Innate control of the inflammatory process during fungal infections

真菌感染期间炎症过程的先天控制

基本信息

批准号：
10641775
负责人：
Ivan Zanoni
金额：
$ 51.38万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10641775
关键词：
Address Adjuvant Affect Allergic Disease Anatomy Antibodies Antibody Formation Antifungal Agents Antigens Attention Autoimmune Diseases B-Lymphocytes Binding Bypass C Type Lectin Receptors Candida Candida albicans Candidiasis Cell Wall Cells Centers for Disease Control and Prevention (U.S.)Data Detection Development Disease Epithelium Event 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 Life Ligands Location Lymph Node Subcapsular Sinus Macrophage Mediating Medical Modeling Modernization Mycoses NF-kappa B Outcome Pathway interactions Patients Pattern recognition receptor Peripheral Persons Phagocytes Polysaccharides Predisposition Process Production Role Sentinel Sepsis Signal Transduction Solubility Stimulus 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 microbial migration novel novel therapeutic intervention pathogen physical property prevent protein function relB protein response therapeutically effective

项目摘要

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.

项目摘要免疫系统的先天和适应性分支之间的对话是现代的中心范式免疫学对于防御感染以及自身免疫性过敏性的发病机理至关重要和炎症性疾病。根据当前的模型，先天免疫哨兵分散了外围组织通过其模式识别受体（PRR），微生物线索或感染期间释放的内源性部分被激活，并迁移到排水淋巴结（DLN）。该过程使“信息”从外围组织转移到DLN，抗原依赖性启动针对病原体的自适应免疫反应。 DLN还托管一个初始抗原独立的，先天免疫反应由迁移的吞噬细胞迁移，该吞噬细胞能够扩展LN并建立亲炎的环境。这些事件是自适应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源自念珠菌细胞壁的配体能力上（C.）白色疾病决定LN先天反应。我们的工作假设是激活PRR的刺激不仅会影响LN先天反应本身，还会影响免疫反应。此外，坚固真菌配体发起的LN先天反应可以是利用以发展潜在和受保护的适应性免疫反应以防止威胁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，从而确定适应性的激活免疫。特别是，我们发现在周围免疫的小固体真菌配体并且不会在组织中注射注射，一旦到达DLN，就会成为潜在的免疫原子。另外，这些配体发起的LN先天反应完全绕过了对吞噬细胞迁移的需求外围进入DLN，相反，需要一个独特的基因特征，其特征是产生干扰素，这是由亚囊中非规范NFKB转录因子RELB的激活所驱动的鼻窦巨噬细胞。值得注意的是，此过程需要Dectin，但Card9是关键信号适配器下游的dectins基本上是可分配的。另外，最初对DLN的先天反应指示有效 1型自适应免疫，并允许针对最外层的抗体产生真菌细胞壁。真菌疾病是全球健康问题，念珠菌物种是最常见的原因侵入性真菌感染。我们建议解散如何将弹丸的物理特性当作在美国，是针对全身真菌感染的治疗干预措施。我们预计确定在解剖学上仅限于LN的免疫响应的新功能将有所帮助通过针对无法控制的病原体进行改进的疫苗设计。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Microbiome studies in the medical sciences and the need for closer multidisciplinary interplay.

医学中的微生物组研究以及更密切的多学科相互作用的需要。

DOI：
10.1126/scisignal.aba9911
发表时间：
2020
期刊：
Science signaling
影响因子：
7.3
作者：
Mancini,Nicasio;Peri,Francesco;Rescigno,Maria;Zanoni,Ivan
通讯作者：
Zanoni,Ivan

μMAPPS: a novel phasor approach to second harmonic analysis for in vitro-in vivo investigation of collagen microstructure.

DOI：
10.1038/s41598-017-17726-y
发表时间：
2017-12-12
期刊：
Scientific reports
影响因子：
4.6
作者：
Radaelli F;D'Alfonso L;Collini M;Mingozzi F;Marongiu L;Granucci F;Zanoni I;Chirico G;Sironi L
通讯作者：
Sironi L

Immunobiology of Carbohydrates: Implications for Novel Vaccine and Adjuvant Design Against Infectious Diseases.