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Host persistence: exploitation of anti-inflammatory pathways by Toxoplasma GONDII

Abstract

Hosts that are infected with Toxoplasma gondii must mount a powerful immune response to contain dissemination of the parasite and to prevent mortality. After parasite proliferation has been contained by interferon-γ-dependent responses, the onset of the chronic phase of infection is characterized by continuous cell-mediated immunity. Such potent responses are kept under tight control by a class of anti-inflammatory eicosanoid, the lipoxins. Here, we review such immune-containment strategies from the perspective of the host, which attempts to keep pro-inflammatory responses under control during chronic disease, as well as from the perspective of the pathogen, which hijacks the lipoxygenase machinery of the host for its own advantage, probably as an immune-escape mechanism.

Key Points

  • Dendritic cell (DC)-derived interleukin-12 (IL-12) production is an important component of induction of interferon-γ-dependent protective responses to infection with Toxoplasma gondii.

  • T. gondii-secreted proteins trigger activation of DCs that depends on CC-chemokine receptor 5 (CCR5) and on MyD88 (myeloid differentiation primary-response protein 88)-dependent Toll-like receptor pathways. Parasite-derived cyclophilin-18 binds and activates CCR5 at the cell surface of DCs.

  • Excessive IL-12 production can be lethal to the host, and several anti-inflammatory mediators are known to dampen this response and prevent host damage during immune responses.

  • Lipoxin A4 (LXA4) is produced in vivo during infection with T. gondii and regulates pro-inflammatory cytokine production. Animals lacking one of the enzymes involved in LXA4 biosynthesis, 5-lipoxygenase, succumb to infection as a result of uncontrolled inflammation.

  • T. gondii has a 15-lipoxygenase activity that leads to the generation of LXA4 in vitro and in vivo.

  • The cystic-fibrosis-associated pathogen Pseudomonas aeruginosa also has a 15-lipoxygenase. The development of cystic fibrosis is associated with lack of generation of LXA4 and therefore uncontrolled neutrophil accumulation in the lungs of patients.

  • The inhibition of pro-inflammatory responses that is mediated by induction of LXA4 might function as an immune-evasion mechanism for pathogens, through promoting inhibition of immune responses to allow microbial proliferation, or it might maintain the health of the host. Regardless of the strategy adopted by the pathogen, the common objective is to succeed in promoting transmission to other hosts.

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Figure 1: The life cycle of Toxoplasma gondii.
Figure 2: Control of pro-inflammatory responses during infection with Toxoplasma gondii.
Figure 3: General and pathogen-dependent lipoxin A4 biosynthetic pathways.

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References

  1. Morisaki, J. H., Heuser, J. E. & Sibley, L. D. Invasion of Toxoplasma gondii occurs by active penetration of the host cell. J. Cell Sci. 108, 2457–2464 (1995). An important review of T. gondii invasion mechanisms.

    CAS  PubMed  Google Scholar 

  2. Black, M. W. & Boothroyd, J. C. Lytic cycle of Toxoplasma gondii. Microbiol. Mol. Biol. Rev. 64, 607–623 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Martinez, A. J. et al. The neuropathology and epidemiology of AIDS. A Berlin experience. A review of 200 cases. Pathol. Res. Pract. 191, 427–443 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Hay, J. & Hutchison, W. M. Toxoplasma gondii — an environmental contaminant. Ecol. Dis. 2, 33–43 (1983).

    CAS  PubMed  Google Scholar 

  5. Hunter, C. A., Subauste, C. S., Van Cleave, V. H. & Remington, J. S. Production of γ interferon by natural killer cells from Toxoplasma gondii-infected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor α. Infect. Immun. 62, 2818–2824 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Sher, A., Oswald, I. P., Hieny, S. & Gazzinelli, R. T. Toxoplasma gondii induces a T-independent IFN-γ response in natural killer cells that requires both adherent accessory cells and tumor necrosis factor-α. J. Immunol. 150, 3982–3989 (1993).

