Skip to main content

Advertisement

SpringerLink
Log in

Toxoplasma: Immunity and Pathogenesis

  • Parasitology (N Kumar, Section Editor)
  • Published:
Current Clinical Microbiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Toxoplasmosis is an apicomplexan parasite that can be found in all countries, which causes an infection of the central nervous system. This review outlines some of the recent immunological advances that have been made against this chronic infection that poses a major problem for the immunocompromised individuals.

Recent Findings

Recent studies have demonstrated that in a mouse model of chronic toxoplasmosis, the infection leads to T cell dysfunctionality. The exhaustion that is observed in both CD4 and CD8 T cells is manifested by increased expression of co-inhibitory molecules like PD-1 and leads to reactivation of latent infection. Blockade of PD-1-PDL-1 interaction reverses the exhaustion and prevents reactivation of latent infection in the host.

Summary

Prevention of loss of CD4 T cell function can be important therapeutic strategy for controlling chronic toxoplasmosis and preventing reactivation of latent infection.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Luft BJ, Castro KG. An overview of the problem of toxoplasmosis and pneumocystosis in AIDS in the USA: implication for future therapeutic trials. Eur J Clin Microbiol Infect Dis. 1991;10(3):178–81.

    Article  CAS  PubMed  Google Scholar 

  2. Clumeck N, Hermans P. New therapeutic approaches in the acquired immune deficiency syndrome. Antibiot Chemother (1971). 1991;43:235–56.

    Article  CAS  Google Scholar 

  3. Zumla A, Savva D, Wheeler RB, Hira SK, Luo NP, Kaleebu P, et al. Toxoplasma serology in Zambian and Ugandan patients infected with the human immunodeficiency virus. Trans R Soc Trop Med Hyg. 1991;85(2):227–9.

    Article  CAS  PubMed  Google Scholar 

  4. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363(9425):1965–76.

    Article  CAS  PubMed  Google Scholar 

  5. Bharti AR, McCutchan A, Deutsch R, Smith DM, Ellis RJ, Cherner M, et al. Latent toxoplasma infection and higher Toxoplasma gondii immunoglobulin G levels are associated with worse neurocognitive functioning in HIV-infected adults. Clin Infect Dis. 2016;63:1655–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cuervo G, Simonetti AF, Alegre O, Sanchez-Salado JC, Podzamczer D. Toxoplasma myocarditis: a rare but serious complication in an HIV-infected late presenter. AIDS. 2016;30(14):2253–4.

    Article  PubMed  Google Scholar 

  7. Kravetz JD, Federman DG. Prevention of toxoplasmosis in pregnancy: knowledge of risk factors. Infect Dis Obstet Gynecol. 2005;13(3):161–5.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gazzinelli RT, Mendonça-Neto R, Lilue J, Howard J, Sher A. Innate resistance against Toxoplasma gondii: an evolutionary tale of mice, cats, and men. Cell Host Microbe. 2014;15(2):132–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sasai M, Pradipta A, Yamamoto M. Host immune responses to Toxoplasma gondii. Int Immunol. 2018;30(3):113–9.

    Article  CAS  PubMed  Google Scholar 

  10. Sasai M, Yamamoto M. Pathogen recognition receptors: ligands and signaling pathways by toll-like receptors. Int Rev Immunol. 2013;32(2):116–33.

    Article  CAS  PubMed  Google Scholar 

  11. Yarovinsky F. Innate immunity to Toxoplasma gondii infection. Nat Rev Immunol. 2014;14(2):109–21.

    Article  CAS  PubMed  Google Scholar 

  12. Denkers EY, Butcher BA, del Rio L, Bennouna S. Neutrophils, dendritic cells and Toxoplasma. Int J Parasitol. 2004;34(3):411–21.

    Article  CAS  PubMed  Google Scholar 

  13. Shah S, Grotenbreg GM, Rivera A, Yap GS. An extrafollicular pathway for the generation of effector CD8(+) T cells driven by the proinflammatory cytokine, IL-12. Elife. 2015;4.

  14. Liesenfeld O, Kosek J, Remington JS, Suzuki Y. Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii. J Exp Med. 1996;184(2):597–607.

