Single-cell transcriptome analysis reveals mechanism of phosphodiesterase inhibitor in neonatal mouse infection-associated liver injury treatment

Abstract

Virus-induced neonatal liver failure remains a critical health challenge with poorly understood mechanisms. This study employed a comprehensive approach to investigate the pathological role of phosphodiesterase 4B (PDE4B) in rotavirus-associated liver injury. In this study, we utilized a mouse model of virus-induced liver injury model through the intraperitoneal injection of rhesus rotavirus (RRV) into newborn BALB/c mice, and applied dipyridamole as treatment strategy. We performed single cell sequencing and high-resolution immune landscape exploration on liver samples (n = 3 per group) from control (50 μL phosphate-buffered saline [PBS]), RRV-infected mice (50 μL PBS with 1.5 × 10⁶ plaque-forming units of RRV on the first day), and dipyridamole-treated mice (RRV-injected mice with 2.5 mg/kg/day dipyridamole for 12 days). We showed that dipyridamole-mediated inhibition of phosphodiesterases (PDEs) restored the differentiation trajectory of neutrophils by suppressing their activation and promoting clearance. In addition, dipyridamole suppressed the activation of autoreactive B cells and cytotoxic lymphocytes, which collectively ameliorated liver pathology and improved neonatal survival following RRV infection. In summary, we demonstrated that inhibition of phosphodiesterase signaling alleviates liver failure in murine models of neonatal rotavirus infection, thereby revealing a candidate strategy to treat rotavirus-associated diseases in neonates.