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(肺炎球菌)仍然是美国CAP最常见的原因。 继续上升，导致住院和死亡率增加。CAP的一个主要原因是 脆弱人群的免疫功能。锌是正常免疫功能所必需的，但不足。 饮食摄入量在脆弱人群中非常普遍。锌缺乏的人更容易患上 病原体和肺炎的发病率较高，而补锌则降低了 肺炎。该项目的长期目标是确定人类锌转运蛋白ZIP8和ZIP8的作用 膳食锌摄入量在肺炎球菌肺炎宿主免疫反应中的作用我们小组最先揭开了 ZIP8是接触细菌后髓系细胞激活所必需的。这一点很重要，因为一个亲戚 在寄主环境中，由于饲料限制或ZIP8介导的锌转运不足而导致的锌缺乏 对肺部细菌入侵的反应会导致免疫功能障碍，增加肺损伤，并导致 死亡率(见初步数据)。我们推测ZIP8在肺巨噬细胞和树突状细胞中起着关键作用。 通过维持先天免疫反应和获得性免疫反应的良好平衡。因此，是有缺陷的 锌的摄入或ZIP8功能抑制了锌促进正常免疫功能和宿主防御的能力。如果 证明是正确的，这将对肺炎的发病机制有重要的影响，并增加我们的能力 预测疾病易感性，预防发病率和死亡率。在强有力的初步证据的指导下，这 假设将通过追求三个具体目标来检验，这三个目标将：1)确定ZIP8损失对 活体肺髓系形态及其对病原体清除和宿主存活的影响；2)确定 ZIP8对巨噬细胞和DC功能的影响；以及3)确定补锌对 肺炎链球菌体内锌代谢紊乱的设置。为了实现我们的目标，我们有 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 以及一个膳食锌限制模型，该模型将探索锌转运蛋白ZIP8在维持 肺炎球菌肺炎中髓系细胞驱动的免疫平衡。在成功完成 这项研究，我们将更好地理解锌稳态和ZIP8之间的相互作用 肺部肺炎球菌感染。预计这将产生积极影响，因为它将揭示之前 在宿主防御中起重要作用的未知分子途径。此外，我们有可能确定 新的微量营养素和基因监测以及治疗战略，将提高我们预防 肺炎球菌肺炎在全世界最脆弱的人群中。我们预计，这也将为 为治疗或预防其他有害病原体提供新的方法。

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.