Defective Zn Homeostasis impairs host defense against pneumococcal pneumonia

社区获得性肺炎（CAP）是世界范围内发病率和死亡率的主要原因。链球菌 肺炎球菌（pneumococcus）仍然是美国CAP最常见的病因。 继续上升，导致住院率和死亡率上升。CAP的主要原因是 脆弱人群的免疫功能。锌（Zn）是必要的适当的免疫功能和不足 饮食摄入在弱势群体中非常普遍。锌缺乏的受试者更容易患上 病原体，并有较高的发病率肺炎，而锌补充剂降低发病率 肺炎该项目的长期目标是确定人类锌转运蛋白ZIP 8的作用， 膳食锌摄入量在宿主对肺炎球菌肺炎的免疫应答中的作用。我们是第一个发现 ZIP 8是暴露于细菌后骨髓细胞活化所必需的。这是相关的，因为一个亲戚 锌缺乏，无论是通过饮食限制或ZIP 8介导的锌转运缺陷，在宿主的设置 对肺部细菌入侵的反应导致免疫功能障碍，增加肺损伤， 死亡率（见初步数据）。我们假设ZIP 8在肺巨噬细胞和树突状细胞中起着关键作用。 通过维持先天性和适应性免疫反应的有利平衡来保护细胞。因此，缺陷 锌摄入或ZIP 8功能抑制锌促进正常免疫功能和宿主防御的能力。如果 被证明是正确的，这将对肺炎发病机制产生重要影响，并提高我们的能力， 预测疾病易感性，预防发病率和死亡率。根据初步证据， 假设将通过追求三个具体目标进行测试，这些目标将：1）确定ZIP 8损失对 体内肺髓样景观及其对病原体清除和宿主存活的影响; 2）确定 ZIP 8如何影响巨噬细胞和DC功能;以及3）确定Zn补充对 肺炎球菌肺炎在体内锌稳态失调的设置。为了实现我们的目标， 组建了一个强大而经验丰富的团队，将在两个新的基因敲除小鼠模型中进行新的研究 以及一个饮食锌限制的模型，该模型将探索锌转运蛋白ZIP 8在维持 髓样细胞驱动的免疫平衡在肺炎球菌肺炎的设置。在圆满完成 这项研究，我们将更好地了解锌稳态和ZIP 8之间的相互作用， 肺部肺炎球菌感染预计这将产生积极的影响，因为它将揭示以前 在宿主防御中起重要作用的未知分子途径。此外，我们有可能识别出 新的微量营养素和遗传监测以及治疗策略，将提高我们的能力， 肺炎球菌肺炎在世界上最脆弱的人群。我们设想，这也将有助于 新的方法来治疗或预防其他有害的病原体。

Community acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Streptococcus pneumoniae (pneumococcus) remains the most common cause of CAP in the U.S. The incidence of CAP continues to rise contributing to increased hospitalization and mortality. A major cause of CAP is decline in immune function in vulnerable populations. Zinc (Zn) is required for proper immune function and insufficient dietary intake is highly prevalent within vulnerable populations. Zn deficient subjects are more susceptible to pathogens and have a higher incidence of pneumonia whereas Zn supplementation reduces the incidence of pneumonia. The long-term goal of this project is to determine the role of the human zinc transporter ZIP8 and dietary Zn intake in the host immune response to pneumococcal pneumonia. Our group was the first to reveal that ZIP8 is required for myeloid cell activation following exposure to bacteria. This is relevant because a relative deficit of Zn, either by dietary restriction or deficits in ZIP8-mediated Zn transport, in the setting of the host response to bacterial invasion in the lung leads to immune dysfunction, increased lung damage, and higher mortality (see preliminary data). We hypothesize that ZIP8 plays a pivotal role in lung macrophages and dendritic cells by maintaining favorable balance of both the innate and adaptive immune response. Accordingly, defective Zn intake or ZIP8 function prohibits the ability of Zn to facilitate normal immune function and host defense. If proven correct, this will have important implications on pneumonia pathogenesis and increase our capacity to predict disease susceptibility and prevent morbidity and mortality. Guided by strong preliminary evidence, this hypothesis will be tested by pursuing three specific aims that will: 1) Determine the impact of ZIP8 loss on the lung myeloid landscape in vivo and its impact on pathogen clearance and host survival; 2) Determine how ZIP8 impacts Macrophage and DC function; and 3) Determine the impact of Zn supplementation on pneumococcal pneumonia in vivo in the setting of Zn dyshomeostasis. To accomplish our goals we have assembled a strong and experienced team that will pursue novel studies in two novel knockout mouse models and a model of dietary Zn restriction that will explore the role of the zinc transporter protein ZIP8 in maintaining myeloid cell-driven immune balance in the setting pneumococcal pneumonia. At the successful completion of this study, we will better understand the interplay between Zn homeostasis and ZIP8 in the context of pneumococcal infection in the lung. This is expected to have a positive impact because it will reveal previously unidentified molecular pathways that are instrumental in host defense. Further, we have the potential to identify novel micronutrient and genetic surveillance as well as treatment strategies that will improve our ability to prevent pneumococcal pneumonia in the most vulnerable populations worldwide. We envision that this will also lend itself to new approaches to treat or prevent other harmful pathogens.