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.

项目总结 免疫系统的先天分支和适应性分支之间的对话是现代 免疫学，对预防感染以及自身免疫性过敏性疾病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 外周组织通过其模式识别受体(PRR)感知微生物线索或 在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)。 这一过程使“信息”从周围组织转移到DLN，在DLN中依赖于抗原 启动针对病原体的适应性免疫反应。DLN还拥有一种最初的抗原非依赖性、 由迁徙的吞噬细胞控制的先天免疫反应，使LN扩张并建立 一个有利于发炎的环境。这些事件是适应性发展和两极分化所必需的 免疫反应。在这里，我们将注意力集中在念珠菌细胞壁衍生的配体的能力上。 (C.)白念珠菌决定了LN的先天反应。我们的工作假设是，大小和溶解度 激活PRRs的刺激不仅影响LN固有反应本身，还影响LN的最终结果 免疫反应。此外，由可溶性真菌配体启动的LN先天反应可以是 被利用来开发有效的保护性适应性免疫反应，以防止危及生命 系统性真菌感染。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，从而决定适应性免疫的激活 豁免权。特别是，我们发现在外周免疫沉默的小的可溶性真菌配体 并且不会在组织中引起炎症，一旦到达DLN就会成为有效的免疫原。还有，就是 由这些配体启动的层粘连蛋白先天反应完全绕过了吞噬细胞从 而是需要一种独特的基因签名，其特征是产生 干扰素，这是由被膜下非规范转录因子RelB激活所驱动的 鼻窦巨噬细胞。值得注意的是，这个过程需要Dectins，但关键的信令适配器CARD9 在迪金斯的下游，基本上是可有可无的。此外，对DLN的最初先天反应指示了一种强有力的 1型获得性免疫，并允许产生针对病毒最外层的抗体 真菌细胞壁。真菌疾病是一个全球性的健康问题，而念珠菌是最常见的原因 侵袭性真菌感染。我们建议解开如何利用PAMP的物理性质作为 针对系统性真菌感染的治疗性干预，这是美国的一个主要医疗问题。我们 预计识别解剖学上局限于LN的免疫反应的新特征将有所帮助 设计了一种针对控制不佳的病原体的改进疫苗。