Mechanisms of Human Innate Immune Evasion by Toxoplasma gondii

Abstract

Toxoplasma gondii is an intracellular protozoan parasite of global importance that can remarkably infect, survive, and replicate in nearly all mammalian cells. Notably, 110 years after its discovery, Toxoplasmosis is still a neglected parasitic infection. Although most human infections with T. gondii are mild or asymptomatic, T. gondii infection can result in life-threatening disease in immunocompromised individuals and in the developing fetus due to congenital infection, underscoring the role of the host immune system in controlling the parasite. Recent evidence indicates that T. gondii elicits a robust innate immune response during infection. Interestingly, however, T. gondii has evolved strategies to successfully bypass or manipulate the immune system and establish a life-long infection in infected hosts. In particular, T. gondii manipulates host immunity through the control of host gene transcription and dysregulation of signaling pathways that result in modulation of cell adhesion and migration, secretion of immunoregulatory cytokines, production of microbicidal molecules, and apoptosis. Many of these host-pathogen interactions are governed by parasite effector proteins secreted from the apical secretory organelles, including the rhoptries and dense granules. Here, we review recent findings on mechanisms by which T. gondii evades host innate immunity, with a focus on parasite evasion of the human innate immune system.

Keywords: IFN-γ; Toxoplasma gondii; apoptosis; immune evasion; innate immunity; pro-inflammatory cytokines.

Figure 1

Modulation of host immune signaling by T. gondii. After invasion of the host cell, T gondii manipulation of host signaling pathways and gene expression impair innate immune responses. Parasite effector proteins that govern many of these host-pathogen interactions are secreted from the apical secretory organelles and are found in the host cytosol, associate with the PVM, or translocate to the host nucleus. Although a variety of mechanisms of immune evasion are shown, it should be noted that the function of specific effector proteins may depend on the T gondii strain and human cell type that is infected, as described in the review. Figures were created using BioRender.

Figure 2

T. gondii inhibition of host cell apoptosis. T gondii impairs both cell-intrinsic (mitochondrial) and -extrinsic (death receptor-mediated) pathways of apoptosis, which allows the parasite to maintain its replicative niche. T gondii can interfere with the initiation, activation, or signaling of the apoptotic cascade, which may result from an indirect mechanism or the direct effect of secreted parasite effector proteins. ACT-D, actinomycin D; STSN, staurosporine; Cyt c, cytochrome c.