Neuroinflammation during cerebral Toxoplasma gondii infection

脑弓形虫感染期间的神经炎症

基本信息

项目摘要

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.
项目总结

项目成果

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Melissa Bruckner Lodoen其他文献

Melissa Bruckner Lodoen的其他文献

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{{ truncateString('Melissa Bruckner Lodoen', 18)}}的其他基金

Neuroinflammation during cerebral Toxoplasma gondii infection
脑弓形虫感染期间的神经炎症
  • 批准号:
    10374176
  • 财政年份:
    2021
  • 资助金额:
    $ 21.76万
  • 项目类别:
Role of caspase-8 in innate immunity to infection
Caspase-8 在针对感染的先天免疫中的作用
  • 批准号:
    10331886
  • 财政年份:
    2021
  • 资助金额:
    $ 21.76万
  • 项目类别:
Parasite dissemination in Toxoplasmic encephalitis
弓形虫脑炎中的寄生虫传播
  • 批准号:
    9889871
  • 财政年份:
    2016
  • 资助金额:
    $ 21.76万
  • 项目类别:
Mechanisms of Toxoplasma gondii dissemination and transmigration
弓形虫传播和迁移机制
  • 批准号:
    8893191
  • 财政年份:
    2014
  • 资助金额:
    $ 21.76万
  • 项目类别:

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