The influenza virus infects the respiratory tract and may result in acute respiratory distress syndrome and pneumonia associated with a high mortality rate. The long-term goal of this project is to understand the molecular mechanisms how the lung epithelial cells responds to and restricts respiratory virus infection. Innate immunity is the first responder to respiratory pathogen invasion and provides the first line of defense in the lung. Thus enhancing the host defense response against respiratory virus by targeting lung epithelial host factors is a strategy to restrict respiratory virus infection regardless of any viral changes. Long non-coding RNAs (lncRNAs) are mRNA-like transcripts with a size of > 200 nucleotides, but that do not encode proteins and are involved in diverse cellular processes including innate immunity. Through RNA sequencing analysis and molecular cloning, we have identified a novel lncRNA transcript, lnc-PINK1-2:5 in lung epithelial cells that reduces influenza virus infection and up-regulates the expression of thioredoxin interacting protein (TXNIP) that activates NLRP3 inflammasomses. Based on this preliminary data, we hypothesized that lnc-PINK1-2:5 restricts respiratory virus infection by activating NLRP3 inflammasomes via upregulating TXNIP gene expression in lung epithelial cells.
Aim I will establish the functional roles of lnc-PINK1-2:5 in influenza virus infection of human lung epithelial cells.
Aim II will delineate the molecular mechanisms of lnc-PINK1-2:5- mediated restriction of influenza virus in human lung epithelial cells.
The establishment of the role of the host factor lnc-PINK1-2:5 in influenza virus infection in lung epithelial cells will provide a rationale for the development of pharmacological lnc-PINK-1-2:5 modulators to treat influenza virus infection that will be unaffected by viral mutations.
