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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-TWD-A (CB))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oklahoma State University Stillwater
United States
Zip Code
Mishra, Amarjit; Guo, Yujie; Zhang, Li et al. (2016) A Critical Role for P2X7 Receptor-Induced VCAM-1 Shedding and Neutrophil Infiltration during Acute Lung Injury. J Immunol 197:2828-37
Wu, Wenxin; Zhang, Wei; Booth, J Leland et al. (2016) Human primary airway epithelial cells isolated from active smokers have epigenetically impaired antiviral responses. Respir Res 17:111
Wang, Lingyan; Li, Wenjun; Li, Shitao (2016) A High Throughput Assay for Screening Host Restriction Factors and Antivirals Targeting Influenza A Virus. Front Microbiol 7:858
Wu, Lei; Guo, Xin; Wang, Weiqun et al. (2016) Molecular aspects of β, β-carotene-9', 10'-oxygenase 2 in carotenoid metabolism and diseases. Exp Biol Med (Maywood) 241:1879-1887
Sahoo, Kaustuv; Koralege, Rangika S Hikkaduwa; Flynn, Nicholas et al. (2016) Nanoparticle Attachment to Erythrocyte Via the Glycophorin A Targeted ERY1 Ligand Enhances Binding without Impacting Cellular Function. Pharm Res 33:1191-203
Patel, Vineet Indrajit; Metcalf, Jordan Patrick (2016) Identification and characterization of human dendritic cell subsets in the steady state: a review of our current knowledge. J Investig Med 64:833-47
Rudd, Jennifer M; Ashar, Harshini K; Chow, Vincent Tk et al. (2016) Lethal Synergism between Influenza and Streptococcus pneumoniae. J Infect Pulm Dis 2:
Narasaraju, Teluguakula; Harshini, Ashar (2016) Neutrophils as Possible Therapeutic Targets in Severe Influenza Pneumonia. J Infect Pulm Dis 2:
Xiao, Xiao; Huang, Chaoqun; Zhao, Chunling et al. (2015) Regulation of myofibroblast differentiation by miR-424 during epithelial-to-mesenchymal transition. Arch Biochem Biophys 566:49-57
Wu, Wenxin; Zhang, Wei; Duggan, Elizabeth S et al. (2015) RIG-I and TLR3 are both required for maximum interferon induction by influenza virus in human lung alveolar epithelial cells. Virology 482:181-8

Showing the most recent 10 out of 20 publications