The alveolar epithelium is the site of infection for many emerging viral infections. Alveolar type II cells produce pulmonary surfactant, are the progenitor cells for the type I alveolar epithelial cells, and pump sodium from the alveolar fluid into the interstitium to prevent alveolar flooding. Alveolar epithelial cells also have the ability to initiate both innate and adaptive immune responses. We have shown that human type II cells produce large amounts of IL-29 (interferon ?), a type III interferon, and CXCL10 (IP-10) and CXCL11 (I- TAC), which are important cytokines for initiating the adaptive immune response, as well as a variety of other cytokines in response to influenza. In this application we will determine the regulation of the antiviral interferon response with a focus on IL-29 and the cytokine inflammatory response with a focus on CXCL10, CXCL11, RANTES, and IL-6. We will also determine the role of surfactant protein D (SP-D) in the innate immune response to influenza and its ability to enhance clearance of viral infected apoptotic cells to limit the spread of infection. We believe that SP-D will be very important in alveolar defense against influenza. In addition we will determine if these processes are altered in two susceptible populations, the elderly and current cigarette smokers. Finally we will begin to determine if these responses are regulated by the virus itself by comparing the effects of contemporary circulating viruses to avian influenza and by the presence or absence of the NS-1 gene in the A/PR/8/34 (H1N1) virus. These studies should highlight two new understudied potential therapeutic targets, (i.e., IL-29 and clearance of apoptotic virally infected cells), and provide more insight into the cells that are actually infected in influenza pneumonia. These studies could be easily expanded in the future to other emerging infections after influenza that cause pneumonia or to the pathogenesis of secondary bacterial infections in collaboration with other IMVC awardees.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1-BDP-I (J4))
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Miller, Lara R
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National Jewish Health
United States
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