Skip to main content

Advertisement

SpringerLink
Log in

Toxoplasma gondii profilin and tachyzoites RH strain may manipulate autophagy via downregulating Atg5 and Atg12 and upregulating Atg7

  • Short Communication
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Autophagy process is an important defense mechanism against intracellular infection. This process plays a critical role in limiting the development of Toxoplasma gondii. This study aimed to investigate the effects of T. gondii profilin and tachyzoites on the expression of autophagy genes.

Methods and results

PMA-activated THP-1 cell line was incubated with T. gondii profilin and tachyzoites for 6 h. After RNA extraction and cDNA synthesis, the expression of Atg5, Atg7, Atg12, and LC3b was evaluated using real-time PCR. The results revealed statistically significant downregulation of Atg5 for 1.43 (P-value = 0.0062) and 4.15 (P-value = 0.0178) folds after treatment with T. gondii profilin and tachyzoites, respectively. Similar to Atg 5, Atg 12 revealed a statistically significant downregulation for profilin (1.41 fold; P-value = 0.0047) and T. gondii tachyzoites (3.25 fold; P-value = 0.011). The expression of Atg7 elevated in both T. gondii profilin (2.083 fold; P-value = 0.0087) and tachyzoites (1.64 fold; P-value = 0.206). T. gondii profilin and tachyzoites downregulated (1.04 fold; P-value = 0.0028) and upregulated (twofold; P-value = 0.091) the expression of LC3b, respectively.

Conclusions

Our findings suggest that T. gondii and profilin may manipulate autophagy via preventing from the formation of Atg5-12-16L complex to facilitate replication of T. gondii and development of toxoplasmosis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Data availability

All generated data from the current study are included in the article.

References

  1. Dubey JP (2008) The history of Toxoplasma gondii—the first 100 years. J Eukaryot Microbiol 55(6):467–475. https://doi.org/10.1111/j.1550-7408.2008.00345.x

    Article  PubMed  Google Scholar 

  2. Montoya JG, Liesenfeld O (2004) Toxoplasmosis. Lancet (London, England) 363(9425):1965–1976. https://doi.org/10.1016/s0140-6736(04)16412-x

    Article  CAS  Google Scholar 

  3. Simpore J, Savadogo A, Ilboudo D, Nadambega MC, Esposito M, Yara J, Pignatelli S, Pietra V, Musumeci S (2006) Toxoplasma gondii, HCV, and HBV seroprevalence and co-infection among HIV-positive and-negative pregnant women in Burkina Faso. J Med Virol 78(6):730–733

    Article  PubMed  Google Scholar 

  4. Kim K, Weiss LM (2004) Toxoplasma gondii: the model apicomplexan. Int J Parasitol 34(3):423–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang Y, Lai BS, Juhas M, Zhang Y (2019) Toxoplasma gondii secretory proteins and their role in invasion and pathogenesis. Microbiol Res 227:126293. https://doi.org/10.1016/j.micres.2019.06.003

    Article  CAS  PubMed  Google Scholar 

  6. Plattner F, Yarovinsky F, Romero S, Didry D, Carlier M-F, Sher A, Soldati-Favre D (2008) Toxoplasma profilin is essential for host cell invasion and tlr11-dependent induction of an interleukin-12 response. Cell Host Microbe 3(2):77–87. https://doi.org/10.1016/j.chom.2008.01.001

    Article  CAS  PubMed  Google Scholar 

  7. Wetzel DM, Håkansson S, Hu K, Roos D, Sibley LD (2003) Actin filament polymerization regulates gliding motility by apicomplexan parasites. Mol Biol Cell 14(2):396–406. https://doi.org/10.1091/mbc.e02-08-0458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Meissner M, Schlüter D, Soldati D (2002) Role of Toxoplasma gondii myosin A in powering parasite gliding and host cell invasion. Science 298(5594):837–840

    Article  CAS  PubMed  Google Scholar 

  10. Pantaloni D, Carlier M-F (1993) How profilin promotes actin filament assembly in the presence of thymosin β4. Cell 75(5):1007–1014. https://doi.org/10.1016/0092-8674(93)90544-Z