    CAS  PubMed  Google Scholar 

  7. Gazzinelli, R. T. et al. Parasite-induced IL-12 stimulates early IFN-γ synthesis and resistance during acute infection with Toxoplasma gondii. J. Immunol. 153, 2533–2543 (1994).

    CAS  PubMed  Google Scholar 

  8. Denkers, E. Y. From cells to signaling cascades: manipulation of innate immunity by Toxoplasma gondii. FEMS Immunol. Med. Microbiol. 39, 193–203 (2003). An up-to-date review of signalling cascades that are triggered by T. gondii.

    Article  CAS  PubMed  Google Scholar 

  9. Reis e Sousa, C. et al. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J. Exp. Med. 186, 1819–1829 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Aliberti, J. et al. CCR5 provides a signal for microbial induced production of IL-12 by CD8α+ dendritic cells. Nature Immunol. 1, 83–87 (2000).

    Article  CAS  Google Scholar 

  11. Aliberti, J. et al. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nature Immunol. 4, 485–490 (2003). Identification of a CCR5 ligand mimic from T. gondii that activates IL-12 production by DCs.

    Article  CAS  Google Scholar 

  12. Golding, H. et al. Inhibition of HIV-1 infection by a CCR5-binding cyclophilin from Toxoplasma gondii. Blood 102, 3280–3286 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Yarovinsky, F. et al. Structural determinants of the anti-HIV activity of a CCR5 antagonist derived from Toxoplasma gondii. J. Biol. Chem. 279, 53635–53642 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Scanga, C. A. et al. MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J. Immunol. 168, 5997–6001 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Scharton-Kersten, T., Contursi, C., Masumi, A., Sher, A. & Ozato, K. Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction. J. Exp. Med. 186, 1523–1534 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Rev. Immunol. 3, 133–146 (2003). An up-to-date review of IL-12 biology.

    Article  CAS  Google Scholar 

  17. Mason, N. J. et al. TRAF6-dependent mitogen-activated protein kinase activation differentially regulates the production of interleukin-12 by macrophages in response to Toxoplasma gondii. Infect. Immun. 72, 5662–5667 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tsujimura, H. et al. ICSBP/IRF-8 retrovirus transduction rescues dendritic cell development in vitro. Blood 101, 961–969 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Yap, G. S. & Sher, A. Cell-mediated immunity to Toxoplasma gondii: initiation, regulation and effector function. Immunobiology 201, 240–247 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Karp, C. L. & Wills-Karp, M. Complement and IL-12: yin and yang. Microbes Infect. 3, 109–119 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Son, E. S., Song, K. J., Shin, J. C. & Nam, H. W. Molecular cloning and characterization of peroxiredoxin from Toxoplasma gondii. Korean J. Parasitol. 39, 133–141 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Salek-Ardakani, S., Arrand, J. R. & Mackett, M. Epstein–Barr virus encoded interleukin-10 inhibits HLA-class I, ICAM-1, and B7 expression on human monocytes: implications for immune evasion by EBV. Virology 304, 342–351 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Fiorentino, D. F. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by TH1 cells. J. Immunol. 146, 3444–3451 (1991).

    CAS  PubMed  Google Scholar 

  24. Haig, D. M. Poxvirus interference with the host cytokine response. Vet. Immunol. Immunopathol. 63, 149–156 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. van de Loo, F. A. & van den Berg, W. B. Gene therapy for rheumatoid arthritis. Lessons from animal models, including studies on interleukin-4, interleukin-10, and interleukin-1 receptor antagonist as potential disease modulators. Rheum. Dis. Clin. North Am. 28, 127–149 (2002).

    Article  PubMed  Google Scholar 

  26. Wille, U., Villegas, E. N., Striepen, B., Roos, D. S. & Hunter, C. A. Interleukin-10 does not contribute to the pathogenesis of a virulent strain of Toxoplasma gondii. Parasite Immunol. 23, 291–296 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Deckert-Schluter, M. et al. Interleukin-10 downregulates the intracerebral immune response in chronic Toxoplasma encephalitis. J. Neuroimmunol. 76, 167–176 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Suzuki, Y. et al. IL-10 is required for prevention of necrosis in the small intestine and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice following peroral infection with Toxoplasma gondii. J. Immunol. 164, 5375–5382 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Gazzinelli, R. T. et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J. Immunol. 157, 798–805 (1996).

