Metal withholding responses in the gut mucosa

描述（由申请人提供）：粘膜表面通常是宿主、正常菌群和致病菌之间的第一界面。粘膜上皮参与维持与正常菌群的平衡，并构成黏膜屏障对抗病原体。宿主应对细菌感染的一种策略是通过限制必需营养素和金属（如铁和锌）的可用性来抑制细菌生长。金属抑制反应在肠道黏膜中对病原体的反应和与微生物群的动力学中的作用尚不清楚。我们的长期目标是了解上皮细胞通过与常驻微生物群相互作用和对粘膜病原体作出反应而构成粘膜屏障的机制。本应用的目的是研究金属在肠道粘膜中的作用，以及它是如何在细菌感染的反应中被触发的。我们的中心假设是，在对细菌感染的反应中，肠上皮细胞分泌脂钙素-2和钙保护蛋白，这两种抗菌肽分别隔离铁和锌。虽然粘膜病原体对金属滞留有抵抗力，因此定植在肠道，但常驻微生物群的生长受到抑制。我们计划通过追求以下具体目标来检验我们的假设并实现本申请的目标：1。确定细菌感染期间肠道粘膜中金属滞留是如何诱导的。我们将验证在细菌感染期间上皮细胞对IL-17和IL-22刺激的反应中分泌脂钙素-2和钙保护蛋白的假设。2. 确定细菌感染期间肠道粘膜中金属抑制反应的作用。我们将验证肠道对脂钙素-2介导的铁饥饿和钙保护蛋白介导的锌饥饿的抵抗是否有助于炎症期间细菌的定植。提出的工作是创新的，因为它建立了新的概念，上皮作为粘膜屏障的组成部分，在其与病原体和常驻微生物群的动态作用。这是我们的期望，这项研究的结果将确定在细菌感染期间金属保留反应的作用。这一结果将具有重要意义，因为它将有助于理解上皮细胞、共生细胞和病原体之间在粘膜表面的复杂相互作用。粘膜上皮参与维持与正常菌群的平衡，并构成黏膜屏障对抗病原体。宿主应对细菌感染的一种策略是通过限制必需营养素和金属（如铁和锌）的可用性来抑制细菌生长。金属抑制反应在肠道黏膜中对病原体的反应和与微生物群的动力学中的作用尚不清楚。

DESCRIPTION (provided by applicant): The mucosal surfaces are often the first interface between the host, the normal flora, and pathogenic bacteria. The mucosal epithelium is involved in maintaining the homeostasis with the normal flora and in constituting the mucosal barrier against pathogens. One host strategy in response to bacterial infection is to inhibit bacterial growth by limiting availability of essential nutrients and metals, like iron and zinc. The role of metal withholding responses in the gut mucosa in response to pathogens and in the dynamics with the microbiota is not well understood. Our long-range goal is to understand the mechanisms by which epithelial cells constitute the mucosal barrier by interacting with the resident microbiota and responding to mucosal pathogens. The objectives of this application are to investigate the role of metal withholding in the gut mucosa and how it is triggered in response to bacterial infection. Our central hypothesis is that in response to bacterial infection intestinal epithelial cells secrete lipocalin-2 and calprotectin, two antimicrobial peptides that sequester iron and zinc, respectively. While mucosal pathogens are resistant to metal withholding and thus colonize the gut, growth of the resident microbiota is suppressed. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following specific aims: 1. Determine how metal withholding is induced in the gut mucosa during bacterial infections. We will test the hypothesis that lipocalin-2 and calprotectin are secreted by epithelial cells in response to IL-17 and IL-22 stimulation during bacterial infection. 2. Determine the role of metal withholding responses in the gut mucosa during bacterial infections. We will test the hypothesis that resistance to lipocalin-2-mediated iron starvation and calprotectin-mediated zinc starvation in the gut facilitate bacterial colonization during inflammation. The proposed work is innovative because it establishes new concepts on the role of the epithelium as component of the mucosal barrier in its dynamics with pathogens and the resident microbiota. It is our expectation that the outcome of this study will identify the role of metal withholding responses during bacterial infections. This outcome will be significant because it will contribute to understanding the complex interplay at the mucosal surfaces between epithelial cells, commensals and pathogens. The mucosal epithelium is involved in maintaining the homeostasis with the normal flora and in constituting the mucosal barrier against pathogens. One host strategy in response to bacterial infection is to inhibit bacterial growth by limiting availability of essential nutrients and metals, like iron and zinc. The role of metal withholding responses in the gut mucosa in response to pathogens and in the dynamics with the microbiota is not well understood.