IL-27 utilizes IRF1 for IFN-I-independent ISG expression during IAV infection of human macrophages

Abstract

Influenza virus (IAV) is a respiratory virus spread through aerosols or respiratory fomites causing seasonal epidemics resulting in up to 650,000 deaths annually and with the potential to cause more serious life-threatening pandemics. Recognition of IAV by host innate immune cells, such as macrophages (M), signals to activate the immune response, including key cytokines, like type I interferons (IFN-I) and the antiviral cytokine, interleukin-27 (IL-27). IFN-I signalling induces the expression of interferon-stimulated genes (ISGs), which collectively function to limit virus infection. Relatively new research has indicated a role for IL-27 in the induction of ISG expression either in an IFN- I-dependent or -independent manner. Furthermore, IL-27 has previously been shown to regulate the function of monocytes and M, including skewing M polarization towards a pro-inflammatory, M1 phenotype. However, the effects of IL-27 on polarized M during IAV infection are unknown. Therefore, we set out to characterize the relationship between IFN-I and IL-27 in the induction of ISGs in response to pandemic IAV infection (A/NY/18/2009) and to determine if IL-27 plays a role in M polarization and how this changes IAV infection. Here we show that IL-27-mediated IFN-I-independent induction of ISGs requires the presence of the transcription factor IRF1, and in the absence of IRF1, IL-27 is dependent on IFN-I to induce ISGs. As well, we show that post-infection IL-27 treatment does not confer the ability to reduce IAV infection. These results show potential correlation between IAV replication, M subtypes, and IL-27-modulation of the IFN response, allowing for a better understanding of the antiviral function of IL-27.