Influenza is a leading cause of human morbidity and mortality worldwide. In the United States, influenza is responsible for more than 30,000 deaths and 250,000 hospitalizations annually. The molecular mechanisms involved in the interaction of virus-infected resident lung cells and transmigrating antigen-presenting cell (APC) precursors that are recruited in response to viral infection have not been defined fully. Studies have shown that the highly pathogenic influenza strains lead to cytokine dysregulation and a massive infiltration of APC precursors into the lungs. The more pathogenic strains ofthe virus may alter cytokine/chemokine production of the alveolar epithelial cells and alveolar macrophages leading to increased migration and differentiation of activated APCs that drive an excessive inflammatory response. Our goal is to develop a tissue-equivalent respiratory model (TERM) that exhibits a normal immunological response against infectious agents, and to use the model to study the molecular cross talk between influenza-infected resident lung cells and transmigrating APCs. The TERM can be used to study the interplay of cell types within a complex environment, and it can be dissolved easily to isolate and study single cell populations. We propose to develop the TERM and to define the contribution of each cell type to the excessive inflammatory response in a model recapitulating normal human lung with the following specific aims: 1) Create and characterize the TERM, 2) Use the TERM to determine differential abilities of a very pathogenic strain (H1N1) of influenza and a mildly pathogenic strain (H3N2) to drive key differences in the response of alveolar epithelial cells and macrophages that would result in a pathologic proinflammatory response or a protective antiviral immune response, and 3) Validate the TERM with a human lung organ culture model and an animal model of influenza. A better understanding of these mechanisms can aid in the control ofthe delicate balance of an essential innate immune response to control early viral replication and an excessive inflammatory response that leads to cytokine-associated immunopathology.
This project uses a novel tissue-equivalent respiratory model (TERM) to identify the key mechanisms associated with the ability of pathogenic strains ofthe influenza virus to attract and differentiate lung cells to a highly inflammatory phenotype. These mechanisms will provide new targets for preventative and therapeutic interventions of influenza infection that will be tested in the TERM.
|Zhu, Liqian; Thunuguntla, Prasanth; Liu, Yilin et al. (2017) The ?-catenin signaling pathway stimulates bovine herpesvirus 1 productive infection. Virology 500:91-95|
|Feng, Yu; Zhao, Jianan; Chen, Xiaole et al. (2017) An In Silico Subject-Variability Study of Upper Airway Morphological Influence on the Airflow Regime in a Tracheobronchial Tree. Bioengineering (Basel) 4:|
|Eberle, R; Maxwell, L K; Nicholson, S et al. (2017) Genome sequence variation among isolates of monkey B virus (Macacine alphaherpesvirus 1) from captive macaques. Virology 508:26-35|
|Wang, Xiaoqiu; Wu, Wenxin; Zhang, Wei et al. (2017) RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection. Respir Res 18:166|
|Premaratne, Gayan; Al Mubarak, Zainab H; Senavirathna, Lakmini et al. (2017) Measuring Ultra-low Levels of Nucleotide Biomarkers Using Quartz Crystal Microbalance and SPR Microarray Imaging Methods: A Comparative Analysis. Sens Actuators B Chem 253:368-375|
|Fu, Bishi; Zhao, Mengmeng; Wang, Lingyan et al. (2017) RNAi Screen and Proteomics Reveal NXF1 as a Novel Regulator of IRF5 Signaling. Sci Rep 7:2683|
|Wu, Lei; Guo, Xin; Hartson, Steven D et al. (2017) Lack of ?, ?-carotene-9', 10'-oxygenase 2 leads to hepatic mitochondrial dysfunction and cellular oxidative stress in mice. Mol Nutr Food Res 61:|
|Fu, Bishi; Wang, Lingyan; Li, Shitao et al. (2017) ZMPSTE24 defends against influenza and other pathogenic viruses. J Exp Med 214:919-929|
|Zeng, Xiangming; Huang, Chaoqun; Senavirathna, Lakmini et al. (2017) miR-27b inhibits fibroblast activation via targeting TGF? signaling pathway. BMC Cell Biol 18:9|
|Zhu, Liqian; Thompson, Jesse; Ma, Fangrui et al. (2017) Effects of the synthetic corticosteroid dexamethasone on bovine herpesvirus 1 productive infection. Virology 505:71-79|
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