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

Abstract

SummaryDogma 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, we used 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 found 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 revealed that ∼40% of these T. gondii-invaded neurons no longer harbor parasites. Finally, IFN-γ stimulated human stem cell derived neurons showed a ∼ 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.

Analysis of intestinal epithelial cell responses toCryptosporidiumhighlights the temporal effects of IFN-γ on parasite restriction

“…It is also possible that the ability to invade, replicate and lyse IEC within 12h also provides a window for infected cells to evade restriction downstream of IFN-γ. There is precedence for a delayed responsiveness to IFN-γ in other cell types; while macrophages can be rapidly activated with IFN-γ to limit the replication of T. gondii, neurons must be pre-incubated with IFN-γ for 24h for parasite control (42,43). In this context, low basal expression of STAT1 causes neurons to be comparatively "slow" to respond to IFN-γ, with maximal expression of Stat1 and other IFN-γ-inducible genes occurring 24-48h post-stimulation (42,44).…”

“…There is precedence for a delayed responsiveness to IFN-γ in other cell types; while macrophages can be rapidly activated with IFN-γ to limit the replication of T. gondii, neurons must be pre-incubated with IFN-γ for 24h for parasite control (42,43). In this context, low basal expression of STAT1 causes neurons to be comparatively "slow" to respond to IFN-γ, with maximal expression of Stat1 and other IFN-γ-inducible genes occurring 24-48h post-stimulation (42,44). Since IFN-γ can also cause cell death, delayed responsiveness to IFN-γ observed with IEC may be a host protective mechanism that reflects the immune tolerant state of the small intestine and could indicate a higher threshold of activation for IEC compared to other immune cells.…”