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.
|Dominguez, Samuel R; Travanty, Emily A; Qian, Zhaohui et al. (2013) Human coronavirus HKU1 infection of primary human type II alveolar epithelial cells: cytopathic effects and innate immune response. PLoS One 8:e70129|
|Funk, C Joel; Wang, Jieru; Ito, Yoko et al. (2012) Infection of human alveolar macrophages by human coronavirus strain 229E. J Gen Virol 93:494-503|
|Wang, Jieru; Nikrad, Mrinalini P; Travanty, Emily A et al. (2012) Innate immune response of human alveolar macrophages during influenza A infection. PLoS One 7:e29879|
|Watanabe, Tokiko; Shinya, Kyoko; Watanabe, Shinji et al. (2011) Avian-type receptor-binding ability can increase influenza virus pathogenicity in macaques. J Virol 85:13195-203|
|Wang, Jieru; Nikrad, Mrinalini P; Phang, Tzulip et al. (2011) Innate immune response to influenza A virus in differentiated human alveolar type II cells. Am J Respir Cell Mol Biol 45:582-91|
|Yu, Wendy C L; Chan, Renee W Y; Wang, Jieru et al. (2011) Viral replication and innate host responses in primary human alveolar epithelial cells and alveolar macrophages infected with influenza H5N1 and H1N1 viruses. J Virol 85:6844-55|