Unprecedented and frequent outbreaks by influenza viruses with rapid world-wide spread portend considerable global threats and are a major public health concern. Complications of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury, remain major causes of death in influenza pneumonia. Due to high mutation rates introduced by the viral RNA polymerase and consequent resistance to antiviral drugs, controlling influenza-induced morbidity and mortality is a major challenge. Although typespecific immunization is effective, treatment of non-immunized infected patients with current antiviral agents is relatively ineffective. Because the pathology of the disease is largely mediated by the host response to infection, a therapeutic approach targeting both the virus and the host response is desirable. The objective of this project is to understand the role of neutrophils in the pathogenesis of influenza virus and to develop a 'combination drug therapy'that targets both neutrophil-induced acute lung injury and the virus itself. Influenza infection in mice induces excessive neutrophil influx and high cytokine response in the lungs, which contributes to the immunopathology. Although neutrophil-mediated lung injury is clearly linked with influenza pathogenesis, the phenotypic characteristics and functional responsiveness of the neutrophils mediating the damage are not completely known. Preliminary studies show that C-C chemokine receptor type 1 and type 3 (CCR1 and CCRS) are induced in neutrophils during influenza infection and that these neutrophils produce neutrophil extracellular traps, which exacerbate lung injury by causing endothelial damage. Overall hypothesis of this proposal is that induced CCR1 and CCR3 in neutrophils during influenza virus infection alter neutrophil's functions and induction of neutrophil extracellular traps, thus contributing to lung injury. This hypothesis will be tested by evaluating CCRI and CCRS regulation during influenza virus pneumonia (Aim I) and establish the functional roles of induced CCR1 and CCRS in neutrophils in acute lung injury (Aim II). The results will be used to develop a combination drug therapy targeting neutrophil-mediated acute lung injury and the virus itself (Aim III). These studies may lead to the development of new therapeutic treatments for influenza pneumonia.

Public Health Relevance

The difficulty in vaccine preparation due to unprecedented emergence of new strains and high mutative ability of the virus, controlling influenza-induced morbidity and mortality is a major challenge. Because the pathology ofthe disease is largely mediated by the host response to infection, a therapeutic approach targeting both the virus and the host response is desirable, especially in influenza outbreaks. Thus, this proposal addresses a maior problem in inflenza treament

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103648-02
Application #
8686895
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oklahoma State University Stillwater
Department
Type
DUNS #
City
Stillwater
State
OK
Country
United States
Zip Code
74078
Ektate, Kalyani; Munteanu, Maria Cristina; Ashar, Harshini et al. (2018) Chemo-immunotherapy of colon cancer with focused ultrasound and Salmonella-laden temperature sensitive liposomes (thermobots). Sci Rep 8:13062
Haghnegahdar, Ahmadreza; Feng, Yu; Chen, Xiaole et al. (2018) Computational Analysis of Deposition and Translocation of Inhaled Nicotine and Acrolein in the Human Body with E-cigarette Puffing Topographies. Aerosol Sci Technol 52:483-493
Zhu, Liqian; Jones, Clinton (2018) The canonical Wnt/?-catenin signaling pathway stimulates herpes simplex virus 1 productive infection. Virus Res 256:29-37
Ashar, Harshini K; Mueller, Nathan C; Rudd, Jennifer M et al. (2018) The Role of Extracellular Histones in Influenza Virus Pathogenesis. Am J Pathol 188:135-148
Patil, Girish; Zhao, Mengmeng; Song, Kun et al. (2018) TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection. J Virol 92:
Senavirathna, Lakmini Kumari; Huang, Chaoqun; Yang, Xiaoyun et al. (2018) Hypoxia induces pulmonary fibroblast proliferation through NFAT signaling. Sci Rep 8:2709
Booth, J Leland; Duggan, Elizabeth S; Patel, Vineet I et al. (2018) Gene expression profiling of primary human type I alveolar epithelial cells exposed to Bacillus anthracis spores reveals induction of neutrophil and monocyte chemokines. Microb Pathog 121:9-21
Maria, Zahra; Lacombe, VĂ©ronique A (2018) Quantification of Cell-Surface Glucose Transporters in the Heart Using a Biotinylated Photolabeling Assay. Methods Mol Biol 1713:229-240
Workman, Aspen; Zhu, Liqian; Keel, Brittney N et al. (2018) The Wnt Signaling Pathway Is Differentially Expressed during the Bovine Herpesvirus 1 Latency-Reactivation Cycle: Evidence That Two Protein Kinases Associated with Neuronal Survival, Akt3 and BMPR2, Are Expressed at Higher Levels during Latency. J Virol 92:
McGill, Jodi L; Wang, Ying; Ganta, Chanran K et al. (2018) Antigen-Specific CD4+CD8+ Double-Positive T Cells Are Increased in the Blood and Spleen During Ehrlichia chaffeensis Infection in the Canine Host. Front Immunol 9:1585

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