    Article  CAS  PubMed  Google Scholar 

  15. Hwang S, Khan IA. CD8+ T cell immunity in an encephalitis model of Toxoplasma gondii infection. Semin Immunopathol. 2015;37(3):271–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Khan IA, Smith KA, Kasper LH. Induction of antigen-specific parasiticidal cytotoxic T cell splenocytes by a major membrane protein (P30) of Toxoplasma gondii. J Immunol. 1988;141(10):3600–5.

    CAS  PubMed  Google Scholar 

  17. Khan IA, Ely KH, Kasper LH. Antigen-specific CD8+ T cell clone protects against acute Toxoplasma gondii infection in mice. J Immunol. 1994;152(4):1856–60.

    CAS  PubMed  Google Scholar 

  18. Gazzinelli RT, et al. Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. J Immunol. 1991;146(1):286–92.

    CAS  PubMed  Google Scholar 

  19. Brown CR, McLeod R. Class I MHC genes and CD8+ T cells determine cyst number in Toxoplasma gondii infection. J Immunol. 1990;145(10):3438–41.

    CAS  PubMed  Google Scholar 

  20. Suzuki Y, Wang X, Jortner BS, Payne L, Ni Y, Michie SA, et al. Removal of Toxoplasma gondii cysts from the brain by perforin-mediated activity of CD8+ T cells. Am J Pathol. 2010;176(4):1607–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Feliu V, Vasseur V, Grover HS, Chu HH, Brown MJ, Wang J, et al. Location of the CD8 T cell epitope within the antigenic precursor determines immunogenicity and protection against the Toxoplasma gondii parasite. PLoS Pathog. 2013;9(6):e1003449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bhadra R, Cobb DA, Khan IA. Donor CD8+ T cells prevent Toxoplasma gondii de-encystation but fail to rescue the exhausted endogenous CD8+ T cell population. Infect Immun. 2013;81(9):3414–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Suzuki Y, Orellana M, Schreiber R, Remington J. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988;240(4851):516–8.

    Article  CAS  PubMed  Google Scholar 

  24. Denkers EY, et al. Perforin-mediated cytolysis plays a limited role in host resistance to Toxoplasma gondii. J Immunol. 1997;159(4):1903–8.

    CAS  PubMed  Google Scholar 

  25. Bhadra R, Gigley JP, Khan IA. PD-1-mediated attrition of polyfunctional memory CD8+ T cells in chronic toxoplasma infection. J Infect Dis. 2012;206(1):125–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xia D, Hao S, Xiang J. CD8+ cytotoxic T-APC stimulate central memory CD8+ T cell responses via acquired peptide-MHC class I complexes and CD80 costimulation, and IL-2 secretion. J Immunol. 2006;177(5):2976–84.

    Article  CAS  PubMed  Google Scholar 

  27. Brown CR, et al. Effects of human class I transgenes on Toxoplasma gondii cyst formation. J Immunol. 1994;152(9):4537–41.

    CAS  PubMed  Google Scholar 

  28. Deckert-Schluter M, et al. Toxoplasma encephalitis in congenic B10 and BALB mice: impact of genetic factors on the immune response. Infect Immun. 1994;62(1):221–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hiszczynska-Sawicka E, et al. Comparison of immune response in sheep immunized with DNA vaccine encoding Toxoplasma gondii GRA7 antigen in different adjuvant formulations. Exp Parasitol. 2010;124(4):365–72.

    Article  CAS  PubMed  Google Scholar 

  30. Beghetto E, Nielsen HV, del Porto P, Buffolano W, Guglietta S, Felici F, et al. A combination of antigenic regions of Toxoplasma gondii microneme proteins induces protective immunity against oral infection with parasite cysts. J Infect Dis. 2005;191(4):637–45.

    Article  CAS  PubMed  Google Scholar 

  31. Scorza T, D’Souza S, Laloup M, Dewit J, de Braekeleer J, Verschueren H, et al. A GRA1 DNA vaccine primes cytolytic CD8(+) T cells to control acute Toxoplasma gondii infection. Infect Immun. 2003;71(1):309–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Blanchard N, Gonzalez F, Schaeffer M, Joncker NT, Cheng T, Shastri AJ, et al. Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum. Nat Immunol. 2008;9(8):937–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wilson DC, Grotenbreg GM, Liu K, Zhao Y, Frickel EM, Gubbels MJ, et al. Differential regulation of effector- and central-memory responses to Toxoplasma gondii infection by IL-12 revealed by tracking of Tgd057-specific CD8+ T cells. PLoS Pathog. 2010;6(3):e1000815.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Gazzinelli R, et al. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. J Immunol. 1992;149(1):175–80.

