Mechanisms of balancing the immune response during cryptococcal meningoencephalitis
隐球菌性脑膜脑炎期间平衡免疫反应的机制
基本信息
- 批准号:10761918
- 负责人:
- 金额:$ 19.23万
- 依托单位:
- 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:2023-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAddressAffectAnti-Inflammatory AgentsBrainBrain InjuriesCD4 Positive T LymphocytesCell secretionCellsCellular ImmunityCerebrospinal FluidCessation of lifeClinicalClinical DataComaCryptococcosisCryptococcusCryptococcus neoformansCryptococcus neoformans infectionDiseaseEncephalitisEquilibriumFOXP3 geneGenesGenetic PolymorphismGrowthHIVHIV SeronegativityHIV SeropositivityHIV/AIDSHumanImmuneImmune responseImmunityImmunocompromised HostImpairmentIndividualInfectionInflammationInflammatoryInflammatory ResponseInhalationInterleukin-10LifeLungMaintenanceMediatingMeningoencephalitisMicrobeMolecularMusMycosesOutcomePatientsPersonsPlayPredispositionProductionProliferatingPropertyRegulationRegulatory T-LymphocyteRoleSeveritiesSignal TransductionSourceSyndromeTestingTherapeuticantiretroviral therapyblood-brain barrier crossingbrain sizecytokinefungusimmune reconstitutionimmunopathologyimmunoregulationimprovedinterleukin-10 receptormRNA Expressionmigrationmortalitymouse modelpathogenpathogenic funguspreventreceptorresponsetherapeutic development
项目摘要
Project Summary
Cryptococcosis is an opportunistic fungal infection that is caused by Cryptococcus neoformans and
often occurs in immunocompromised individuals including HIV/AIDS patients. Although the infection starts in
the lung via inhalation of the pathogenic fungus, the most common manifestation of cryptococcosis is
meningoencephalitis, which is a leading cause of mortality of HIV/AIDS patients and accounts for proximately
181,000 deaths worldwide annually. The high susceptibility of HIV/AIDS patients to C. neoformans infection is
attributed to their impaired cellular immunity. Consequently, C. neoformans proliferates in the brain without
control, leading to microbe-mediated brain damage. Antiretroviral therapy (ART) is a major advance in treating
HIV/AIDS patients by restoring cellular immune responses. However, after initiation of ART, up to 30% of
HIV/AIDS patients with cryptococcosis develop immune reconstitution inflammatory syndrome (IRIS), an
aberrant excessive immune response leading to host-mediated brain damage. Furthermore, post-infectious
inflammatory response syndrome (PIIRS) occurs frequently in HIV-negative patients with cryptococcal
meningoencephalitis. Therefore, a robust immune response is required for controlling the fungal growth;
however, the immune response must be tightly controlled to avoid host-mediated brain damage during
cryptococcal meningoencephalitis. A critical gap in our understanding remains: what are the mechanisms of
maintaining the balance between protective immune responses and immunopathology during cryptococcal
meningoencephalitis-associated IRIS? IL-10 is an important cytokine with anti-inflammatory properties and its
production was enhanced in the cerebrospinal fluid of HIV/AIDS patients during cryptococcal IRIS. Based on
clinical data and our preliminary murine studies, we hypothesize that IL-10 is critically involved in balancing the
immune responses during cryptococcal meningoencephalitis-associated IRIS. We will test the hypothesis in a
murine model that closely mimics cryptococcal IRIS of HIV/AIDS patients, by addressing the following aims: (1)
To determine the mechanism(s) involved in regulation of the immune responses by IL-10 during cryptococcal
meningoencephalitis-associated IRIS; (2) To determine the mechanism(s) involved in induction of IL-10 in the
brain during cryptococcal meningoencephalitis-associated IRIS. If successful, the findings from this study
would be fundamental for understanding regulation of immune balance during cryptococcal
meningoencephalitis-associated IRIS and provide scientific basis for targeting this cytokine aiming at
controlling deleterious inflammation in the brain of cryptococcal IRIS/AIDS patients.
项目摘要
隐球菌病是一种机会性真菌感染,由新型隐球菌引起,
通常发生在免疫功能低下的个体,包括HIV/AIDS患者。虽然感染开始于
隐球菌病最常见的表现是
脑膜脑炎是艾滋病毒/艾滋病患者死亡的主要原因,
全球每年有18.1万人死亡。HIV/AIDS患者对C.新形式感染是
这是因为他们的细胞免疫力受损。因此,C.新生儿在大脑中增殖,
控制,导致微生物介导的脑损伤。抗逆转录病毒疗法(ART)是治疗艾滋病的一项重大进展。
艾滋病毒/艾滋病患者恢复细胞免疫反应。然而,在开始抗逆转录病毒疗法后,
HIV/AIDS隐球菌病患者发生免疫重建炎症综合征(IRIS),
异常的过度免疫反应导致宿主介导的脑损伤。此外,感染后
炎症反应综合征(PIIRS)经常发生在HIV阴性的隐球菌感染患者中,
脑膜脑炎因此,需要强有力的免疫应答来控制真菌生长;
然而,免疫反应必须严格控制,以避免宿主介导的脑损伤,
隐球菌脑膜脑炎在我们的理解中仍然存在一个关键的差距:
维持隐球菌感染期间保护性免疫应答和免疫病理学之间的平衡
脑膜脑炎相关IRIS?IL-10是一种重要的具有抗炎特性的细胞因子,
在隐球菌IRIS期间,HIV/AIDS患者的脑脊液中产生增强。基于
根据临床数据和我们的初步小鼠研究,我们假设IL-10在平衡免疫系统中发挥着关键作用。
隐球菌性脑膜脑炎相关IRIS期间的免疫应答。我们将在一个
通过解决以下目标,建立了密切模拟HIV/AIDS患者隐球菌IRIS的鼠模型:(1)
为了确定隐球菌感染期间IL-10调节免疫应答的机制,
(2)探讨脑膜脑炎相关IRIS中IL-10的诱导机制。
隐球菌脑膜脑炎相关IRIS期间的大脑。如果成功,这项研究的结果
将是理解隐球菌感染过程中免疫平衡调节的基础。
并为靶向这种细胞因子提供科学依据,
控制隐球菌IRIS/AIDS患者大脑中的有害炎症。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Meiqing Shi', 18)}}的其他基金
Interactions of Cryptococcus neoformans with mononuclear phagocytes in the brain
新型隐球菌与大脑中单核吞噬细胞的相互作用
- 批准号:
10667732 - 财政年份:2023
- 资助金额:
$ 19.23万 - 项目类别:
Filtering of disseminating Cryptococcus neoformans out of vasculature
将传播的新型隐球菌从脉管系统中过滤出来
- 批准号:
9387721 - 财政年份:2017
- 资助金额:
$ 19.23万 - 项目类别:
In vivo mechanisms of brain invasion by Cryptococcus neoformans
新型隐球菌脑侵袭的体内机制
- 批准号:
9912711 - 财政年份:2017
- 资助金额:
$ 19.23万 - 项目类别:
Brain dissemination of Cryptococcus neoformans mediated by neutrophils
中性粒细胞介导的新型隐球菌的脑传播
- 批准号:
8808266 - 财政年份:2014
- 资助金额:
$ 19.23万 - 项目类别:
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