Daprodustat activates HIF signaling, enhancing innate immunity to limit pneumovirus replication.

Pneumoviral infections, such as those caused by Human Respiratory Syncytial Virus (hRSV), pose significant global health challenges, particularly in infants and immunocompromised individuals. Current antiviral strategies are limited, and the precise immune mechanisms governing both protection and pathogenesis remain incompletely understood. A critical gap exists in identifying host-directed therapeutic targets that can bolster intrinsic antiviral defenses. The hypoxia-inducible factor (HIF) signaling axis is a master regulator of cellular responses to low oxygen, influencing metabolism, angiogenesis, and inflammation, making it a compelling pathway for modulating immune responses against viral threats.

Researchers investigated the role of HIF signaling in pneumovirus infection using both in vitro and in vivo models. They pharmacologically activated the HIF pathway with daprodustat in human A549 lung epithelial cells infected with pneumovirus. Viral replication was assessed, and transcriptional profiling (RNA-seq) was performed to identify changes in gene expression. Further mechanistic studies involved genetic knockdown of key immune genes. In vivo, daprodustat was administered to C57BL/6 mice challenged with pneumovirus, with viral load and lung pathology serving as primary endpoints.

Pharmacological activation of the HIF signaling axis using daprodustat significantly limited pneumovirus replication across both in vitro and in vivo models. In A549 cells, HIF activation induced a robust antiviral state. Transcriptional profiling revealed this state was characterized by increased expression of a broad array of interferon-stimulated genes (ISGs) and pattern recognition receptors (PRRs), specifically highlighting RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5).