Neuroinflammation during cerebral Toxoplasma gondii infection

脑弓形虫感染期间的神经炎症

• 批准号: 10258923
• 负责人: Melissa Bruckner Lodoen
• 金额: $ 21.76万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258923
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Address; Antiparasitic Agents; Astrocytes; Behavior; Behavioral; Biology; Brain; Brain region; CCL2 gene; Cells; Central Nervous System Diseases; Central Nervous System Infections; Cerebral Toxoplasmosis; Cerebrum; Chronic; Cognition; Cues; Cyst; Data; Development; Disease; Encephalitis; Genetic Transcription; Goals; HIV; HIV Encephalopathy; HIV Infections; Host Defense; Host Defense Mechanism; Human; Image; Immune; Immunity; Immunocompetent; Immunological Models; Immunosuppression; Infection; Infection Control; Infiltration; Inflammatory; Inflammatory Response; Interferon Type II; Lead; Light; Mediating; Microglia; Microscopy; Modeling; Molecular; Mus; Myeloid Cells; Odors; Olfactory tubercle; Optics; Outcome; Parasite Control; Parasites; Parasitic infection; Pathogenesis; Pathology; Patients; Peripheral; Play; Predisposition; Production; Proteins; Research; Rewards; Role; T-Lymphocyte; Testing; Toxoplasma gondii; Toxoplasmosis; Transgenic Mice; antimicrobial; base; chemokine; chronic infection; co-infection; flexibility; monocyte; mouse model; multisensory; neuroinflammation; response; social; toxoplasmic encephalitis; trafficking; transcriptome sequencing

PROJECT SUMMARY Toxoplasma gondii is an intracellular parasite that infects one-third of humans worldwide and can cause fatal disease during co-infection of HIV/AIDS patients. The parasites establish a long-term brain infection, and reactivation of the infection causes Toxoplasmic encephalitis in immune-compromised HIV/AIDS patients. T. gondii is among the most common opportunistic parasitic infections in AIDS patients and is the leading cause of focal CNS infection complicating AIDS. Although T cells are essential for protective immunity against T. gondii, recent evidence indicates that myeloid cells, including monocytes, also play a key role in host defense. The trafficking of inflammatory monocytes from the blood to the CNS during chronic T. gondii infection is critical for host protection against cerebral toxoplasmosis. Despite the important role of monocytes in CNS immunity against T. gondii infection, remarkably little is known about the chemokines that drive monocyte infiltration to the brain or the outcome of the neuroinflammatory response mediated by monocytes in the brain. We recently performed a brain-wide imaging and neuroanatomical analysis of T. gondii infection in mice, which revealed that inflammatory monocytes infiltrate the brain in a highly regionalized manner and preferentially localize to the olfactory tubercle, a multisensory brain region involved in odor-guided behavior, social and reward cognition, and behavioral flexibility. The objective of this proposal is to determine the molecular cues that drive neuroinflammation during T. gondii infection and to define the outcome of this response on the parasites and brain-resident cells. A model of chronic and reactivated T. gondii infection in mice will be used. In this model, chronically-infected mice are subject to immune suppression to induce parasite reactivation, thereby modeling the immune compromise of HIV/AIDS patients. In Aim 1, we will localize inflammatory monocytes and T. gondii in the brains of mice during chronic and reactivated T. gondii infection by performing light sheet microscopy on optically transparent, intact brains from infected transgenic mice. We will also evaluate a role for astrocyte CCL2 in inflammatory monocyte infiltration of the CNS and in parasite control by using mice deficient in astrocyte production of CCL2. In Aim 2, we will define the outcome of the focal neuroinflammatory response on the parasites and on brain-resident cells during T. gondii infection. We will investigate microglia and astrocyte activation, the levels of antimicrobial iNOS and IRG proteins, and parasite burden in brain regions with high and low monocyte infiltration. We will also conduct an unbiased RNA-Seq analysis comparing brain regions with high and low levels of infiltrating monocytes to determine the effects of neuroinflammation on the transcriptional landscape during infection. This research is significant because focal neuroinflammation may underlie a variety of CNS pathologies, including HIV encephalopathies. An understanding of how neuroinflammation is regulated will inform our basic understanding of the effects of neuroinflammation on CNS biology in the context of immune deficiency associated with HIV/AIDS.

项目摘要 弓形虫是一种细胞内寄生虫，感染全球三分之一的人类， 艾滋病病毒/艾滋病患者合并感染期间的疾病。寄生虫会造成长期的脑部感染， 感染的再激活导致免疫受损的HIV/AIDS患者中的弓形体脑炎。T. 弓形虫是艾滋病患者最常见的机会性寄生虫感染之一， 中枢神经系统感染并发艾滋病虽然T细胞对于针对T细胞的保护性免疫是必需的。 最近的证据表明，包括单核细胞在内的骨髓细胞在宿主防御中也起着关键作用。 慢性T淋巴细胞炎性单核细胞从血液到中枢神经系统的运输。弓形虫感染是 对保护宿主免受脑弓形虫感染至关重要。尽管单核细胞在CNS中的重要作用 抗T.在弓形虫感染后，人们对驱动单核细胞的趋化因子知之甚少 脑内单核细胞介导的神经炎症反应的结果。 我们最近对T进行了全脑成像和神经解剖分析。小鼠的弓形虫感染， 这表明炎性单核细胞以高度区域化的方式浸润大脑， 优先定位于嗅结节，一个涉及气味引导行为的多感觉脑区， 社会和奖励认知以及行为灵活性。本提案的目的是确定 在T.弓形虫感染，并确定这一结果 寄生虫和脑细胞的反应。建立慢性T.弓形虫感染 将使用小鼠。在该模型中，使慢性感染的小鼠经受免疫抑制以诱导 寄生虫再激活，从而模拟HIV/AIDS患者的免疫妥协。在目标1中，我们 定位于炎性单核细胞和T.弓形虫在小鼠脑中的慢性和重新激活的T。弓形虫 通过在来自感染的转基因小鼠的光学透明的完整脑上进行光片显微镜检查来感染 小鼠我们还将评估星形胶质细胞CCL 2在中枢神经系统炎症性单核细胞浸润中的作用， 利用星形胶质细胞产生CCL 2缺陷的小鼠控制寄生虫。在目标2中，我们将定义结果 在T.弓形虫感染 我们将研究小胶质细胞和星形胶质细胞的活化，抗微生物iNOS和IRG蛋白的水平， 具有高和低单核细胞浸润的脑区域中的寄生虫负荷。我们还将进行一次公正的 比较具有高和低水平浸润单核细胞的脑区域的RNA-Seq分析， 感染期间神经炎症对转录景观的影响。这项研究意义重大 因为局灶性神经炎症可能是多种CNS病理的基础，包括HIV脑病。 了解神经炎症是如何调节的，将有助于我们基本了解 在与HIV/AIDS相关的免疫缺陷背景下，神经炎症对CNS生物学的影响。