Review Article | Published:

Innate immunity to Toxoplasma gondii infection

Nature Reviews Immunology volume 14, pages 109121 (2014) | Download Citation

Abstract

Toxoplasma gondii is a protozoan parasite of global importance. In the laboratory setting, T. gondii is frequently used as a model pathogen to study mechanisms of T helper 1 (TH1) cell-mediated immunity to intracellular infections. However, recent discoveries have shown that innate type 1 immune responses that involve interferon-γ (IFNγ)-producing natural killer (NK) cells and neutrophils, rather than IFNγ-producing T cells, predetermine host resistance to T. gondii. This Review summarizes the Toll-like receptor (TLR)-dependent mechanisms that are responsible for parasite recognition and for the induction of IFNγ production by NK cells, as well as the emerging data about the TLR-independent mechanisms that lead to the IFNγ-mediated elimination of T. gondii.

Key points

  • Toxoplasma gondii is a protozoan parasite that infects more than 1 billion people in the world. In addition to humans, T. gondii can infect all mammals and birds. Mice are a natural host for T. gondii and are a thoroughly studied animal model for T. gondii infection.

  • In mice, Toll-like receptor 11 (TLR11) is the principal innate immune sensor for T. gondii. TLR11 recognizes the unconventional actin-binding protein profilin, which is essential for parasite invasion into host cells.

  • In humans, TLR11 is a nonfunctional pseudogene. Consequently, the mechanisms through which the human immune system recognizes T. gondii are not well understood. Additional TLRs, in particular TLR2, TLR7 and TLR9, as well as the NLRP1 (NOD-, LRR- and pyrin domain-containing 1) inflammasome are all possible candidates for innate immune sensors that could be involved in human defence against T. gondii.

  • In a mouse model, activation of TLR11 and myeloid differentiation primary-response protein 88 (MYD88) in dendritic cells leads to the induction of interleukin-12 (IL-12) expression and the activation of interferon-γ (IFNγ) production by natural killer (NK) cells. In addition, both CD4+ T cell-derived and CD8+ T cell-derived IFNγ is essential for host resistance to the parasite.

  • An emerging source of IFNγ that does not require TLR-mediated parasite recognition is the neutrophil.

  • IFNγ mediates host protection via multiple mechanisms including induction of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs). IFNγ also triggers the induction of the antimicrobial molecules nitric oxide and reactive oxygen species and is responsible for changes in host metabolism that restrict T. gondii replication.

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Acknowledgements

F.Y. gratefully thanks colleagues and the members of his laboratory for the many discussions that contributed to this manuscript. Work in F.Y.'s laboratory is supported by the US National Institutes of Health (AI085263) and the Burroughs Wellcome Fund.

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  1. Department of Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9093, USA.

    • Felix Yarovinsky

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The author declares no competing financial interests.

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Correspondence to Felix Yarovinsky.

Glossary

Apicomplexan parasite

A member of a large group of protozoan parasites possessing a unique apical complex structure that is involved in host cell invasion. This phylogenetic group includes more than 5,000 species, all of which are parasitic. The best known examples of apicomplexan parasites are Plasmodium spp. (the cause of malaria), Toxoplasma gondii and Cryptosporidium spp.

Oocysts

Ovoid structures that contain two sporocysts, each of which contains four sporozoites. The sporozoites may then become tachyzoites or bradyzoites. Cats shed faecal Toxoplasma gondii oocysts in the soil, grass and water. The oocyst wall is an extremely resistant multilayer structure that protects the parasite from mechanical and chemical damage, which enables the parasite to survive for long periods of time.

Parasitophorous vacuole

A vacuole surrounded by a parasitophorous vacuolar membrane (PVM), which forms as a result of the invasion of Toxoplasma gondii into the host cell. The PVM is formed during active invasion of the host cell and depends on actin polymerization in T. gondii, but not in the host. The physical force created by the parasite initiates the formation of a membrane, which surrounds the intracellular parasite within the parasitophorous vacuole and which differs from endosomal or phagolysosomal membranes.

Soluble tachyzoite antigen

(STAg). A soluble extract from Toxoplasma gondii that is obtained by sonication of the parasites.

Congenital toxoplasmosis

A disease that occurs when a developing child is infected with the parasite Toxoplasma gondii. The developing child can be infected during pregnancy, labour or delivery.

Bradyzoites

A slow replicating form of Toxoplasma gondii. Bradyzoites in the form of cysts are responsible for the chronic stage of T. gondii infection.

Cysts

Structures that contain bradyzoites. Cysts grow and remain intracellular despite variations in their size. Young cysts may be as small as 5μm and may contain only two bradyzoites, whereas older cysts may contain hundreds of bradyzoites.

'Non-professional' APCs

Cells that do not constitutively express MHC class II molecules, but that upregulate MHC class II following stimulation with certain cytokines, particularly interferon-γ. Important examples of non-professional APCs include fibroblasts and thymic epithelial cells.

Tachyzoites

Fast-replicating forms of Toxoplasma gondii that are responsible for the acute stage of infection.

Sexual cycle

Sexual replication of Toxoplasma gondii occurs in the gut of the cat during the enteroepithelial stage of the parasite life cycle, which takes about 310 days. Sexual replication leads to the production of oocysts. A host in which parasites sexually reproduce is known as the definitive, final or primary host.

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DOI

https://doi.org/10.1038/nri3598

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