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：
Jatin M Vyas
金额：
$ 73.66万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
https://reporter.nih.gov/project-details/10375410
关键词：
Address Affect Antifungal Antibiotics Applications Grants CD86 gene CISH gene Candida Candida albicans Candidiasis Cells Clinical Complex Data Dendritic Cells Endosomes Exposure to Feedback Gene Family Genes Glucans Goals Hospitals Host Defense Human IRF3 gene Immune Immune response Immune system Immunocompromised Host Infection Inflammation Innate Immune System Interferon Activation Interferon Receptor Interferon Type I Interferon-alpha Interferons Intravenous Knock-out Knowledge Lead Licensing Ligation Macrophage-1 Antigen Mediating Methods Microarray Analysis Modeling Mus Mutant Strains Mice Mycoses Outcome Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Phagocytes Phagosomes Phosphorylation Play Polystyrenes Predisposition Production Proteome Regulation Resistance Role Sepsis Signal Pathway Signal Transduction Signal Transduction Pathway Stimulator of Interferon Genes TBK1 gene TLR7 gene TNFRSF5 gene Tissues Ubiquitination Up-Regulation Wild Type Mouse Work base candidemia cell type chemokine cost cytokine dectin 1 functional genomics immunopathology improved in vivo Model macrophage monocyte mortality neutrophil new therapeutic target particle pathogen pathogenic bacteria pathogenic virus receptor recruit response trafficking viral 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.

项目概要尽管有抗真菌药物可用，但侵袭性真菌感染对免疫功能低下的患者构成了主要威胁。真菌抗生素的死亡率仍高达 50%，在医院获得性病原体中排名第五。人类 I 型干扰素 (IFN) 途径中的 SNP 与血液感染有关。虽然这些数据表明 I 型干扰素在白色念珠菌宿主防御中发挥着重要作用，在白色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（IFNα 和 IFNβ）的主要生产者尽管其他细胞（即巨噬细胞和单核细胞）会产生 I 型干扰素，但对病毒和细菌病原体作出反应激活后，Toll 样受体 (TLR) 7 和 9 也可以上调 I 型 IFN 的产生或。尽管 I 型 IFN 的诱导效果良好，但分别通过 IRF-7 和 NF-κB 途径产生趋化因子/细胞因子。尽管针对病毒和细菌病原体的反应进行了描述，但在其机制方面仍然存在重要的知识差距该途径影响真菌发病机制，我们进行了几项关键观察来定义 I 型干扰素在真菌发病机制中的作用。我们发现静脉注射感染白色念珠菌的小鼠的 pDC 显着上调与未感染的小鼠相比，IFNα/β 需要激活标记 CD40 和 CD86。 TLR9 运输到真菌内体需要 Dectin-1 和 Syk 信号传导此外，还需要进行微阵列分析。野生型和 TLR9 敲除巨噬细胞的研究显示 IFN 诱导家族基因（IFI203、Mnda 和 Ifi1）是依赖的 TLR9，暗示其在 IFN 信号传导调节中的作用，I 型 IFN 可提高中性粒细胞的杀伤能力。我们还证明，在缺乏关键的 IFN 信号成分（即 STING、 cGAS、IRF-3 和 IFN 受体）小鼠表现出对念珠菌血症的惊人抵抗力，但代价是更高的真菌感染率这些令人兴奋的数据表明，干扰素信号传导失调会显着影响侵入性治疗的结果。最后，我们的初步研究表明 STING 在负反馈的产生中发挥作用。因此，我们的长期目标是了解 SOCS1（细胞因子信号传导的抑制因子）的调节和作用。 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，我们提出以下三个目标。目标：(1) 阐明白色念珠菌响应 TLR9 依赖性 I 型 IFN 产生的信号通路，(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) 确定机制白色念珠菌诱导的 SOCS1 阻断 TLR9 依赖性 I 型 IFN 的产生这项工作将提供更大的帮助。了解 I 型干扰素对侵袭性念珠菌病的反应，并可能产生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果。