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
• 负责人: Jatin M Vyas
• 金额: $ 73.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/10591418
• 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; Hospitalization; 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; Licensing; Ligation; Macrophage; Macrophage-1 Antigen; Mediating; 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; Work; candidemia; cell type; chemokine; cost; cytokine; dectin 1; functional genomics; immunopathology; immunoregulation; improved; in vivo Model; monocyte; mortality; neutrophil; new therapeutic target; particle; pathogen; pathogenic bacteria; pathogenic virus; receptor; recruit; response; trafficking; viral DNA

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 侵入性真菌感染代表了对免疫功能低下的患者的主要威胁，并希望抗 真菌抗生素，死亡率仍然高达50％。念珠菌属。在医院获得的病原体中排名第五 在血液感染中第四。 I类干扰素（IFN）途径中的人类SNP已与 增加对候选血症的敏感性。尽管这些数据表明在白色念珠菌宿主防御中，I型IFN的重要作用，但 在白色念珠菌感染期间获得I型IFN产生和调节的信号通路仍然难以捉摸。 尽管数量很小，但浆细胞样树突状细胞（PDC）是I型IFN（IFNα和IFNβ）的主要生产者 响应病毒和细菌病原体，其他细胞（即巨噬细胞和单核细胞）有助于I型IFN 也生产。激活后，类似收费的受体（TLRS）7和9可以更新I型IFN生产或 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的诱导很好 描述了对病毒和细菌病原体的响应，关键的知识差距仍然相对于通过 该途径会影响真菌发病机理。我们已经进行了几个关键观察，以定义I型IFN的作用 对白色念珠菌的反应。我们表明，感染白色念珠菌的小鼠的PDC静脉注射会显着上调 与未感染的小鼠相比，激活标记CD40和CD86。 IFNα/β需要TLR9和Dectin-1 生产。 TLR9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TLR9-KNOCKOUT巨噬细胞显示IFN诱导的家族基因（IFI203，MNDA和IFI1）作为依赖 在TLR9上，暗示其在IFN信号传导调节中的作用。 I型IFN提高了中性粒细胞的杀死能力 对白色念珠菌的反应。我们还证明，在没有关键的IFN信号成分的情况下（即刺痛， CGA，IRF-3和IFN受体）小鼠表现出对候选血症的抗药性，但以较高的真菌为代价 负担。这些令人兴奋的数据表明，IFN信号的失调显着影响侵入性的结果 念珠菌感染。最后，我们的初步研究暗示了在产生负面反馈中的作用 调节剂SOCS1（细胞因子信号传导的抑制剂）。这是我们的长期目标是了解 I型IFN在宿主防御侵入性念珠菌病中。为了解决我们的长期目标，我们提出以下三个 目的：（1）阐明了响应白色念珠菌的TLR9依赖性I型IFN产生的信号传导途径，（2） 确定CGA，Sting和IRF-3对宿主防御候选血症的影响，（3）确定机制 白色念珠菌诱导的SOCS1以阻断TLR9依赖性I型IFN产生。这项工作将提供更大的 了解I型IFN对侵入性念珠菌病的反应，并可能导致新的治疗靶点以调节 对改变候选患者的临床结果的免疫反应。