    Article  CAS  PubMed  Google Scholar 

  11. Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221(1):3–12. https://doi.org/10.1002/path.2697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Besteiro S (2019) The role of host autophagy machinery in controlling Toxoplasma infection. Virulence 10(1):438–447. https://doi.org/10.1080/21505594.2018.1518102

    Article  CAS  PubMed  Google Scholar 

  13. Parzych KR, Klionsky DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 20(3):460–473. https://doi.org/10.1089/ars.2013.5371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yoshimori T (2004) Autophagy: a regulated bulk degradation process inside cells. Biochem Biophys Res Commun 313(2):453–458. https://doi.org/10.1016/j.bbrc.2003.07.023

    Article  CAS  PubMed  Google Scholar 

  15. Codogno P, Meijer AJ (2005) Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 12(2):1509–1518. https://doi.org/10.1038/sj.cdd.4401751

    Article  CAS  PubMed  Google Scholar 

  16. Das G, Shravage BV, Baehrecke EH (2012) Regulation and function of autophagy during cell survival and cell death. Cold Spring Harb Perspect Biol 4(6):a008813. https://doi.org/10.1101/cshperspect.a008813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290(5497):1717–1721. https://doi.org/10.1126/science.290.5497.1717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yang J-S, Lu C-C, Kuo S-C, Hsu Y-M, Tsai S-C, Chen S-Y, Chen Y-T, Lin Y-J, Huang Y-C, Chen C-J, Lin W-D, Liao W-L, Lin W-Y, Liu Y-H, Sheu J-C, Tsai F-J (2017) Autophagy and its link to type II diabetes mellitus. Biomedicine (Taipei) 7(2):8–8. https://doi.org/10.1051/bmdcn/2017070201

    Article  Google Scholar 

  19. Martinez-Vicente M, Cuervo AM (2007) Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 6(4):352–361. https://doi.org/10.1016/s1474-4422(07)70076-5

    Article  CAS  PubMed  Google Scholar 

  20. Li X, He S, Ma B (2020) Autophagy and autophagy-related proteins in cancer. Mol Cancer 19(1):12. https://doi.org/10.1186/s12943-020-1138-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mizushima N, Klionsky DJ (2007) Protein turnover via autophagy: implications for metabolism. Annu Rev Nutr 27:19–40. https://doi.org/10.1146/annurev.nutr.27.061406.093749

    Article  CAS  PubMed  Google Scholar 

  22. Wu M, Cudjoe O, Shen J, Chen Y, Du J (2020) The host autophagy during Toxoplasma infection. Front Microbiol 11:589604. https://doi.org/10.3389/fmicb.2020.589604

    Article  PubMed  PubMed Central  Google Scholar 

  23. Yu L, Chen Y, Tooze SA (2018) Autophagy pathway: cellular and molecular mechanisms. Autophagy 14(2):207–215. https://doi.org/10.1080/15548627.2017.1378838

    Article  CAS  PubMed  Google Scholar 

  24. Søreng K, Neufeld TP, Simonsen A (2018) Membrane trafficking in autophagy. Int Rev Cell Mol Biol 336:1–92. https://doi.org/10.1016/bs.ircmb.2017.07.001

    Article  CAS  PubMed  Google Scholar 

  25. Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469(7330):323–335. https://doi.org/10.1038/nature09782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Subauste CS (2019) Interplay between Toxoplasma gondii, autophagy, and autophagy proteins. Front Cell Infect Microbiol 9:139. https://doi.org/10.3389/fcimb.2019.00139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Muniz-Feliciano L, Van Grol J, Portillo JA, Liew L, Liu B, Carlin CR, Carruthers VB, Matthews S, Subauste CS (2013) Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite. PLoS Path 9(12):e1003809. https://doi.org/10.1371/journal.ppat.1003809

    Article  CAS  Google Scholar 

  28. Wang Y, Weiss LM, Orlofsky A (2009) Host cell autophagy is induced by Toxoplasma gondii and contributes to parasite growth. J Biol Chem 284(3):1694–1701. https://doi.org/10.1074/jbc.M807890200

