrocytes down-modulate nitric oxide production by gamma interferon-activated microglia and prevent neuronal degeneration. Infect Immun. 2003;71(4):2047–57. doi: 10.1128/iai.71.4.2047-2057.2003 12654825; PubMed Central PMCID: PMC152043.


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