Innate control of the inflammatory process during fungal infections

真菌感染期间炎症过程的先天控制

• 批准号: 10434924
• 负责人: Ivan Zanoni
• 金额: $ 52.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434924
• 关键词: Address; Adjuvant; Affect; Allergic; Anatomy; Antibodies; Antibody Formation; Antifungal Agents; Antigens; Attention; B-Lymphocytes; Bypass; Candida; Candidiasis; Cell Wall; Cells; Centers for Disease Control and Prevention (U.S.); Data; Detection; Development; Disease; Epithelial; Event; Foundations; Gene Mutation; Genetic Transcription; Goals; Health; Immune; Immune response; Immune system; Immunocompromised Host; Immunology; Incidence; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Interferon Type II; Interferons; Lectin Receptors; Life; Ligands; Location; Lymph Node Subcapsular Sinus; Mediating; Medical; Modeling; Modernization; Mycoses; Outcome; Pathway interactions; Patients; Pattern recognition receptor; Peripheral; Persons; Phagocytes; Polysaccharides; Process; Production; Role; Sentinel; Sepsis; Signal Transduction; Solubility; Stimulus; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Vaccines; adaptive immune response; adaptive immunity; autoimmune pathogenesis; candidemia; design; draining lymph node; fungus; genetic signature; global health; improved; inflammatory milieu; innovation; insight; macrophage; microbial; migration; novel; novel therapeutic intervention; pathogen; physical property; prevent; protein function; relB protein; response; therapeutically effective; treatment strategy

PROJECT SUMMARY The dialogue between innate and adaptive branches of the immune system is a central paradigm of modern immunology and is vital for protection against infections as well as for the pathogenesis of autoimmune, allergic and inflammatory diseases. According to the current model, innate immune sentinels dispersed throughout peripheral tissues sense, via their pattern recognition receptors (PRRs), the presence of microbial clues or endogenous moieties released during an infection, are activated and migrate to the draining lymph node (dLN). This process enables a transfer of “information” from peripheral tissue to the dLN, where the antigen-dependent adaptive immune response against the pathogen is initiated. The dLN also hosts an initial antigen-independent, innate immune response governed by migrating phagocytes that enables expansion of the LN and establishes a pro-inflammatory milieu. These events are required for the development and polarization of the adaptive immune response. Here, we focused our attention on the capacity of ligands derived from the cell wall of Candida (C.) albicans to dictate the LN innate response. Our working hypothesis is that the size and solubility of stimuli that activate the PRRs affect not only the LN innate response itself, but also the final outcome of the immune response. Also, that the LN innate response initiated by soluble fungal ligands can be harnessed to develop a potent and protective adaptive immune response to prevent life-threatening systemic fungal infections. Our preliminary data demonstrate that the physical form of fungal ligands dictates the location where the initial immune response takes place, and thereby determines the activation of adaptive immunity. In particular, we have found that small soluble fungal ligands that are immunosilent in the periphery and do not cause an inflammation in the tissue, become potent immunogens once they reach the dLN. Also, that the LN innate response initiated by these ligands completely bypasses the need of phagocyte migration from the periphery into the dLN and, instead, requires a unique gene signature that is characterized by the production of interferons and that is driven by the activation of the noncanonical NFkB transcription factor RelB in subcapsular sinus macrophages. Notably, Dectins are required for this process but CARD9, the key signaling adaptor downstream of Dectins, is largely dispensable. Plus, the initial innate response to the dLN instructs a potent type 1 adaptive immunity and allows the production of antibodies directed against the most external layer of the fungal cell wall. Fungal diseases are a global health problem and Candida species are the most common cause of invasive fungal infections. We propose to unravel how physical properties of the PAMPs can be harnessed as a therapeutic intervention against systemic fungal infections that are a major medical problem in the US. We anticipate that identifying new features of the immune response that is anatomically restricted to the LN will help with the design of an improved vaccine against poorly controlled pathogens.

项目概要 免疫系统的先天性分支和适应性分支之间的对话是现代免疫系统的核心范例 免疫学，对于预防感染以及自身免疫、过敏的发病机制至关重要 和炎症性疾病。根据目前的模型，先天免疫哨兵分散在各处 外周组织通过其模式识别受体（PRR）感知微生物线索的存在或 感染期间释放的内源性部分被激活并迁移到引流淋巴结（dLN）。 这个过程能够将“信息”从外周组织转移到 dLN，其中抗原依赖性 针对病原体的适应性免疫反应开始。 dLN 还承载着初始的不依赖于抗原的、 由迁移吞噬细胞控制的先天免疫反应使 LN 扩张并建立 促炎环境。这些事件是适应性的发展和极化所必需的 免疫反应。在这里，我们重点关注源自念珠菌细胞壁的配体​​的能力 (C.) 白色念珠菌来决定 LN 的先天反应。我们的工作假设是尺寸和溶解度 激活 PRR 的刺激不仅影响 LN 的先天反应本身，而且还影响 LN 的最终结果。 免疫反应。此外，由可溶性真菌配体引发的 LN 固有反应可以是 用于开发有效的保护性适应性免疫反应，以预防危及生命的情况 全身性真菌感染。我们的初步数据表明真菌配体的物理形式决定了 初始免疫反应发生的位置，从而决定适应性的激活 免疫。特别是，我们发现外周免疫沉默的小可溶性真菌配体 并且不会引起组织炎症，一旦到达 dLN，就会成为有效的免疫原。还有，那个 由这些配体引发的 LN 固有反应完全绕过了吞噬细胞从 LN 迁移的需要。 外围进入 dLN，相反，需要一个独特的基因签名，其特征是产生 干扰素，由荚膜下非典型 NFkB 转录因子 RelB 的激活驱动 窦巨噬细胞。值得注意的是，该过程需要 Dectins，但关键信号适配器 CARD9 Dectins 的下游，很大程度上是可有可无的。另外，对 dLN 的最初先天反应会指示出一种有效的 1 型适应性免疫，并允许产生针对最外层的抗体 真菌细胞壁。真菌疾病是一个全球性的健康问题，念珠菌是最常见的原因 侵袭性真菌感染。我们建议阐明如何利用 PAMP 的物理特性 针对系统性真菌感染的治疗干预，这是美国的一个主要医学问题。我们 预计识别解剖学上仅限于淋巴结的免疫反应的新特征将有助于 设计针对控制不良的病原体的改进疫苗。