The parasite Toxoplasma gondii is extremely widespread in animals and is a common cause of food- and water-borne infection in people. Although most infections are benign, they can have severe consequences in immunocompromised patients and following congenital infection.
T. gondii is regarded as a model intracellular parasite for which forward- and reverse-genetics tools are available. In combination with the mouse model of toxoplasmosis (including the many genetic knockout and transgenic mouse lines that are available), these tools for genetic manipulation of the parasite have enabled researchers to explore the molecular determinants of T. gondii pathogenesis and host defence.
Forward-genetics crosses conducted in T. gondii, using strains of different genotypes and virulences in mice, revealed that acute virulence is largely mediated by a family of effector proteins that are secreted into the host cell cytoplasm during parasite invasion. These proteins are derived from a secretory organelle called the rhoptry and, hence, are called ROP effectors.
ROPs include a family of serine/threonine kinases that affect host targets and have important roles in infection in the mouse. Among these, ROP18 phosphorylates immunity-related GTPases, thus promoting parasite survival in activated macrophages, whereas ROP16 phosphorylates signal transducer and activator of transcription 3 (STAT3) and STAT6 and, hence, alters host gene transcription. Curiously, the activity of ROP18 is mediated by another family member called ROP5, which is a pseudokinase.
Although a limited subset of ROP kinases can largely explain the virulence of T. gondii in the mouse, their role in other hosts has not been established. The genome encodes more than 40 ROPs, and these different proteins might have distinct roles during infection in the wide range of hosts infected by T. gondii. Understanding these patterns might help in the prevention and treatment of human infections.
Toxoplasma gondii is a common parasite of animals and humans and can cause serious opportunistic infections. However, the majority of infections are asymptomatic, possibly because the organism has co-evolved with its many vertebrate hosts and has developed multiple strategies to persist asymptomatically for the lifetime of the host. Over the past two decades, infection studies in the mouse, combined with forward-genetics approaches aimed at unravelling the molecular basis of infection, have revealed that T. gondii virulence is mediated, in part, by secretion of effector proteins into the host cell during invasion. Here, we review recent advances that illustrate how these virulence factors disarm innate immunity and promote survival of the parasite.
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Work in the authors' laboratories is supported by the US National Institutes of Health (L.D.S. and C.A.H.) and the State of Pennsylvania, USA (C.A.H.). The authors regret not being able to cite all of the appropriate primary literature owing to space limitations.
The authors declare no competing financial interests.
Supplementary information Table S1
Major mediators of resistance to T. gondii as defined by genetic knockouts in the mouse. (PDF 315 kb)
Supplementary information Table S1
Host pathways altered by T. gondii infection (PDF 306 kb)
Protozoans of the phylum Apicomplexa that are known for their apical complex consisting of a specialized microtubule-organizing centre, called the conoid, and secretory organelles involved in host cell invasion. Toxoplasma spp. belong to the tissue cyst-forming coccidian group of apicomplexans.
The diploid stages of parasite development, resulting from the fusion of Toxoplasma gondii gametes. Oocysts are shed in cat faeces and thus contaminate the environment, giving rise to infection by accidental ingestion.
The rapidly replicating intracellular forms of many tissue cyst-forming coccidians, such as Toxoplasma gondii. The name is derived from the Greek tachys, meaning fast.
The slow-growing forms of certain parasites; these forms reside within long-lived tissue cysts that are associated with chronic infection. The bradyzoite is one of the parasite stages that is specialized for transmission if ingested. The name is derived from the Greek bradys, meaning slow.
Organelles that are discharged in response to elevated cytoplasmic calcium levels. Microneme proteins mediate parasite adhesion to substrates and host cells.
- Toll-like receptors
(TLRs). Pattern recognition receptors that mediate immune responses by detecting pathogen-associated molecular patterns.
- Glycosylphosphatidylinositol-anchored proteins
Proteins with a common glycolipid anchor that is covalently attached to the carboxyl terminus as a post-translational modification.
- Inducible nitric oxide synthase
(iNOS). A soluble enzyme that produces nitric oxide from l-arginine. This enzyme is upregulated by interferon-γ and tumour necrosis factor, and constitutes a major antimicrobial activity of macrophages. It is encoded by NOS2.
