The impact of dietary zinc deficiency on innate immunity to lung infection

缺锌是肺炎的一个主要危险因素，估计导致16%的肺炎

Zinc deficiency is a major risk factor for pneumonia, and is estimated to contribute to 16% of lower respiratory infections globally by the World Health Organization. Acinetobacter baumannii is a leading cause of ventilator associated pneumonia and is a critically important opportunistic pathogen due to its rising rates of multi-drug resistance. Patients at risk for hospital and community acquired A. baumannii are also at increased risk of zinc deficiency. Our exciting preliminary data show that zinc deficiency significantly increases mortality from A. baumannii pneumonia by 24 h post infection, and that neutralization of the type 2 cytokine IL-13 protects mice from mortality. These preliminary data form the basis of investigating the unknown mechanisms linking zinc deficiency and pneumonia that will identify new therapeutic targets to support immunity during lung infection of zinc deficient patients. The central hypothesis of this proposal is that dietary Zn deficiency promotes type 2 inflammation during lung infection, preventing A. baumannii killing by leukocytes. The research plan will identify molecular mechanisms underlying the link between zinc deficiency and pneumonia. The proposed experiments use an innovative multi-disciplinary approach to uncover potential therapeutic targets to promote lung innate immunity during infection by a multi-drug resistant organism. In order to determine the effect of Zn deficiency on leukocyte-mediated bacterial killing, we will test the effect of zinc deficiency on leukocyte function using sophisticated animal models and an engineered suite of fluorescent A. baumannii to probe the host-pathogen interface. We will additionally identify the mechanism by which Zn deficiency promotes IL-13 production and pathogenic effects. Finally, we will determine the effect of Zn deficiency on the lung epithelium in type 2 signaling and A. baumannii translocation. These aims were developed independently and form the basis of my future research program to identify the molecular mechanisms by which changes in host zinc metabolism affect susceptibility to the emerging pathogen A. baumannii.