Neutrophils infected with highly virulent influenza H3N2 virus exhibit augmented early cell death and rapid induction of type I interferon signaling pathways

We developed a model of influenza virus infection of neutrophils by inducing differentiation of the MPRO promyelocytic cell line. After 5 days of differentiation, about 20–30% of mature neutrophils could be detected. Only a fraction of neutrophils were infected by highly virulent influenza (HVI) virus, but were unable to support active viral replication compared with MDCK cells. HVI infection of neutrophils augmented early and late apoptosis as indicated by annexin V and TUNEL assays. Comparison between the global transcriptomic responses of neutrophils to HVI and low virulent influenza (LVI) revealed that the IFN regulatory factor and IFN signaling pathways were the most significantly overrepresented pathways, with activation of related genes in HVI as early as 3 h. Relatively consistent results were obtained by real-time RT-PCR of selected genes associated with the type I IFN pathway. Early after HVI infection, comparatively enhanced expression of apoptosis-related genes was also elicited.

► Only a fraction of MPRO-derived neutrophils were infected by HVI virus. ► MPRO-derived neutrophils were unable to support active influenza viral replication. ► HVI infection of neutrophils causes apoptosis and rapid type I IFN hyperinduction. ► Early after HVI infection, enhanced expression of apoptosis genes was elicited. ► These may predispose to severe lung injury and secondary bacterial pneumonia.