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

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1)
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Oklahoma State University Stillwater
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