IFN-γ stimulated murine and human neurons mount anti-parasitic defenses against the intracellular parasite Toxoplasma gondii

Abstract

Dogma holds that Toxoplasma gondii persists in neurons because neurons cannot clear intracellular parasites, even with IFN-γ stimulation. As several recent studies questioned this idea, here we use primary murine neuronal cultures from wild type and transgenic mice in combination with IFN-γ stimulation and parental and transgenic parasites to reassess IFN-γ dependent neuronal clearance of intracellular parasites. We find that neurons respond to IFN-γ and that a subset of neurons clear intracellular parasites via immunity regulated GTPases. Whole neuron reconstructions from mice infected with parasites that trigger neuron GFP expression only after full invasion reveal that ~50% of these T. gondii-invaded neurons no longer harbor parasites. Finally, IFN-γ stimulated human pluripotent stem cell derived neurons show an ~50% decrease in parasite infection rate when compared to unstimulated cultures. This work highlights the capability of human and murine neurons to mount cytokine-dependent anti-T. gondii defense mechanisms in vitro and in vivo.

A heterotrimeric complex ofToxoplasmaproteins promotes parasite survival in interferon gamma stimulated human cells

“…HFFs are extensively used for the continuous culture of Toxoplasma and are often considered as ‘non-immune’ cells, but these results support that structural cells can be important components of the innate immune response to Toxoplasma infection (Krausgruber et al ., 2020). Other human non-hematopoietic cells have also been demonstrated to restrict Toxoplasma in response to IFNγ signalling, including neurons (Chandrasekaran et al ., 2022), epithelial (Selleck et al ., 2015) and endothelial cells (Clough et al ., 2016).…”

The determinants regulating Toxoplasma gondii bradyzoite development

“…Thus, a good balance between host anti-parasitic immunity and T. gondii antagonism of host immunity is achieved in the chronic phase. Since a subset of neurons can clear intracellular parasites via immunity-regulated GTPases (Chandrasekaran et al, 2022), is there a rule to follow that some T. gondii-infected neurons actively harbor cysts while others do not? Single-cell RNA sequencing approaches may be necessary for revealing cell status to detect cell-to-cell differences.…”

“…Analysis of host-parasite interactions in vivo using T. gondii expressing Cre recombinase reveals that neurons are the primary host cells for cysts (Wohlfert et al, 2017). However, a recent study shows that a subset of neurons can respond to IFN-γ and clear intracellular parasites (Chandrasekaran et al, 2022). Thus, more studies are needed to update the research progress of the cyst-neuron interactions from metabolic or immunological analysis to unveil unknown niche that neurons provide for bradyzoite development and parasite clearance.…”

“…A recent study has found that a portion of murine neurons can clear intracellular parasites in an IFN-γ-IRG-dependent manner both in vitro and in vivo. IFN-γ stimulation also results in parasite resistance in human neurons (Chandrasekaran et al, 2022). Furthermore, CD40 signaling has also been associated with decreasing cyst emergence in mouse neuroblastoma cells (Doherty et al, 2022).…”

From the immune system to mood disorders especially induced by Toxoplasma gondii: CD4+ T cell as a bridge

“…Significantly, recent studies have found that IFN-γ stimulates neurons and upregulates IFN-γ-responsive related genes and proteins [e.g., GTPase system (IRG)] in vivo and in vitro , killing intracellular T. gondii in neurons via IRG and mediating T. gondii resistance in neurons. The data suggest that IFN-γ reduces neuronal infection in both mouse and human neurons, but this clearance efficiency is strain type dependent, for example, RH strains are IRG resistant and cannot be cleared ( Chandrasekaran et al., 2022 ). This important IFN-γ-dependent mechanism of T. gondii clearance may be the focus of research on cerebral toxoplasmosis.…”