Saturday, September 14, 2024
9/14/2024
Influenza virus is a major pathogen causing seasonal epidemics of disease in the world. Airway epithelium acts as the first line of host antiviral defense. Influenza virus-induced innate immunity plays a critical role in viral clearance. However, if uncontrolled, dysregulated innate immune responses contribute significantly to the morbidity and mortality. Therefore, influenza virus-induced innate immune responses must be tightly regulated. The molecular mechanisms underlying the tight regulation of influenza virus-induced innate immunity remain largely unknown. Currently available influenza vaccines and antiviral drugs have a limited impact on influenza virus infection due to the mismatches between the vaccine strains and the circulating strains as well as newly emerging mutant viruses and drug-resistant virus strains. There is an urgent need for developing innovative therapeutic strategies for improving innate immunity. Our long-term goal is to elucidate the molecular mechanisms underlying the tight regulation of host innate immune responses in influenza virus infection and identify novel therapeutic targets. In contrast to the relatively well-studied positive regulators such as RIG-I like receptor (RLR) in regulating antiviral response, the molecular mechanisms, in particular the negative regulators, involved in the tight regulation of host antiviral innate immune responses still remain largely unknown. Pirin, a key signaling regulatory protein, has been shown to be involved in cancer and fibrosis. Its role in infectious diseases, in particular in regulating host innate immune responses remains unclear. Our encouraging preliminary data suggest that Pirin may negatively regulate influenza virus-induced innate immunity in Adenosine Deaminases Acting on RNA 1 (ADAR1)- and phosphoglycerate kinase 1 (PGK1)-dependent manners in airway epithelial cells in vitro and in the mouse models of influenza virus infection. Moreover, Pirin is highly expressed in lung, especially in airway epithelium, and Pirin depletion improves anti-viral innate immune responses, viral clearance and host survival. Together, these exciting preliminary data have thus laid a solid foundation for us to hypothesize that [1] Pirin acts as a key negative regulator for influenza virus-induced innate immunity in airway epithelium; [2] Pirin inhibits influenza virus-induced innate immunity via (1) interacting with ADAR1, and Pirin- ADAR1 signaling axis inhibits RIG-I-dependent anti-viral innate immune response via negatively cross-talking with Ras-related Nuclear protein (RAN), a positive regulator of anti-viral response and (2) inhibiting PGK1, a positive regulator, in influenza virus infection (hypothesis). To test our hypothesis, we will pursue three specific aims to determine (Aim 1) the role of Pirin in airway epithelium in influenza virus infection and its therapeutic potential; (Aim 2 & 3) the molecular mechanisms underlying negative regulation of antiviral innate immunity by Pirin via ADAR1-dependent negative cross-talk with RAN (Aim 2) and inhibiting PGK1 (Aim 3). These studies may not only significantly advance our understanding of the negative regulation of innate immunity but may also lead to the identification of novel therapeutic targets for treating influenza virus infections.
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