    CAS  PubMed  Google Scholar 

  30. Reis e Sousa, C. et al. Paralysis of dendritic cell IL-12 production by microbial products prevents infection-induced immunopathology. Immunity 11, 637–647 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Aliberti, J., Hieny, S., Reis e Sousa, C., Serhan, C. N. & Sher, A. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nature Immunol. 3, 76–82 (2002). An original report on the inhibitory effects of LXA 4 on DC function in vivo and in vitro.

    Article  CAS  Google Scholar 

  32. Kieran, N. E., Maderna, P. & Godson, C. Lipoxins: potential anti-inflammatory, proresolution, and antifibrotic mediators in renal disease. Kidney Int. 65, 1145–1154 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Samuelsson, B. Arachidonic acid metabolism: role in inflammation. Z. Rheumatol. 50 (Suppl. 1), 3–6 (1991).

    PubMed  Google Scholar 

  34. Goh, J., Godson, C., Brady, H. R. & Macmathuna, P. Lipoxins: pro-resolution lipid mediators in intestinal inflammation. Gastroenterology 124, 1043–1054 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Van Dyke, T. E. & Serhan, C. N. Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases. J. Dent. Res. 82, 82–90 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Bandeira-Melo, C. et al. Lipoxin (LX) A4 and aspirin-triggered 15-epi-LXA4 block allergen-induced eosinophil trafficking. J. Immunol. 164, 2267–2271 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Clish, C. B. et al. Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo. Proc. Natl Acad. Sci. USA 96, 8247–8252 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hachicha, M., Pouliot, M., Petasis, N. A. & Serhan, C. N. Lipoxin (LX)A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor 1α-initiated neutrophil responses and trafficking: regulators of a cytokine–chemokine axis. J. Exp. Med. 189, 1923–1930 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ohira, T. et al. A stable aspirin-triggered lipoxin A4 analog blocks phosphorylation of leukocyte-specific protein 1 in human neutrophils. J. Immunol. 173, 2091–2098 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Ramstedt, U., Ng, J., Wigzell, H., Serhan, C. N. & Samuelsson, B. Action of novel eicosanoids lipoxin A and B on human natural killer cell cytotoxicity: effects on intracellular cAMP and target cell binding. J. Immunol. 135, 3434–3438 (1985).

    CAS  PubMed  Google Scholar 

  41. Maddox, J. F. et al. Lipoxin A4 stable analogs are potent mimetics that stimulate human monocytes and THP-1 cells via a G-protein-linked lipoxin A4 receptor. J. Biol. Chem. 272, 6972–6978 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Schaldach, C. M., Riby, J. & Bjeldanes, L. F. Lipoxin A4: a new class of ligand for the Ah receptor. Biochemistry 38, 7594–7600 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Devchand, P. R. et al. Human ALX receptor regulates neutrophil recruitment in transgenic mice: roles in inflammation and host defense. FASEB J. 17, 652–659 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Leonard, M. O. et al. 15-Epi-16-(para-fluorophenoxy)-lipoxin A4-methyl ester, a synthetic analogue of 15-epi-lipoxin A4, is protective in experimental ischemic acute renal failure. J. Am. Soc. Nephrol. 13, 1657–1662 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Alexander, W. S. & Hilton, D. J. The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu. Rev. Immunol. 22, 503–529 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Kile, B. T. et al. The SOCS box: a tale of destruction and degradation. Trends Biochem. Sci. 27, 235–241 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Hong, S., Gronert, K., Devchand, P. R., Moussignac, R. L. & Serhan, C. N. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J. Biol. Chem. 278, 14677–14687 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Serhan, C. N. et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025–1037 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Aliberti, J., Serhan, C. & Sher, A. Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection. J. Exp. Med. 196, 1253–1262 (2002). An original report on the role of endogenous lipoxins in modulating pro-inflammatory responses during infection with T. gondii.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Funk, C. D., Chen, X. S., Johnson, E. N. & Zhao, L. Lipoxygenase genes and their targeted disruption. Prostaglandins Other Lipid Mediat. 68–69, 303–312 (2002).

