Control of Type I Interferon Production in Response to Candida albicans
控制白色念珠菌产生的 I 型干扰素的产生
基本信息
- 批准号:10375410
- 负责人:
- 金额:$ 73.66万
- 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:2020-04-10 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAntifungal AntibioticsApplications GrantsCD86 geneCISH geneCandidaCandida albicansCandidiasisCellsClinicalComplexDataDendritic CellsEndosomesExposure toFeedbackGene FamilyGenesGlucansGoalsHospitalsHost DefenseHumanIRF3 geneImmuneImmune responseImmune systemImmunocompromised HostInfectionInflammationInnate Immune SystemInterferon ActivationInterferon ReceptorInterferon Type IInterferon-alphaInterferonsIntravenousKnock-outKnowledgeLeadLicensingLigationMacrophage-1 AntigenMediatingMethodsMicroarray AnalysisModelingMusMutant Strains MiceMycosesOutcomePathogenesisPathway interactionsPatientsPeripheral Blood Mononuclear CellPhagocytesPhagosomesPhosphorylationPlayPolystyrenesPredispositionProductionProteomeRegulationResistanceRoleSepsisSignal PathwaySignal TransductionSignal Transduction PathwayStimulator of Interferon GenesTBK1 geneTLR7 geneTNFRSF5 geneTissuesUbiquitinationUp-RegulationWild Type MouseWorkbasecandidemiacell typechemokinecostcytokinedectin 1functional genomicsimmunopathologyimprovedin vivo Modelmacrophagemonocytemortalityneutrophilnew therapeutic targetparticlepathogenpathogenic bacteriapathogenic virusreceptorrecruitresponsetraffickingviral DNA
项目摘要
PROJECT SUMMARY
Invasive fungal infections represent a major threat to immunocompromised patients and despite the availability of anti-
fungal antibiotics, mortality rates remain as high as 50%. Candida spp. is fifth among hospital-acquired pathogens and
fourth among bloodstream infections. Human SNPs in the type I interferon (IFN) pathway have been associated with
increased susceptibility to candidemia. While these data suggest a significant role of type I IFNs in C. albicans host defense,
the signaling pathway that licenses type I IFN production and regulation during C. albicans infection remains elusive.
Although small in numbers, plasmacytoid dendritic cells (pDCs) are the primary producers of type I IFNs (IFNα and IFNβ)
in response to viral and bacterial pathogens though other cells (i.e. macrophages and monocytes) contribute to type I IFN
production as well. Upon activation, toll-like receptors (TLRs) 7 and 9 can upregulate type I IFN production or
chemokine/cytokine production via IRF-7 and NF-κB pathways, respectively. Although induction of type I IFNs are well
described in response to viral and bacterial pathogens, a crucial knowledge gap remains with respect to the mechanisms by
which this pathway affects fungal pathogenesis. We have made several key observations to define the role of type I IFNs in
response to C. albicans. We show that pDCs from mice infected with C. albicans intravenously significantly upregulate the
activation markers, CD40 and CD86, as compared to uninfected mice. TLR9 and Dectin-1 are required for IFNα/β
production. TLR9 trafficking to fungal endosomes require Dectin-1 and Syk signaling. Furthermore, a microarray analysis
of wild-type and TLR9-knockout macrophages revealed IFN inducible family genes (IFI203, Mnda, and Ifi1) as dependent
on TLR9, implicating its role in the regulation of IFN signaling. Type I IFNs improve killing capacity of neutrophils in
response to C. albicans. We additionally demonstrated that in the absence of critical IFN signaling components (i.e. STING,
cGAS, IRF-3, and IFN receptor) mice demonstrate striking resistance to candidemia, but at the cost of a higher fungal
burden. These exciting data suggest that dysregulation of IFN signaling significantly affects the outcomes of invasive
Candida infections. Lastly, our preliminary studies implicate a role for STING in the production of the negative feedback
regulator SOCS1 (suppressor of cytokine signaling). Thus, our long-term goal is to understand the regulation and role of
type I IFNs in host defense against invasive candidiasis. To address our long-term goal, we propose the following three
aims: (1) elucidate the signaling pathway for TLR9-dependent type I IFN production in response to C. albicans, (2)
determine the impact of cGAS, STING, and IRF-3 in the host defense against candidemia, and (3) identify the mechanism
of C. albicans-induced SOCS1 to block TLR9-dependent type I IFN production. This work will provide greater
understanding of type I IFN response to invasive candidiasis and may lead to novel therapeutic targets to modulate the
immune response to alter clinical outcomes in candidemic patients.
