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.
项目总结
侵袭性真菌感染是免疫功能低下患者的主要威胁,尽管有抗真菌药物可用
真菌抗生素中,死亡率仍高达50%。假丝酵母菌在医院获得性病原体中排名第五,
在血液感染中排名第四。人类I型干扰素途径中的单核苷酸多态与
增加了对念珠菌血症的易感性。虽然这些数据表明I型干扰素在白念珠菌的宿主防御中发挥了重要作用,
在白念珠菌感染期间,允许I型干扰素产生和调节的信号通路仍然难以捉摸。
尽管数量很少,但浆细胞样树突状细胞(PDC)是I型干扰素(干扰素α和干扰素β)的主要产生者。
通过其他细胞(即巨噬细胞和单核细胞)参与I型干扰素对病毒和细菌病原体的反应
生产也是如此。一旦激活,Toll样受体(TLRs)7和9可以上调I型干扰素的产生或
趋化因子/细胞因子的产生分别通过IRF-7和NF-κB途径。虽然I型IFN的诱导效果很好
在对病毒和细菌病原体的反应中,关于以下机制的关键知识缺口仍然存在
这条途径影响真菌的发病机制。我们已经提出了几个关键的观察结果,以定义I型IFN在
对白色念珠菌的反应。我们发现,静脉感染白色念珠菌的小鼠的pDC显著上调了
激活标志物CD40和CD86,与未感染的小鼠相比。干扰素α/β需要TLR9和Dectin-1
制作。TLR9转运到真菌内体需要Dectin-1和Syk信号。此外,一种微阵列分析
野生型和TLR9基因敲除的巨噬细胞显示干扰素诱导的家族基因(IFI203、MNDA和IFI1)是依赖的
在TLR9上,提示其在干扰素信号调节中的作用。I型干扰素提高中性粒细胞的杀伤能力
对白色念珠菌的反应。我们还证明了在缺少关键的干扰素信号组件(即,
CGAS、IRF-3和干扰素受体)小鼠对念珠菌血症表现出显著的抗药性,但代价是更高的真菌
负担。这些令人兴奋的数据表明,干扰素信号的失调显著影响侵袭性疾病的结局。
念珠菌感染。最后,我们的初步研究表明,SING在负面反馈的产生中起着一定的作用
调节因子SOCS1(细胞因子信号的抑制因子)。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,我们提出了以下三项建议
目的:(1)阐明白念珠菌产生TLR9依赖的I型干扰素的信号通路,(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)确定其机制
白念珠菌诱导的SOCS1阻断依赖TLR9的I型干扰素的产生。这项工作将提供更大的
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来调节
免疫反应改变念珠菌病患者的临床结局。
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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Jatin M Vyas其他文献
Jatin M Vyas的其他文献
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{{ 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
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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:
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