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Identifying human neuron IFN-γ dependent anti-Toxoplasma gondii responses

识别人类神经元 IFN-γ 依赖性抗弓形虫反应

基本信息

批准号：
10619781
负责人：
Jared Churko
金额：
$ 19.19万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-12 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10619781
关键词：
Acquired Immunodeficiency Syndrome Acute Address Affect Antiparasitic Agents Antiviral Therapy Astrocytes Benign Brain CRISPR interference Cells Central Nervous System Infections Cessation of life Chronic Clinical Cognition Cyst Data Development Disease DsRed Engineering Focal Neurologic Deficits Foundations Genetic Genetic Recombination Goals Grant HIV HIV/AIDS Human Immune Evasion Immune response In Vitro Infection Interferon Type II Invaded Lesion Mediating Modeling Molecular Mus Neurologic Neurologic Deficit Neurons Outcome Parasites Pathogenesis Pathway interactions Patients Persons Phase Population Populations at Risk Proteins Protocols documentation Reporter Role STAT1 gene Seizures Survivors Technology Toxoplasma gondii Toxoplasmosis Work antiretroviral therapy cell type chronic infection co-infection cognitive function curative treatments cytokine high reward high risk human pluripotent stem cell in vivo infection rate knock-down latent infection mouse model prevent programs response stem cell biology stem cells tool toxoplasmic encephalitis

项目摘要

Project Summary: Toxoplasma gondii is an intracellular parasite that latently infects many hosts, including humans. Successful latent infection requires T. gondii to evade cytokine-induced, cell intrinsic responses and switch from a fast-growing form to a slow-growing encysted form. In humans, this life-long infection occurs in the brain where T. gondii can reactivate in the setting of acquired immune deficiencies. In AIDS patients, toxoplasmic encephalitis is the most common cause of focal brain lesions and can cause prolonged neurologic deficits even after appropriate treatment. Recent studies also suggest that, even in HIV+ patients on effective antiretroviral therapy, persistent T. gondii infection may adversely affect cognition and global immune responses. Despite its clinical importance, we lack a mechanistic understanding of what is actually responsible for T. gondii’s pathogenesis in the CNS, including what enables long-term latent infection. Such understanding is crucial to eventually preventing symptomatic disease in HIV/AIDs patients. Within the CNS, cysts are primarily found in neurons. Based on limited in vitro and in vivo studies, it has been presumed that while infected astrocytes cleared intracellular parasites, neurons did not and thus were the de facto host cell for persistent infection. In the last decade, our pioneering work has questioned this model, including showing that IFN-γ-stimulated neurons mount anti-parasitic defenses. As most of this work has occurred in murine models and neurons, it will have missed human neuron-specific pathways (e.g., humans lack the terminal IFN-γ dependent proteins used by murine cells to kill intracellular parasites). The goal of this grant is to address this gap by establishing robust stem cell derived human neuron models (hPSC neurons) which can be used to mechanistically define human neuron-T. gondii interactions that enable immune evasion and persistence. To accomplish this goal, our will leverage our synergistic expertise in CNS toxoplasmosis (Dr. Koshy) and stem cell biology (Dr. Churko) to generate Cre reporter hPSC neurons and CRISPRi-expressing hPSC neurons (Aim 1) and to begin to define the mechanisms by which cytokine stimulated hPSC-neurons control T. gondii (Aim 2). With the completion of these aims, we will have established and validated tools that will form the essential foundation of a long-term program to molecularly define the neuron-T. gondii interactions that enable control and persistence of T. gondii in human neurons. The work proposed here represents an important first step toward developing human neuron-specific therapies for acute and chronic toxoplasmosis. Such therapies will be of great benefit for the HIV/AIDS population at risk for toxoplasmic encephalitis.

项目总结: