This project aims to determine how human lung epithelial homeostasis is regulated in acute lung injury induced by the 2009 H1N1 pandemic influenza virus. Because of the rapid transmission and high potential for increased pathogenicity of the H1N1 pandemic virus, there is an urgent need to understand the host response against viral infection. This virus targets distal lung cells and causes more severe disease than seasonal influenza virus, including diffuse alveolar damage and pulmonary edema. To define the mechanism of this tissue injury, it is important to study the specific cells that are infected by te virus. Therefore, our studies will focus on the cells in the alveolar region of the human lung. Our approach is novel in that we will study the effect of 2009 H1N1 pandemic virus on primary cultures of human alveolar epithelial cells and alveolar macrophages isolated from the same healthy lung donors. We have preliminary data using this system that suggests the involvement of both the AIM2 inflammasome and the cytokine TSLP in host response to influenza virus infection.
The AIM2 inflammasome is important for host defense against bacteria and DNA virus infection, but a role for it in RNA virus infection has not previously been identified. Here we wil determine the function and mechanism of the AIM2 inflammasome in primary human ATII cells and in a mouse model during H1N1 influenza-induced epithelial injury. We hypothesize that AIM2 is the primary inflammasome induced by influenza virus in alveolar epithelial cells.
AIM2 deficient cells and AIM2 deficient mice will have more impairment of the epithelial barrier during influenza infection. TSLP plays a key role in allergic diseases such as asthma, but its effect on the epithelial barrier is not yet defined. We will determine the role of TSLP in protecting the alveolar epithelial barrier during influenza infection using both in vitro and in vivo models. We hypothesize that inflammasome activation will enhance the TSLP production by alveolar epithelial cells. Influenza-stimulated TSLP will improve the damaged barrier by influenza both in vitro and in vivo through enhancing the tight junctions between cells and/or stimulating epithelial proliferation. In addition, the cell-cell interaction between alveolar epithelial cells and macrophages will enhance the release of TSLP by epithelial cells. Our study will reveal novel mechanisms for the regulation of the alveolar epithelial barrier during acute lung injury by influenza, thereby uncovering potential novel therapeutic strategies for reducing influenza-induced mortality.
Influenza is a common public health problem. It causes more than 35,000 deaths, 200,000 hospitalizations, and more than $37.5 billion in economic loss (www.cdc.gov). Recently, 2009 H1N1 pandemic virus led to over 18,000 verified deaths according to the WHO. The gas exchange cells deep within the human lung are the primary targets for 2009 H1N1 pandemic virus. We propose to study the regulation of the influenza-induced innate immune response with a focus on the epithelial barrier. By studying influenza infection in human lung alveolar epithelial cells and alveolar macrophages, our proposed studies aim to identify the regulation mechanism of lung epithelial homeostasis during influenza-induced acute lung injury and to reveal novel therapeutic agents to protect the epithelial barrier, therefore reducing influenza-induced mortality.
|Shinde, Apurva; Luo, Jiadi; Bharathi, Sivakama S et al. (2018) Increased mortality from influenza infection in long-chain acyl-CoA dehydrogenase knockout mice. Biochem Biophys Res Commun 497:700-704|
|Robinson, Keven M; Ramanan, Krishnaveni; Clay, Michelle E et al. (2018) The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice. JCI Insight 3:|
|Du, Yushen; Xin, Li; Shi, Yuan et al. (2018) Genome-wide identification of interferon-sensitive mutations enables influenza vaccine design. Science 359:290-296|
|Wonderlich, Elizabeth R; Swan, Zachary D; Bissel, Stephanie J et al. (2017) Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques. J Immunol 198:1616-1626|
|Zhang, Hongbo; Luo, Jiadi; Alcorn, John F et al. (2017) AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality. J Immunol 198:4383-4393|
|Tang, Xinying; Zhang, Hongbo; Song, Yufeng et al. (2016) Hemagglutinin-targeting Artificial MicroRNAs Expressed by Adenovirus Protect Mice From Different Clades of H5N1 Infection. Mol Ther Nucleic Acids 5:e311|
|Travanty, Emily; Zhou, Bin; Zhang, Hongbo et al. (2015) Differential Susceptibilities of Human Lung Primary Cells to H1N1 Influenza Viruses. J Virol 89:11935-44|
|Hidvegi, Tunda; Stolz, Donna B; Alcorn, John F et al. (2015) Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy. J Biol Chem 290:29742-57|
|Otsubo, Chikara; Bharathi, Sivakama; Uppala, Radha et al. (2015) Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant. J Biol Chem 290:23897-904|
|Li, Li; Hamzeh, Nabeel; Gillespie, May et al. (2015) Beryllium increases the CD14(dim)CD16+ subset in the lung of chronic beryllium disease. PLoS One 10:e0117276|
Showing the most recent 10 out of 17 publications