Interactions of pDCs with Aspergilus

pDC 与曲霉的相互作用

• 批准号: 8605547
• 负责人: Stuart Michael Levitz
• 金额: $ 40.83万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605547
• 关键词: Acute Disease; Address; Allergic; Animal Model; Antifungal Agents; Apoptosis; Aspergillosis; Aspergillus fumigatus; Autoimmune Diseases; Bacteria; Biology; CD8B1 gene; Cells; Cessation of life; Chelating Agents; Chronic; Data; Dendritic Cells; Diagnostic; Early treatment; Environment; Flow Cytometry; Funding; Fungal Drug Resistance; Gliotoxin; Growth; Host Defense; Human; Hyphae; Immune; Immune response; Immune system; Immunocompromised Host; Immunology; Immunosuppressive Agents; In Vitro; Incubated; Infection; Inflammatory Response; Interferon Type I; Interferons; Intravenous; Knockout Mice; Knowledge; Lead; Leukocyte L1 Antigen Complex; Leukocytes; Life; Link; Lung; Maintenance; Mediating; Microscopy; Modeling; Molds; Morbidity - disease rate; Mus; Mycoses; Mycotoxins; Natural Killer Cells; Necrosis; Neoplasms; Neutropenia; Nucleic Acids; Pathogenesis; Pathology; Patients; Pattern recognition receptor; Persons; Play; Pneumonia; Population; Prevention; Role; T-Lymphocyte; TLR7 gene; TNF gene; Viral; Virus; Zinc; adaptive immunity; arm; base; cell type; chemokine; cytokine; defined contribution; follow-up; fungus; in vivo; in vivo Model; macrophage; monocyte; mortality; neutrophil; novel strategies; pathogen; peripheral blood; prevent; public health relevance; receptor; response; Acute Disease; Address; Allergic; Animal Model; Antifungal Agents; Apoptosis; Aspergillosis; Aspergillus fumigatus; Autoimmune Diseases; Bacteria; Biology; CD8B1 gene; Cells; Cessation of life; Chelating Agents; Chronic; Data; Dendritic Cells; Diagnostic; Early treatment; Environment; Flow Cytometry; Funding; Fungal Drug Resistance; Gliotoxin; Growth; Host Defense; Human; Hyphae; Immune; Immune response; Immune system; Immunocompromised Host; Immunology; Immunosuppressive Agents; In Vitro; Incubated; Infection; Inflammatory Response; Interferon Type I; Interferons; Intravenous; Knockout Mice; Knowledge; Lead; Leukocyte L1 Antigen Complex; Leukocytes; Life; Link; Lung; Maintenance; Mediating; Microscopy; Modeling; Molds; Morbidity - disease rate; Mus; Mycoses; Mycotoxins; Natural Killer Cells; Necrosis; Neoplasms; Neutropenia; Nucleic Acids; Pathogenesis; Pathology; Patients; Pattern recognition receptor; Persons; Play; Pneumonia; Population; Prevention; Role; T-Lymphocyte; TLR7 gene; TNF gene; Viral; Virus; Zinc; adaptive immunity; arm; base; cell type; chemokine; cytokine; defined contribution; follow-up; fungus; in vivo; in vivo Model; macrophage; monocyte; mortality; neutrophil; novel strategies; pathogen; peripheral blood; prevent; public health relevance; receptor; response

