Targeting PDE to reprogram neutrophil development as a therapeutic strategy for neonatal rotavirus-associated liver injury.
image: In the RRV-infected neonatal BALB/c mouse model, intervention with PDE inhibitor (dipyridamole) and single-cell transcriptomic sequencing analysis of liver tissues revealed that PDE inhibition comprehensively modulates the immune microenvironment through multiple pathways, suggesting its potential as a therapeutic strategy for neonatal infectious liver injury.
Credit: hLife
A new mechanism underlying neonatal liver injury caused by rotavirus infection and the therapeutic potential of phosphodiesterase (PDE) inhibitors has been identified by the research team led by Yuxia Zhang and Zhe Wen from Guangzhou Women and Children’s Medical Center. In this study, they utilized a neonatal mouse model infected with rhesus rotavirus (RRV) to mimic severe liver injury, including biliary atresia-like symptoms. Through single-cell RNA sequencing, the team uncovered that RRV infection disrupts the developmental trajectory of neutrophils in the liver, leading to their hyperactivation and prolonged survival, which exacerbates tissue damage. Notably, the PDE inhibitor dipyridamole (DIP) was found to restore normal neutrophil differentiation, suppress inflammatory cytokines, and improve survival rates in infected mice. The treatment also reduced viral load and attenuated liver fibrosis, highlighting its potential as a therapeutic intervention for neonatal viral infections.
The study further revealed that RRV infection induces a unique inflammatory neutrophil subset (Neu-Il1b) characterized by upregulated Pde4b and aberrant STAT/NF-κB signaling, which potentially promotes resistance to apoptosis. DIP treatment reversed these effects by enhancing cAMP-PKA pathway activity, restoring neutrophil clearance mechanisms, and reducing liver pathology. Additionally, the researchers identified dysregulated interactions between neutrophils and autoreactive B cells via the MIF-CD74 axis, a pathway implicated in autoimmune responses. DIP also rebalanced Tlr7/Tlr9 expression in B cells, mitigating autoantibody production. Similarly, cytotoxic NK and CD8+ T cell subsets, which contribute to liver damage, were suppressed by DIP, while protective Cx3cr1+ CD8+ T cells were enriched, further alleviating fibrosis.
These findings underscore the broad immunomodulatory effects of PDE inhibitors in neonatal infections. By targeting multiple immune cell populations—neutrophils, B cells, and cytotoxic lymphocytes—DIP promotes inflammation resolution without compromising antiviral defenses. The study provides a foundation for exploring cAMP-based therapies in neonatal liver diseases and other inflammatory conditions. The team’s work not only elucidates the mechanisms of rotavirus-induced liver injury but also positions PDE inhibitors as a promising strategy to improve outcomes in infected newborns.
About Author
Zhang Yuxia, Ph.D. Supervisor and Chief Researcher at Guangzhou Women and Children's Medical Center, is a distinguished scholar who received the 2021 National Science Fund for Distinguished Young Scholars. She holds the titles of Pearl River Scholar Distinguished Professor, Guangzhou Medical Leading Talent, and Guangzhou Outstanding Expert. Her laboratory employs an interdisciplinary approach integrating genetics, immunology, bioinformatics, and other advanced technologies to investigate the pathogenesis of digestive system diseases and develop precision treatment strategies.
Dr. Zhang has led several major research projects, including one NSFC Major Research Program, one NSFC Key Cultivation Project, one NSFC General Project, and the NSFC Distinguished Young Scientists Fund. As a corresponding author, she has published groundbreaking research in top-tier journals such as Cell (2019, 2020), Journal of Allergy and Clinical Immunology (2020), and Science Translational Medicine (2016), and filed five patents. Her work has been featured in prestigious publications like Nature Medicine (2019), Science (2016), Nature Reviews Immunology (2016), and JAMA (2016). Notably, she was recognized by the Chinese Academy of Medical Sciences as one of "China's Major Medical Advances in 2019" for pioneering innovative therapies, including the use of phosphodiesterase inhibitors (PDE) to treat gastrointestinal inflammation (Cell, 2019) and targeted B-cell therapy for autoimmune liver injury (Cell, 2020).
Digital Object Identifier (DOI): 10.1016/j.hlife.2025.04.002