    CAS  PubMed  Google Scholar 

  35. Bhadra R, Gigley JP, Weiss LM, Khan IA. Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade. Proc Natl Acad Sci U S A. 2011;108(22):9196–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mueller SN, Ahmed R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A. 2009;106(21):8623–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shin H, Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol. 2007;19(4):408–15.

    Article  CAS  PubMed  Google Scholar 

  38. Green AM, Difazio R, Flynn JL. IFN-gamma from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection. J Immunol. 2013;190(1):270–7.

    Article  CAS  PubMed  Google Scholar 

  39. Williams MA, Holmes BJ, Sun JC, Bevan MJ. Developing and maintaining protective CD8+ memory T cells. Immunol Rev. 2006;211:146–53.

    Article  CAS  PubMed  Google Scholar 

  40. Carvalho LH, Sano GI, Hafalla JCR, Morrot A, de Lafaille MAC, Zavala F. IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages. Nat Med. 2002;8(2):166–70.

    Article  CAS  PubMed  Google Scholar 

  41. Casciotti L, Ely KH, Williams ME, Khan IA. CD8(+)-T-cell immunity against toxoplasma gondii can be induced but not maintained in mice lacking conventional CD4(+) T cells. Infect Immun. 2002;70(2):434–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shearer GM, et al. A model for the selective loss of major histocompatibility complex self-restricted T cell immune responses during the development of acquired immune deficiency syndrome (AIDS). J Immunol. 1986;137(8):2514–21.

    CAS  PubMed  Google Scholar 

  43. Gigley JP, Bhadra R, Moretto MM, Khan IA. T cell exhaustion in protozoan disease. Trends Parasitol. 2012;28(9):377–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. • Hwang S, et al. Blimp-1-mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis. J Exp Med. 2016;213(9):1799–818 These studies for the first time reported BLIMP-1-mediated CD4 T cell exhaustion during chronic T. gondii infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. • Moretto MM, Hwang S, Khan IA. Downregulated IL-21 response and T follicular helper cell exhaustion correlate with compromised CD8 T cell immunity during chronic toxoplasmosis. Front Immunol. 2017;8:1436 In these studies for the first time, exhaustion of FTH population during chronic infection was reported.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. • Melssen M, Slingluff CL Jr. Vaccines targeting helper T cells for cancer immunotherapy. Curr Opin Immunol. 2017;47:85–92 It has been emphasized that CD4 T cells play a critical helper role in the strategies involving cancer immunotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bhadra R, Gigley JP, Khan IA. Cutting edge: CD40-CD40 ligand pathway plays a critical CD8-intrinsic and -extrinsic role during rescue of exhausted CD8 T cells. J Immunol. 2011;187(9):4421–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Phan-Lai V, Dang Y, Gad E, Childs J, Disis ML. The antitumor efficacy of IL2/IL21-cultured polyfunctional Neu-specific T cells is TNFalpha/IL17 dependent. Clin Cancer Res. 2016;22(9):2207–16.

    Article  CAS  PubMed  Google Scholar 

  49. Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM, Reiner SL, et al. A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity. 2009;31(2):309–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Linch SN, McNamara MJ, Redmond WL. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol. 2015;5:34.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Miles B, Miller SM, Connick E. CD4 T follicular helper and regulatory cell dynamics and function in HIV infection. Front Immunol. 2016;7:659.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Yi JS, Du M, Zajac AJ. A vital role for interleukin-21 in the control of a chronic viral infection. Science. 2009;324(5934):1572–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the NIH grant AI33325 awarded to IAK.

Author information

Authors and Affiliations

  1. Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, 20037, USA

    Imtiaz A Khan, Charlotte Ouellette, Keer Chen & Magali Moretto

Authors
  1. Imtiaz A Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charlotte Ouellette
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keer Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Magali Moretto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Imtiaz A Khan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

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

This article is part of the Topical Collection on Parasitology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khan, I.A., Ouellette, C., Chen, K. et al. Toxoplasma: Immunity and Pathogenesis. Curr Clin Micro Rpt 6, 44–50 (2019). https://doi.org/10.1007/s40588-019-0114-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40588-019-0114-5

Keywords

Search

Navigation