    Article  PubMed  PubMed Central  Google Scholar 

  29. Park S-H, Choi H-I, Ahn J, Jang Y-J, Ha T-Y, Seo H-D, Kim Y-S, Lee D-H, Jung CH (2020) Autophagy functions to prevent methylglyoxal-induced apoptosis in hk-2 cells. Oxid Med Cell Longev 2020:8340695–8340695. https://doi.org/10.1155/2020/8340695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fu J, Bian L, Zhao L, Dong Z, Gao X, Luan H, Sun Y, Song H (2010) Identification of genes for normalization of quantitative real-time PCR data in ovarian tissues. Acta Biochim Biophys Sin 42(8):568–574. https://doi.org/10.1093/abbs/gmq062

    Article  CAS  PubMed  Google Scholar 

  31. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, Cuervo AM, Debnath J, Deretic V, Dikic I, Eskelinen EL, Fimia GM, Fulda S, Gewirtz DA, Green DR, Hansen M, Harper JW, Jäättelä M, Johansen T, Juhasz G, Kimmelman AC, Kraft C, Ktistakis NT, Kumar S, Levine B, Lopez-Otin C, Madeo F, Martens S, Martinez J, Melendez A, Mizushima N, Münz C, Murphy LO, Penninger JM, Piacentini M, Reggiori F, Rubinsztein DC, Ryan KM, Santambrogio L, Scorrano L, Simon AK, Simon HU, Simonsen A, Tavernarakis N, Tooze SA, Yoshimori T, Yuan J, Yue Z, Zhong Q, Kroemer G (2017) Molecular definitions of autophagy and related processes. EMBO J 36(13):1811–1836. https://doi.org/10.15252/embj.201796697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Subramani S, Malhotra V (2013) Non-autophagic roles of autophagy-related proteins. EMBO Rep 14(2):143–151. https://doi.org/10.1038/embor.2012.220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19(21):5720–5728. https://doi.org/10.1093/emboj/19.21.5720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stephenson LM, Miller BC, Ng A, Eisenberg J, Zhao Z, Cadwell K, Graham DB, Mizushima NN, Xavier R, Virgin HW, Swat W (2009) Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T lymphocytes. Autophagy 5(5):625–635. https://doi.org/10.4161/auto.5.5.8133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ghosh D, Walton JL, Roepe PD, Sinai AP (2012) Autophagy is a cell death mechanism in Toxoplasma gondii. Cell Microbiol 14(4):589–607. https://doi.org/10.1111/j.1462-5822.2011.01745.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Ann Rev Cell Dev Biol 27:107–132. https://doi.org/10.1146/annurev-cellbio-092910-154005

    Article  CAS  Google Scholar 

  37. van Kooten C, Banchereau J (2000) CD40-CD40 ligand. J Leukoc Biol 67(1):2–17. https://doi.org/10.1002/jlb.67.1.2

    Article  PubMed  Google Scholar 

  38. Andrade RM, Wessendarp M, Gubbels MJ, Striepen B, Subauste CS (2006) CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J Clin Investig 116(9):2366–2377. https://doi.org/10.1172/jci28796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhao Z, Fux B, Goodwin M, Dunay IR, Strong D, Miller BC, Cadwell K, Delgado MA, Ponpuak M, Green KG, Schmidt RE, Mizushima N, Deretic V, Sibley LD, Virgin HW (2008) Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe 4(5):458–469. https://doi.org/10.1016/j.chom.2008.10.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T (2008) The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19(5):2092–2100. https://doi.org/10.1091/mbc.e07-12-1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ, Ishii KJ, Kawai T, Akira S, Suzuki K, Okuda K (2007) The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci USA 104(35):14050–14055. https://doi.org/10.1073/pnas.0704014104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Selleck EM, Orchard RC, Lassen KG, Beatty WL, Xavier RJ, Levine B, Virgin HW, Sibley LD (2015) A noncanonical autophagy pathway restricts Toxoplasma gondii growth in a strain-specific manner in ifn-γ-activated human cells. mBio. https://doi.org/10.1128/mBio.01157-15