项目摘要
侵袭性真菌感染是免疫功能低下患者的主要威胁,
真菌抗生素,死亡率仍高达50%。念珠菌在医院获得性病原体中排名第五,
第四是血液感染。I型干扰素(IFN)途径中的人类SNP与以下因素相关:
增加对念珠菌血症的易感性。虽然这些数据表明I型IFN在C.白色念珠菌宿主防御,
C.期间许可I型IFN产生和调节的信号通路。白色念珠菌感染仍然是难以捉摸的。
浆细胞样树突状细胞(plasmacytoid dendritic cells,pDC)是I型干扰素(IFNα和IFNβ)的主要产生者,但数量较少
尽管其它细胞(即巨噬细胞和单核细胞)也有助于I型IFN
生产也是。在激活后,Toll样受体(TLR)7和9可以上调I型IFN的产生,或
分别通过IRF-7和NF-κB途径产生趋化因子/细胞因子。虽然I型IFN的诱导是良好的,
描述了对病毒和细菌病原体的反应,一个关键的知识缺口仍然是关于机制,
该途径影响真菌的发病机制。我们已经做了几个关键的观察,以确定I型IFN的作用,
回应C。白色念珠菌。我们发现感染C.静脉注射白色念珠菌显著上调
活化标志物,CD 40和CD 86。IFNα/β需要TLR 9和Dectin-1
生产TLR 9运输到真菌内体需要Dectin-1和Syk信号传导。此外,微阵列分析
野生型和TLR 9敲除的巨噬细胞显示IFN诱导型家族基因(IFI 203,Mnda和Ifi 1)依赖于
在TLR 9上,暗示其在IFN信号传导的调节中的作用。I型干扰素提高嗜中性粒细胞的杀伤能力,
回应C。白色念珠菌。我们还证明了在缺乏关键的IFN信号传导组分(即STING,
cGAS、IRF-3和IFN受体)小鼠表现出对念珠菌血症的显著抗性,但以较高的真菌感染为代价。
负担这些令人兴奋的数据表明,干扰素信号的失调显着影响的结果,侵入性
念珠菌感染。最后,我们的初步研究暗示了STING在负反馈产生中的作用
调节器SOCS 1(细胞因子信号传导抑制剂)。因此,我们的长期目标是了解
I型干扰素在宿主防御侵袭性念珠菌病中的作用。为了实现我们的长期目标,我们提出以下三点
目的:(1)阐明C.白色念珠菌,(2)
确定cGAS、STING和IRF-3在宿主防御念珠菌血症中的影响,以及(3)确定机制
梭白色念珠菌诱导的SOCS 1阻断TLR 9依赖的I型IFN的产生。这项工作将提供更大
了解I型干扰素对侵袭性念珠菌病的反应,并可能导致新的治疗靶点,以调节
免疫应答改变念珠菌病患者的临床结果。
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 }}
Jatin M Vyas其他文献
Jatin M Vyas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('Jatin M Vyas', 18)}}的其他基金
2023 Immunology of Fungal Infections GRC/GRS
2023年真菌感染免疫学GRC/GRS
- 批准号:
10608737 - 财政年份:2022
- 资助金额:
$ 73.66万 - 项目类别:
Host Responses to Coccidioides by Human Airway Epithelium
人体气道上皮对球孢子菌的宿主反应
- 批准号:
10373208 - 财政年份:2022
- 资助金额:
$ 73.66万 - 项目类别:
Host Responses to Coccidioides by Human Airway Epithelium
人体气道上皮对球孢子菌的宿主反应
- 批准号:
10616716 - 财政年份:2022
- 资助金额:
$ 73.66万 - 项目类别:
MGH Next Generation Physician-Scientist Through Stimulating Access to Research in Residency Program (MGH-Next Gen StARR)
MGH 下一代医师科学家通过促进住院医师研究项目 (MGH-Next Gen StARR)
- 批准号:
10115797 - 财政年份:2020
- 资助金额:
$ 73.66万 - 项目类别:
MGH Next Generation Physician-Scientist Through Stimulating Access to Research in Residency Program (MGH-Next Gen StARR)
MGH 下一代医师科学家通过促进住院医师研究项目 (MGH-Next Gen StARR)
- 批准号:
10441143 - 财政年份:2020
- 资助金额:
$ 73.66万 - 项目类别:
Control of Type I Interferon Production in Response to Candida albicans
控制白色念珠菌产生的 I 型干扰素的产生
- 批准号:
10591418 - 财政年份:2020
- 资助金额:
$ 73.66万 - 项目类别:
MGH Next Generation Physician-Scientist Through Stimulating Access to Research in Residency Program (MGH-Next Gen StARR)
MGH 下一代医师科学家通过促进住院医师研究项目 (MGH-Next Gen StARR)
- 批准号:
10655348 - 财政年份:2020
- 资助金额:
$ 73.66万 - 项目类别:
Pathways to Mentorship and Research: Training the Next Generation Physician-Scientists
指导和研究途径:培训下一代医生科学家
- 批准号:
10226306 - 财政年份:2019
- 资助金额:
$ 73.66万 - 项目类别:
Pathways to Mentorship and Research: Training the Next Generation Physician-Scientists
指导和研究途径:培训下一代医生科学家
- 批准号:
10672162 - 财政年份:2019
- 资助金额:
$ 73.66万 - 项目类别:
The Functional Role of the Tetraspanin CD82/Kai1 in Fungal Innate Immunity
四跨膜蛋白 CD82/Kai1 在真菌先天免疫中的功能作用
- 批准号:
10090557 - 财政年份:2018
- 资助金额:
$ 73.66万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 73.66万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 73.66万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 73.66万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 73.66万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 73.66万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 73.66万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 73.66万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 73.66万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 73.66万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 73.66万 - 项目类别:
Studentship