CCSP IN INNATE DEFENSE AGAINST LUNG VIRAL INFECTION

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The present application seeks to determine the role of Clara cell secretory protein (CCSP) in modulating host responses to viral infection in vivo. The lung is continually exposed to inhaled pathogens; yet, in healthy individuals, it remains remarkably free from infection. CCSP is an abundant protein of the lung airway fluid, and may have anti- inflammatory properties. Thus, CCSP may constitute an important component of the innate immune system of the lung. CCSP is decreased in the lungs of smokers and patients with ARDS, suggesting a role for CCSP in the modulation of host inflammatory responses. Viral infection is a major cause of lung disease in humans, especially children. To directly determine the role of CCSP in vivo, gene-targeted mice lacking CCSP (CCSP -/-) were generated. These mice survive normally, with no apparent abnormalities. However, recent experiments demonstrate that CCSP -/- mice are susceptible to pulmonary adenoviral infection. CCSP - /-mice following adenoviral infection have increased infiltration of inflammatory cells early during the course of viral-induced inflammation. The infiltrating inflammatory cells consist predominantly of neutrophils. Cytokine and chemokine production is also increased in the lungs of CCSP -/- mice following adenoviral infection, coinciding with the infiltration of inflammatory cells into the lung. These results suggest that CCSP alters the host response to pulmonary adenoviral infection in vivo and may constitute an important mechanism of innate defense in the lung. The present application tests the hypothesis that CCSP modulates host responses through the regulation of lung phagocyte function and augments viral clearance during infection. To determine the role of CCSP in viral innate defense, experiments will determine if CCSP alters phagocyte activation and function in vivo following adenoviral infection. Viral uptake and killing will be assessed in the lungs of CCSP -/- mice following adenoviral infection to determine the role of CCSP in viral clearance. Temporal studies of recombinant CCSP (rCCSP) administration to CCSP -/- mice will determine the role of CCSP in modulating the initiation and resolution of viral-induced lung inflammation. CCSP expression will be restored in CCSP -/- mice through the development of CCSP transgenic mice, and subsequently bred into the CCSP -/- mouse model to assess the spatial relationship of CCSP expression in altering host defense to lung viral infection. This application will determine the role and delineate mechanisms by which CCSP provides innate immunity to viral infection in the lung. Such data may be useful in designing treatment and prevention of viral pneumonia.