Neurons are the Primary Target Cell for the Brain-Tropic Intracellular Parasite Toxoplasma gondii

Abstract

Toxoplasma gondii, a common brain-tropic parasite, is capable of infecting most nucleated cells, including astrocytes and neurons, in vitro. Yet, in vivo, Toxoplasma is primarily found in neurons. In vitro data showing that interferon-γ-stimulated astrocytes, but not neurons, clear intracellular parasites suggest that neurons alone are persistently infected in vivo because they lack the ability to clear intracellular parasites. Here we test this theory by using a novel Toxoplasma-mouse model capable of marking and tracking host cells that directly interact with parasites, even if the interaction is transient. Remarkably, we find that Toxoplasma shows a strong predilection for interacting with neurons throughout CNS infection. This predilection remains in the setting of IFN-γ depletion; infection with parasites resistant to the major mechanism by which murine astrocytes clear parasites; or when directly injecting parasites into the brain. These findings, in combination with prior work, strongly suggest that neurons are not incidentally infected, but rather they are Toxoplasma’s primary in vivo target. Toxoplasma gondii is a ubiquitous intracellular parasite that chronically infects the brain of up to 1/3 of the world’s population. While most infected persons have no symptoms, Toxoplasma’s tropism for the brain underlies the parasite’s ability to cause debilitating neurologic disease in the developing fetus and the immunocompromised, such as AIDS or organ transplant patients. Our understanding of which cells of the brain interact with and are infected by Toxoplasma primarily comes from work in tissue culture, which cannot re-capitulate the complexity of a living animal. Here, we overcome this barrier by studying brain-Toxoplasma interactions using a novel mouse model that allows us to permanently mark and track brain cells that have interacted with parasites. Contrary to what has been shown in cell culture, we find that throughout acute and chronic brain infection Toxoplasma almost exclusively interacts with neurons, and rarely interacts with astrocytes. This neuronal predilection persists even in highly manipulated circumstances such as the introduction of parasites directly into the brain. This work is the first to show that Toxoplasma primarily interacts with neurons in vivo, which suggests that to understand Toxoplasma’s ability to persistently infect the brain, we must understand the neuron-Toxoplasma interaction.