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Principal Investigator: Jian-Dong Li
Organization: GEORGIA STATE UNIVERSITY
Fiscal Year: 2024
Award: $708,660
Funding agency: National Institute of Allergy and Infectious Diseases
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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