Acute lower respiratory tract infections cause a tremendous burden of disease, and an improved understanding of lung immunity and host defense will contribute to advances against such infections. Epithelial cells of the lung form the interface between the body and inhaled or aspirated microbes. Mutations of NF-?B or STAT3 signaling pathways in subsets of epithelial cells are sufficient to exacerbate infection and injury during pneumonia, identifying transcriptional responses from these cells as critical to outcome. However, the roles of epithelial cells in immune responses during pneumonia are understood at only the most superficial levels at present. We do not know which cells make which products for which purposes. The proposed research program will address these major knowledge gaps. We have collected preliminary data which yield initial insights into epithelial biology during pneumonia and provide specific directions for the research. Major goals of the proposed studies will be to better define the expression of immune products by type II cells and type I cells during pneumonia and to determine their significance. We postulate that epithelial cells are unique sources of select immune mediators including CXCL5, GM-CSF, and CCL20, and these products are differentially regulated during distinct infections. We further postulate that NF-?B RelA-dependent epithelial cell responses are essential to recruiting neutrophils, dendritic cells, and lymphocytes to the lungs for innate and adaptive immune responses mediating host defense. We propose the central hypothesis that activation of NF-?B RelA in alveolar epithelial cells directs innate and adaptive immune responses to bacteria in the lung. We will test this hypothesis by pursuing integrated and mutually informative sets of studies that test immune roles of epithelial responses to bacteria in the lung, using a suite of approaches that include an innovative mouse model in which NF-?B RelA is targeted throughout all epithelial cells of the lung, innovative cell sorting strategies for distinguishing transcriptional responses of type II an type I alveolar epithelial cells, and innovative infection models to elucidate how epithelial cells and heterotypic immunity intersect during lung infection. Completion of these proposed studies will fill major knowledge gaps by elucidating epithelial-specific roles of NF-?B RelA-mediated gene expression, discriminating responses of type II cells and type I cells, and unraveling cellular interactions underlying heterotypic immunity in the lungs. This improved knowledge of cellular roles and cytokine functions critical to lung host defense will guide further studies with goals of identifying subjects particularly susceptible to pneumonia and of developing therapeutics to enhance lung immunity and prevent or treat infections.
Pneumonia causes a tremendous public health impact. The basic mechanisms of host defense against microbes in the lung are poorly understood. By elucidating immune functions of epithelial cells and their cytokine products during lung infection, the proposed studies will address major knowledge gaps and help guide future studies aiming to develop diagnostics for identifying susceptible individuals and therapeutics to prevent or cure infection.
|Kamata, Hirofumi; Yamamoto, Kazuko; Wasserman, Gregory A et al. (2016) Epithelial Cell-Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia. Am J Respir Cell Mol Biol 55:407-18|
|Hilliard, Kristie L; Allen, Eri; Traber, Katrina E et al. (2015) The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia. Am J Respir Cell Mol Biol 53:378-90|
|Traber, Katrina E; Hilliard, Kristie L; Allen, Eri et al. (2015) Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia. Am J Respir Cell Mol Biol 53:479-88|
|Quinton, Lee J; Mizgerd, Joseph P (2015) Dynamics of lung defense in pneumonia: resistance, resilience, and remodeling. Annu Rev Physiol 77:407-30|
|Hilliard, Kristie L; Allen, Eri; Traber, Katrina E et al. (2015) Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia. Infect Immun 83:4015-27|
|Ubags, Niki D; Vernooy, Juanita H; Burg, Elianne et al. (2014) The role of leptin in the development of pulmonary neutrophilia in infection and acute lung injury. Crit Care Med 42:e143-51|
|Hyatt, Lynnae D; Wasserman, Gregory A; Rah, Yoon J et al. (2014) Myeloid ZFP36L1 does not regulate inflammation or host defense in mouse models of acute bacterial infection. PLoS One 9:e109072|
|Mizgerd, Joseph P (2014) The infant nose. Introducing the respiratory tract to the world. Am J Respir Crit Care Med 190:1206-7|
|Yamamoto, Kazuko; Ahyi, Ayele-Nati N; Pepper-Cunningham, Zachary A et al. (2014) Roles of lung epithelium in neutrophil recruitment during pneumococcal pneumonia. Am J Respir Cell Mol Biol 50:253-62|
|Wilson, Andrew A; Kwok, Letty W; Porter, Emily L et al. (2013) Lentiviral delivery of RNAi for in vivo lineage-specific modulation of gene expression in mouse lung macrophages. Mol Ther 21:825-33|
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