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
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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.
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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.
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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.
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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.
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T. gondii has a 15-lipoxygenase activity that leads to the generation of LXA4 in vitro and in vivo.
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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.
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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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I thank M. Kamela, F. Machado and W. Zhang for their critical reading of the manuscript and for helpful suggestions.
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Glossary
- CYST
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A modified parasitophorous vacuole in neuronal cells, which contains the slow-replicating form of Toxoplasma gondii, known as bradyzoites.
- PROLYL-ISOMERASE
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An enzyme that catalyses the cis- or trans-isomerization of peptide bonds in proline-containing peptides.
- TOLL-LIKE RECEPTORS
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Pattern-recognition receptors that bind to pathogen-associated molecular patterns.
- TYPE 1 CD4+ AND CD8+ T CELLS
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Antigen-primed T cells that have differentiated into interferon-γ-producing cells.
- LEUKOTRIENE
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An arachidonic-acid-derived eicosanoid — the biosynthesis of which is catalysed by lipoxygenases — that has extensive pro-inflammatory actions.
- SUPPRESSOR OF CYTOKINE SIGNALLING MOLECULES
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(SOCS). Intracellular proteins that are thought to block intracellular signal transduction from cytokine and hormone receptors.
- IONOPHORE
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A compound that increases the transport of ions across cellular membranes, by binding them and carrying them across.
- GRANULOMA
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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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DOI: https://doi.org/10.1038/nri1547
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