DESCRIPTION (provided by applicant): Aspergillus fumigatus is the most common cause of invasive mold infections. Even with advances in therapy and early diagnostics, mortality rates remain high. Plasmacytoid dendritic cells (pDCs) comprise a functionally distinct lineage of DCs that rapidly produce copious amounts of type I interferons (IFNs) upon stimulation with viruses, predominantly via mechanisms dependent on sensing of viral nucleic acids. pDCs link innate to adaptive immunity by secreting cytokines and by priming T cells. The interplay between pDCs and fungi has not been well characterized. The application builds upon compelling preliminary data demonstrating that: 1) human pDCs directly inhibit fungal growth via a mechanism that involves A. fumigatus-induced pDC death; 2) following stimulation with A. fumigatus hyphae, pDCs release cytokines, including type I IFNs; 3) depletion of pDCs renders mice hypersusceptible to pulmonary and intravenous challenge with A. fumigatus by a mechanism that appears to be due, at least in part, to a dysregulated immune response; and 4) pulmonary infection with A. fumigatus results in pDC influx into the lungs. We hypothesize that pDCs play a major role in host defenses against invasive aspergillosis by mediating direct antifungal activity and by modulating the innate and adaptive immune response. To address this hypothesis, we will define the contribution of pDCs in the defense against A. fumigatus using both in vitro and in vivo models. In Aim 1, we will explore the mechanistic basis of our observations that incubation of pDCs with A. fumigatus in vitro results in fungal recognition, antifungal activity and cytokine release. The receptors required for pDC recognition of the conidial and hyphal fungal morphotypes will be explored. The mechanism of pDC death induced by A. fumigatus will be elucidated. How pDCs mediate antifungal activity will be characterized using both intact pDCs and pDC lysates. Finally, the cytokine and chemokine response of pDCs to A. fumigatus will be investigated. In aim 2, we will follow up our demonstration that pDCs have a non- redundant role in host defenses against aspergillosis by illuminating the mechanisms by which this occurs. The effect of pDC depletion on mortality, fungal burden, immune cell recruitment, pathology and cytokine response will be determined in murine models of invasive aspergillosis. The arms of the immune system required for pDC-mediated protection will be examined by co-depleting pDCs and specific leukocyte subsets and with knockout mice. Lastly, we will determine whether pDCs associate with conidia and hyphae in vivo using flow cytometry and microscopy. Completion of these studies over the funding period will result in major conceptual advances in fungal pathogenesis, fungal immunology and pDC biology. Moreover, the knowledge gained may lead to novel strategies to prevent and treat invasive mycoses.

描述（由申请人提供）：曲曲霉的烟曲霉是侵入性霉菌感染的最常见原因。即使在治疗和早期诊断方面取得了进步，死亡率仍然很高。血囊性树突状细胞（PDC）构成了DC的功能不同的谱系，该谱系在用病毒刺激时迅速产生大量的I型干扰素（IFN），主要是通过基于病毒核酸的感知的机制。 PDC通过分泌细胞因子和启动T细胞将先天性与适应性免疫联系起来。 PDC和真菌之间的相互作用尚未得到很好的特征。该应用以引人注目的初步数据为基础，表明：1）人类PDC通过涉及烟曲霉诱导的PDC死亡的机制直接抑制真菌的生长； 2）在用烟曲霉刺激后，PDC释放细胞因子，包括I型IFN； 3）PDCS的耗竭使小鼠通过一种机制过于对免疫反应失调的机制，对肺和静脉内攻击的小鼠对烟曲霉的挑战过敏； 4）烟曲霉的肺部感染导致PDC涌入肺部。我们假设PDC通过介导直接的抗真菌活性并调节先天和适应性免疫反应，在防御侵入性曲霉病中起着重要作用。为了解决这一假设，我们将使用体外和IN定义PDC在防御烟曲霉的防御中的贡献 体内模型。在AIM 1中，我们将探讨观察结果的机械基础，即在体外，将PDC与烟曲霉一起孵育会导致真菌识别，抗真菌活性和细胞因子释放。将探索PDC识别分生孢子和菌丝真菌形态所需的受体。烟曲霉诱导的PDC死亡的机制将被阐明。 PDC如何使用完整的PDC和PDC裂解物来介导抗真菌活性。最后，将研究PDC对烟曲霉的细胞因子和趋化因子反应。在AIM 2中，我们将跟进我们的演示，即PDC通过阐明发生这种情况的机制，在宿主防御中具有非冗余作用。 PDC耗竭对死亡率，真菌负担，免疫细胞募集，病理学和细胞因子反应的影响将在浸润性曲霉病的鼠模型中确定。 PDC介导的保护所需的免疫系统的臂将通过共同消耗的PDC和特定的白细胞亚群和敲除小鼠来检查。最后，我们将使用流式细胞仪和显微镜确定PDC是否在体内与分生孢子和菌丝相关联。在资金期间完成这些研究将导致真菌发病机理，真菌免疫学和PDC生物学的重大概念进步。此外，获得的知识可能会导致预防和治疗侵入性真菌的新型策略。