The human immune response to Toxoplasma: Autophagy versus cell death

Introduction Toxoplasma gondii is an obligate intracellular parasite that can infect a broad range of warmblooded animals. In humans, it can cause serious disease in immune-compromised individuals or if contracted congenitally. In North America and Europe, strains belonging to the clonal types I, II, and III haplogroups predominate, while in South America a large variety of other “atypical” strains exist. These strains differ enormously in virulence in mice and there is evidence that different strains can also cause variable pathology in humans. In mice, the cytokine interferon gamma (IFNγ) induces multiple toxoplasmacidal mechanisms and therefore plays a crucial role in immunity to Toxoplasma. Compared to mice, humans are more resistant to Toxoplasma. This is surprising because humans lack the Toll-like receptors 11/12 (TLR11/12) found in mice that bind to the Toxoplasma protein profilin and trigger a signaling cascade leading to the production of interleukin 12 (IL12), a key cytokine that stimulates IFNγ production. Humans also lack the multitude of murine immunity-related GTPases (IRGs) that are induced upon IFNγ stimulation and play a crucial role in the destruction of the membrane surrounding the parasitophorous vacuole (PV) in which Toxoplasma resides in the host cytoplasm. Thus, the mechanisms involved in the production of IFNγ in humans (Fig 1) differ from those in mice and the pathways that mediate parasite clearance are less well understood (reviewed in [1]). In this review, we focus on two mechanisms of Toxoplasma clearance by human cells: autophagy and cell death.