Defining how neurons drive CNS toxoplasmosis outcomes

Toxoplasma gondii is a common intracellular parasite that chronically and asymptomatically infects neurons in the central nervous system (CNS) of humans and rodents. The asymptomatic nature of this infection is notable as most microbes that enter CNS cause devastating disease. At the same time, T. gondii’s tropism for and persistence in the CNS underlies the symptomatic and potentially lethal disease seen in the immunocompromised and rarely, the immune competent. This neuronal persistence has traditionally been thought to arise from an inability of neurons to mount IFN-γ induced, cell-intrinsic, anti-parasitic responses. However, using an innovative Cre-based system that permanently marks CNS cells injected with T. gondii protein, over the last decade, we have deter- mined that: 1) T. gondii predominantly and extensively interacts with neurons during in vivo infections; 2) that >90% of these interactions do not result in a persistent infection; 3) that human and murine neurons generate IFN- γ dependent, cell-intrinsic anti-T. gondii responses; 4) that neuronal clearance of parasites is more effective in vivo than in vitro; and 5) that >80% of these T. gondii injected neurons are destined to die within several weeks. These findings are significant because they question long-held ideas about the capabilities of neurons to mount anti- parasitic defenses and challenge the concept that neurons tolerate persistent infections because these long-lived cells must be preserved at almost any cost. Collectively, these findings strongly suggest that we have a substantial gap in our understanding of the role neuron-T. gondii interactions play in determining the establishment and outcome of CNS infection. The goal of this proposal is to address this gap by beginning to develop a mechanistic understanding of how neurons counter T. gondii while avoiding immune pathology. Here we will define the IFN-γ de- pendent, anti-parasitic mechanism utilized by human neurons (Aim 1); determine the IFN-γ independent mechanisms that enhance neuronal clearance of intracellular parasites in vivo (Aim 2); and identify how and why neurons injected with T. gondii protein die (Aim 3). The outcomes of these studies represent essential steps for developing a nuanced understanding of neuron immune responses and identifying new therapeutic targets for ultimately developing curative treatments that address the CNS phase of disease. Project Number: 1R01NS147431-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Anita Koshy | Institution: UNIVERSITY OF ARIZONA, TUCSON, AZ | Award Amount: $711,256 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CN-Q (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11390139