Date Published: February 19, 2016
Publisher: Public Library of Science
Author(s): Carla M. Cabral, Shraddha Tuladhar, Hans K. Dietrich, Elizabeth Nguyen, Wes R. MacDonald, Tapasya Trivedi, Asha Devineni, Anita A. Koshy, Eric Y Denkers.
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.
Host cell-microbe interactions govern the survival and propagation of intracellular microbes. The importance of these interactions is particularly pronounced in chronic infections where persistence in specific cell types eludes pharmacologic or immunologic cures, leaving the pathogen to reactivate at opportunistic times. Understanding host cell-pathogen dynamics–from how pathogens find permissive cells to how they manipulate those cells–will provide opportunities to develop therapies that eliminate currently incurable persistent pathogens.
In this study, we used a novel in vivo system to address an essential question: why does Toxoplasma gondii, a parasite with no clear host cell preference in vitro, show host cell preferences during in vivo infection of the CNS? Our ability to answer this question arose from the development of the Toxoplasma-Cre system, which is capable of identifying transient host cell-parasite interactions and allows imaging and analysis of entire infected neurons [22,24,42]. The data derived from this system and presented here strongly suggest that neuron-parasite interactions predominate throughout CNS infection and persist even in highly manipulated circumstances such as IFN-γ depletion, infection with IRG-resistant parasites, and direct intracranial inoculation of parasites. These data in combination with the recognition that cysts are most commonly found in distal neuronal processes indicate that during in vivo infection, Toxoplasma displays a distinct propensity for neurons, which may in part be driven by physical properties of the CNS and its cells.