- Immunity-related GTPases
(IRGs). A family of 45–47kDa GTPases that are strongly upregulated by interferon-γ and contribute to resistance to intracellular pathogens. These GTPases are ubiquitous in the mouse, but are more rare in other vertebrates and largely absent in humans.
- p67 guanylate-binding proteins
(GBPs). A family of 65 kDa GTPases that are upregulated by interferon-γ and contribute to resistance to intracellular pathogens. These GTPases are widely distributed in vertebrates, indicating that they might have an important general role in resistance to intracellular pathogens.
- Major histocompatibility complex
A cell surface molecule that allows recognition of epitopes from foreign or self antigens through presentation of these antigens to T cells.
- Signal transducer and activator of transcription 1
(STAT1). One of a family of transcription factors that are activated by Janus kinases (JAKs) and regulate gene expression by binding to nuclear promoters. STATs have a role in development and the immune system.
- Nuclear factor-κB
(NF-κB). A complex that controls DNA transcription in response to various signalling inputs and has a key role in regulating innate and adaptive immune responses.
- Suppressor of cytokine signalling
(SOCS). A family of intracellular proteins that regulate cytokine signalling by either direct inhibition of receptors or increased degradation of signalling proteins.
- Tumour necrosis factor
(TNF). A cytokine involved in inflammation, tumour suppression and host defence.
A protein that contains a conserved protein kinase fold but lacks key residues in the nucleotide-binding pocket, resulting in an inability to transfer phosphate to a donor substrate. Although these proteins are not catalytically active, they serve regulatory or scaffolding roles.
- Quantitative trait locus
(QTL). A genetic region (or locus) that contributes to a quantitative trait (a trait that varies by degree). Such traits are typically polygenic, with multiple QTLs contributing to the phenotype.
- Mitogen-activated protein kinases
(MAPKs). Serine/threonine kinases that are involved in cellular signalling in response to a diverse array of stimuli.
A genetic unit used for establishing genetic linkage based on recombination frequency in the progeny of a genetic cross. 1 centimorgan is equal to the distance over which the average proportion of recombination events in a single generation is 1%. Named in honour of Thomas Hunt Morgan.
An enzyme that mediates the consumption of arginine in the urea cycle and thus has an antagonistic role to nitric oxide synthase, as they both rely on the same substrate.
- Alternatively activated macrophages
Macrophages that have a T helper 2 type phenotype, dampening inflammation and promoting repair; these cells also typically express arginase. This is one of two polar phenotypes that macrophages can adopt following stimulation by cytokines.
- TIR domain-containing adaptor inducing interferon-β
(TRIF). An adaptor protein for signalling from Toll-like receptors, which also contain TIR domains.
- TNF receptor-associated factor 6
(TRAF6). A protein adaptor that is involved in signalling through tumour necrosis factor (TNF), interleukin-1 and Toll-like receptors.
- IκB kinase
(IKK). A kinase comprising two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ (also known as NEMO). IKK targets inhibitor of NF-κB (IκB) to induce its degradation, allowing nuclear factor-κB (NF-κB) to translocate to the nucleus.
- Inhibitor of NF-κB
(IκB). A protein that binds nuclear factor-κB (NF-κB), preventing its translocation to the nucleus. Under certain conditions, IκB becomes phosphorylated by inhibitor of IκB (IKK), and this triggers IκB ubiquitylation and proteasome-mediated degradation allowing active NF-κB to translocate to the nucleus.
- Classically activated macrophage
A macrophages that has a T helper 1 type phenotype, promoting inflammation and the expression of nitric oxide synthase. This is one of two polar phenotypes that macrophages can adopt following stimulation by cytokines.
- Unfolded-protein response
A cellular stress response triggered by unfolded proteins accumulating in the ER. This response leads to stalled translation and to upregulation of chaperones for protein folding.
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Hunter, C., Sibley, L. Modulation of innate immunity by Toxoplasma gondii virulence effectors. Nat Rev Microbiol 10, 766–778 (2012). https://doi.org/10.1038/nrmicro2858
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