    Article  PubMed  PubMed Central  Google Scholar 

  43. Liu E, Van Grol J, Subauste CS (2015) Atg5 but not Atg7 in dendritic cells enhances IL-2 and IFN-γ production by Toxoplasma gondii-reactive CD4+ T cells. Microbes Infect 17(4):275–284. https://doi.org/10.1016/j.micinf.2014.12.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nishida Y, Arakawa S, Fujitani K, Yamaguchi H, Mizuta T, Kanaseki T, Komatsu M, Otsu K, Tsujimoto Y, Shimizu S (2009) Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461(7264):654–658. https://doi.org/10.1038/nature08455

    Article  PubMed  Google Scholar 

  45. Niedelman W, Sprokholt JK, Clough B, Frickel EM, Saeij JP (2013) Cell death of gamma interferon-stimulated human fibroblasts upon Toxoplasma gondii infection induces early parasite egress and limits parasite replication. Infect Immun 81(12):4341–4349. https://doi.org/10.1128/iai.00416-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW (2007) A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 204(1):25–31. https://doi.org/10.1084/jem.20061303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A, Mizushima N, Grinstein S, Iwasaki A (2010) In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32(2):227–239. https://doi.org/10.1016/j.immuni.2009.12.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mukhopadhyay D, Arranz-Solís D, Saeij JPJ (2020) Influence of the host and parasite strain on the immune response during Toxoplasma infection. Front Cell Infect Microbiol 10:580425. https://doi.org/10.3389/fcimb.2020.580425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fox BA, Sanders KL, Rommereim LM, Guevara RB, Bzik DJ (2016) Secretion of rhoptry and dense granule effector proteins by nonreplicating Toxoplasma gondii uracil auxotrophs controls the development of antitumor immunity. PLoS Genet 12(7):e1006189–e1006189. https://doi.org/10.1371/journal.pgen.1006189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Murillo-León M, Müller UB, Zimmermann I, Singh S, Widdershooven P, Campos C, Alvarez C, Könen-Waisman S, Lukes N, Ruzsics Z, Howard JC, Schwemmle M, Steinfeldt T (2019) Molecular mechanism for the control of virulent Toxoplasma gondii infections in wild-derived mice. Nat Commun 10(1):1233. https://doi.org/10.1038/s41467-019-09200-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rommereim LM, Fox BA, Butler KL, Cantillana V, Taylor GA, Bzik DJ (2019) Rhoptry and dense granule secreted effectors regulate CD8(+) T Cell recognition of Toxoplasma gondii infected host cells. Front Immunol 10:2104–2104. https://doi.org/10.3389/fimmu.2019.02104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank all members of the Foodborne and Waterborne Diseases Research Center for their supports.

Funding

This study was financially supported by the Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences with grant number: RIGLD-1060.

Author information

Authors and Affiliations

  1. Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sara Nemati, Hanieh Mohammad Rahimi & Hamed Mirjalali

  2. Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Hossein Pazoki, Hamid Asadzadeh Aghdaei & Kaveh Baghaei

  3. Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Shabnam Shahrokh & Mohammad Reza Zali

Authors
  1. Sara Nemati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hossein Pazoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hanieh Mohammad Rahimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hamid Asadzadeh Aghdaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shabnam Shahrokh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kaveh Baghaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hamed Mirjalali
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mohammad Reza Zali
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived and designed the experiments: HM. Performed the experiments: SN, HMR, HP. Analyzed the data: HM, KB, SS. Contributed reagents/materials/analysis/tools/positive samples: MRZ, HAA. Wrote the paper: SN, HM. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Hamed Mirjalali.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards (IR.SBMU.RIGLD.REC.1398.032) released by Ethical Review Committee of the Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Consent for publication

All authors declare that they have seen and approved the submitted version of this manuscript.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nemati, S., Pazoki, H., Mohammad Rahimi, H. et al. Toxoplasma gondii profilin and tachyzoites RH strain may manipulate autophagy via downregulating Atg5 and Atg12 and upregulating Atg7. Mol Biol Rep 48, 7041–7047 (2021). https://doi.org/10.1007/s11033-021-06667-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06667-5

Keywords

Search

Navigation