CD8 T cell-dependent pathways leading to immunopathology in cutaneous leishmaniasis
CD8 T 细胞依赖性途径导致皮肤利什曼病的免疫病理学
基本信息
- 批准号:10556387
- 负责人:
- 金额:$ 55.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-12 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Antiparasitic AgentsAutomobile DrivingBenignBindingBioinformaticsCCL3 geneCCL4 geneCCR5 geneCD8-Positive T-LymphocytesCD8B1 geneCXCL3 geneCXCL9 geneCXCR3 geneCell DeathCellsChronicClinicalCultured CellsCutaneousCutaneous LeishmaniasisCytolysisCytotoxic T-LymphocytesDataDiseaseDisease ProgressionEquilibriumExperimental ModelsFutureGenerationsGenetic TranscriptionImmune responseImmunologicsImmunotherapyIn VitroIndividualInfectionInflammasomeInflammationInflammatoryIntegration Host FactorsKnowledgeLeishmaniaLeishmaniasisLesionLinkLymphocyteMediatingModelingMolecularMusOutcomeParasitesPathologicPathologyPathway interactionsPatientsPatternPharmaceutical PreparationsPharmacotherapyPhysiologicalPlayProductionPublicationsRegulatory T-LymphocyteReporterRoleSeriesSeveritiesSignal TransductionSterilityTestingTreatment Failurecell typechemokinechronic infectiondesigndisorder controlex vivo imagingexperimental studyimaging approachimmunopathologyimprovedin vitro Modelin vivoinsightmouse modelneglected tropical diseasesperforinrecruitresponse
项目摘要
Project Summary
Cutaneous leishmaniasis is a major neglected tropical disease that is associated with clinical manifestations
ranging in severity from relatively benign lesions to chronic highly ulcerated lesions to metastatic disease.
Optimally, drug treatment would eliminate the parasites, but drugs developed to date fail to induce sterile
cure and are often woefully inefficient at controlling the disease. Our new data strongly suggests that
optimal control of cutaneous leishmaniasis requires a response that not only effectively eliminates the
parasite, but also reduces the potential for immunopathology. In a series of publications, we have outlined
the role of CD8 cytolytic T cells in driving inflammation by upregulating the inflammasome and inducing the
release of IL-1. Thus, our studies indicate that an immunopathologic pathway involving the inflammasome
and IL-1 production is a major driver of disease. We further found that blocking NLRP3 or IL-1 in
experimental models of severe cutaneous leishmaniasis ameliorates pathology mediated by CTLs without
blocking protective immune responses, suggesting that either would be excellent targets for host-directed
immunotherapy that could be used in conjunction with conventional anti-parasitic treatments. However,
significant gaps in our knowledge of this pathologic response remain. Here we will utilize a combination of in
vitro and in vivo approaches that will identify the cells undergoing inflammasome activation, determine the
proximal signals that activate NLRP3, and define the chemokines that maintain this chronic
immunopathologic response. To accomplish this in Aim 1 we will determine which cells contribute to NLRP3
dependent pathology during cutaneous leishmaniasis disease progression by defining when
inflammasomes are activated following infection, identifying the cells involved and determining which cells
are required for disease-promoting inflammasome activation. In Aim 2 we will identify the triggers of NLRP3
inflammasome activation in cutaneous leishmaniasis. Finally, we found that the chemokines CCL3 and
CCL4 are associated with treatment failure in patients, and therefore in Aim 3 we will determine if these
chemokines drive the chronicity of cutaneous leishmania lesions by promoting CD8 T cell or regulatory T
cell recruitment to leishmanial lesions. Our proposed experiments have clear translational significance since
they are founded upon substantial data obtained from leishmaniasis patients and are designed to identify
the essential cells and signals required for disease. Such information will allow for a more specific targeting
of immunopathology in leishmaniasis and identify additional targets for host-directed therapies in this
chronic infection. Finally, these studies will be of more general significance, as this pathologic pathway is
not unique to cutaneous leishmaniasis.
项目总结
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
PHILLIP SCOTT其他文献
PHILLIP SCOTT的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('PHILLIP SCOTT', 18)}}的其他基金
2023 Woods Hole Immunoparasitology Meeting
2023 年伍兹霍尔免疫寄生虫学会议
- 批准号:
10680864 - 财政年份:2023
- 资助金额:
$ 55.78万 - 项目类别:
2022 WOODS HOLE IMMUNOPARASITOLOGY MEETING
2022 年伍兹霍尔免疫寄生虫学会议
- 批准号:
10458244 - 财政年份:2022
- 资助金额:
$ 55.78万 - 项目类别:
CD8 T cell-dependent pathways leading to immunopathology in cutaneous leishmaniasis
CD8 T 细胞依赖性途径导致皮肤利什曼病的免疫病理学
- 批准号:
10329958 - 财政年份:2020
- 资助金额:
$ 55.78万 - 项目类别:
23rd Annual Woods Hole Immunoparasitology (WHIP) Meeting
第 23 届伍兹霍尔免疫寄生虫学 (WHIP) 年度会议
- 批准号:
9750405 - 财政年份:2019
- 资助金额:
$ 55.78万 - 项目类别:
20th Annual Woods Hole Immunoparasitology Meeting
第 20 届伍兹霍尔免疫寄生虫学年度会议
- 批准号:
9126050 - 财政年份:2016
- 资助金额:
$ 55.78万 - 项目类别:
Annual Woods Hole Immunoparasitology (WHIP) Meeting
年度伍兹霍尔免疫寄生虫学 (WHIP) 会议
- 批准号:
8899229 - 财政年份:2015
- 资助金额:
$ 55.78万 - 项目类别:
Protective and Pathologic Roles for CD8+ T cells in Leishmaniasis
CD8 T 细胞在利什曼病中的保护和病理作用
- 批准号:
8758136 - 财政年份:2014
- 资助金额:
$ 55.78万 - 项目类别:
Protective and Pathologic Roles for CD8+ T cells in Leishmaniasis
CD8 T 细胞在利什曼病中的保护和病理作用
- 批准号:
8895257 - 财政年份:2014
- 资助金额:
$ 55.78万 - 项目类别:
Protective and Pathologic Roles for CD8+ T cells in Leishmaniasis
CD8 T 细胞在利什曼病中的保护和病理作用
- 批准号:
9300849 - 财政年份:2014
- 资助金额:
$ 55.78万 - 项目类别:
相似海外基金
Establishment of a method for evaluating automobile driving ability focusing on frontal lobe functions and its application to accident prediction
以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
- 批准号:
20K07947 - 财政年份:2020
- 资助金额:
$ 55.78万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Evaluation of the Effectiveness of Multi-Professional Collaborative Assessment of Cognitive Function and Automobile Driving Skills and Comprehensive Support
认知功能与汽车驾驶技能多专业协同评估效果评价及综合支持
- 批准号:
17K19824 - 财政年份:2017
- 资助金额:
$ 55.78万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Development of Flexible Automobile Driving Interface for Disabled People
残疾人灵活汽车驾驶界面开发
- 批准号:
25330237 - 财政年份:2013
- 资助金额:
$ 55.78万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Automobile driving among older people with dementia: the effect of an intervention using a support manual for family caregivers
患有痴呆症的老年人的汽车驾驶:使用家庭护理人员支持手册进行干预的效果
- 批准号:
23591741 - 财政年份:2011
- 资助金额:
$ 55.78万 - 项目类别:
Grant-in-Aid for Scientific Research (C)