HIF-1α translation mediated by PKCδ facilitates RSV-induced production of innate inflammatory cytokines in vitro and in vivo.

A cytokine storm caused by respiratory syncytial virus (RSV) significantly influences the progression of pneumonia and bronchiolitis. It is essential to comprehend the underlying mechanism of the RSV-triggered cytokine storm to effectively manage RSV. Hypoxia-inducible factor-1 Alpha (HIF-1α) plays a pivotal role in innate immunity. It is known that RSV enhances HIF-1α expression, but the molecular mechanism of RSV-induced HIF-1α expression and its role in the production of innate inflammatory cytokines during RSV infection are not fully understood. Our research demonstrates that RSV infection increases HIF-1α expression both in vitro and in vivo. Further investigation into the mechanism of RSV-induced HIF-1α expression indicates that PKCδ regulates RSV-induced HIF-1α translation through the PI3K/Akt/mTOR signaling pathway. Additionally, HIF-1α expression, mediated by PKCδ/PI3K/Akt/mTOR signaling, stimulates the production of innate inflammatory cytokines by activating the NLRP3-inflammasome during RSV infection. Inhibition of HIF-1α or PKCδ markedly suppresses RSV-induced inflammation in vitro and in vivo. In summary, these findings elucidate the molecular mechanism of RSV-induced HIF-1α expression and identify HIF-1α as a novel target for anti-RSV drug development.