    Article  PubMed  Google Scholar 

  51. Goulet, J. L. et al. Deficiency of 5-lipoxygenase abolishes sex-related survival differences in MRL-lpr/lpr mice. J. Immunol. 163, 359–366 (1999).

    CAS  PubMed  Google Scholar 

  52. Bannenberg, G. L., Aliberti, J., Hong, S., Sher, A. & Serhan, C. Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis. J. Exp. Med. 199, 515–523 (2004). Identification of a lipoxygenase activity in T. gondii that has immunomodulatory effects in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Levy, B. D., Clish, C. B., Schmidt, B., Gronert, K. & Serhan, C. N. Lipid mediator class switching during acute inflammation: signals in resolution. Nature Immunol. 2, 612–619 (2001).

    Article  CAS  Google Scholar 

  54. Vance, R. E., Hong, S., Gronert, K., Serhan, C. N. & Mekalanos, J. J. The opportunistic pathogen Pseudomonas aeruginosa carries a secretable arachidonate 15-lipoxygenase. Proc. Natl Acad. Sci. USA. 101, 2135–2139 (2004). Identification of a 15-lipoxygenase in the cystic-fibrosis-causing pathogen P. aeruginosa.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Karp, C. L. et al. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nature Immunol. 5, 388–392 (2004). Identification of a defect in the generation of lipoxin in patients with cystic fibrosis.

    Article  CAS  Google Scholar 

  56. Chan, J. & Flynn, J. The immunological aspects of latency in tuberculosis. Clin. Immunol. 110, 2–12 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Flynn, J. L. & Chan, J. Immune evasion by Mycobacterium tuberculosis: living with the enemy. Curr. Opin. Immunol. 15, 450–455 (2003). An up-to-date review on the immune-evasion mechanisms of M. tuberculosis.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I thank M. Kamela, F. Machado and W. Zhang for their critical reading of the manuscript and for helpful suggestions.

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DATABASES

Entrez Gene

AHR

CCL4

CCR5

CD4

CD8

COX2

FLAP

IFN-γ

IL-1

IL-10

IL-12

IRF8

MyD88

SOCS1

SOCS2

SOCS3

TLR2

TNF

Glossary

CYST

A modified parasitophorous vacuole in neuronal cells, which contains the slow-replicating form of Toxoplasma gondii, known as bradyzoites.

PROLYL-ISOMERASE

An enzyme that catalyses the cis- or trans-isomerization of peptide bonds in proline-containing peptides.

TOLL-LIKE RECEPTORS

Pattern-recognition receptors that bind to pathogen-associated molecular patterns.

TYPE 1 CD4+ AND CD8+ T CELLS

Antigen-primed T cells that have differentiated into interferon-γ-producing cells.

LEUKOTRIENE

An arachidonic-acid-derived eicosanoid — the biosynthesis of which is catalysed by lipoxygenases — that has extensive pro-inflammatory actions.

SUPPRESSOR OF CYTOKINE SIGNALLING MOLECULES

(SOCS). Intracellular proteins that are thought to block intracellular signal transduction from cytokine and hormone receptors.

IONOPHORE

A compound that increases the transport of ions across cellular membranes, by binding them and carrying them across.

GRANULOMA

A collection of modified macrophages that resemble epithelial cells, usually surrounded by a layer of lymphocytes, which often includes multinucleated giant cells. Granuloma formation is a chronic inflammatory response that is initiated by various infectious and non-infectious agents.

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Aliberti, J. Host persistence: exploitation of anti-inflammatory pathways by Toxoplasma GONDII. Nat Rev Immunol 5, 162–170 (2005). https://doi.org/10.1038/nri1547

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