Innate control of the inflammatory process during fungal infections

项目摘要 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的中心范式。 免疫学和是至关重要的保护免受感染以及发病机制的自身免疫性，过敏 和炎症性疾病。根据目前的模型，先天免疫哨兵分散在整个 外周组织通过它们的模式识别受体（PRR）感知微生物线索的存在， 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）。 该过程使得“信息”能够从外周组织转移到dLN，在dLN中抗原依赖性的免疫应答被激活。 启动针对病原体的适应性免疫应答。dLN还具有初始的抗原非依赖性， 先天性免疫反应由迁移的吞噬细胞控制，使LN扩张并建立 一个促炎的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，我们集中我们的注意力，从念珠菌细胞壁衍生的配体的能力， （C.）白念珠菌决定LN的先天反应。我们的工作假设是， 激活PRRs的刺激不仅影响LN固有反应本身，而且影响LN的最终结果。 免疫反应。此外，由可溶性真菌配体引发的LN先天性应答可以是 利用它来发展一种有效的和保护性的适应性免疫反应， 全身真菌感染。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，从而决定了适应性免疫反应的激活。 免疫力特别是，我们发现在外周免疫沉默的小的可溶性真菌配体， 并且不会引起组织炎症，一旦到达dLN就成为有效的免疫原。还有那个 由这些配体引发的LN先天性应答完全绕过了吞噬细胞从淋巴结迁移的需要， 外周进入dLN，而是需要一个独特的基因签名，其特征在于产生 干扰素，并由包膜下非经典NFkB转录因子RelB的激活驱动 窦巨噬细胞值得注意的是，这个过程需要Dectins，但关键的信号转导适配器CARD9 德廷斯的下游，很大程度上是水。另外，最初对dLN的先天反应指示了一种强有力的 1型适应性免疫，并允许产生针对最外层的抗体。 真菌细胞壁真菌性疾病是一个全球性的健康问题，念珠菌属是最常见的原因 侵袭性真菌感染我们建议解开如何利用PAMP的物理特性， 一种针对全身性真菌感染的治疗干预，在美国这是一个主要的医疗问题。我们 我预计，识别解剖学上局限于LN的免疫反应的新特征将有助于 设计一种针对控制不佳的病原体的改进疫苗。

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.