P109 The role of the Type I interferon receptor during influenza virus infection

Abstract

Introduction Type I interferons (IFNs) are an important component of the innate anti-viral response. Type I IFNs initiate signaling cascades that lead to the modulation of expression of a number of anti-viral, IFN-regulated genes (IRGs). Type I IFNs signal through a common heterodimeric receptor (Ifnar), which is comprised of two chains, Ifnar1 and Ifnar2. Furthermore, the Ifnar2 gene is alternatively spliced resulting in a transmembrane (Ifnar2c) and a soluble (sIfnar2) isoform. While a number of studies have illustrated that Ifnar1 knockout mice are more susceptible to influenza virus infection, the role of each receptor chain during infection is currently not well understood. We hypothesized that binding of IFN to the Ifnar1 or Ifnar2 chain alone, results in a non-classical type I IFN response during influenza virus infection. Methods To examine the role of each component of Ifnar during influenza virus infection, wild-type, Ifnar1 and Ifnar2 knockout C57BL/6 mice were intranasally infected with 102 PFU of the HKx31 (H3N2) influenza strain. Viral loads in lung and nasal tissue homogenates were determined by standard plaque assay. Flow cytometry and cytokine bead array were utilized to examine cellular infiltrate and cytokines in the bronchoalveolar lavage (BAL), respectively. Results Ifnar2−/− mice were more susceptible to influenza virus infection than Ifnar1−/− and wild-type following inoculation with a low dose of virus. Loss of either Ifnar1 or Ifnar2 inhibited the production of monocyte chemotactic protein-1 (MCP-1) in the lungs, which correlated with a reduction in the numbers of inflammatory macrophages recruited into the lung airspaces. Levels of RANTES in BAL supernatants were also significantly reduced in Ifnar1 and Ifnar2 knockout mice compared to wild-type mice. Ifnar1−/− and Ifnar2−/− mice displayed increased numbers of neutrophils in the airways. Furthermore, in comparison to wild-type mice, viral replication was elevated in both the lower (lungs) and upper (nasal tissues) respiratory tract of Ifnar1 and Ifnar2 knockout mice at day 1 and 3 post-infection. Conclusion The type I IFN receptor plays an important role in controlling influenza virus replication in the respiratory tract. Ifnar2 knockout mice were more susceptible to influenza virus infection than mice lacking Ifnar1. We hypothesize that IFN signaling by cells lacking either Ifnar1 or Ifnar2, may result in a non-classical type I IFN response. In addition, we postulate that the type and/or modulation of IRGs in the lungs of Ifnar1 and Ifnar2 knockout mice following influenza virus infection differ. Future studies will utilize microarrays to examine the modulation of IRGs in the lungs of Ifnar1−/− and Ifnar2−/− mice following influenza virus infection. Overall, we suggest each Ifnar chain may have distinct roles in the anti-viral host defence during influenza infections.