Ifnar2 plays an important role in limiting inflammation and disease following influenza virus infection — ASN Events

Ifnar2 plays an important role in limiting inflammation and disease following influenza virus infection (#181)

Michelle D Tate 1 , Jennifer K Dowling 1 , Rebecca A Piganis 1 , Paul J Hertzog 1
  1. MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia

Aims:
Excessive inflammation is associated with severe influenza virus infections in both mice and humans. The type I interferon (IFN) receptor (Ifnar) is comprised of two chains, Ifnar1 and Ifnar2. We hypothesized that Ifnar1 and Ifnar2 play differing roles during influenza virus infection. We therefore aimed to investigate and compare the involvement of Ifnar1 and Ifnar2 in host defence, using a mouse model of influenza virus infection.

Methods:
Wildtype, Ifnar1-/- and Ifnar2-/- mice were intranasally infected with 102 PFU of HKx31 (H3N2) and weighed daily. Viral loads in respiratory tact was determined by plaque assay. Cellular infiltrate in the airways was examined by flow cytometry and cytokines in bronchoalveolar lavage (BAL) fluid and sera were quantified by cytokine bead array and ELISA. Protein concentrations of BAL fluid and lung wet to dry ratios were utilised to examine vascular leakage and edema, respectively.

Results:
Ifnar1 and Ifnar2 knockout mice differed markedly in their susceptibility to influenza virus infection; Ifnar2-/- > Infar1-/- > wildtype. By day 7 post-infection, Ifnar2-/- mice displayed evidence of severe disease and were therefore euthanised. We observed no striking differences in viral loads between Ifnar1-/- and Ifnar2-/- mice. Severe disease displayed by Ifnar2-/- mice was associated with increased neutrophil infiltration and elevated levels of IL-1β in the airways and blood. Furthermore, mice lacking Ifnar2 but not Ifnar1, displayed evidence of pulmonary edema and vascular leakage.

Conclusions:
Overall, our data demonstrates that Infar1 and Infar2 play distinct roles in host defence during influenza virus infection. In particular, Ifnar2 plays an important role in controlling the production of IL-1β and the induction of severe disease. Understanding further this role of Ifnar2 and how type I IFNs control inappropriate or damaging immune responses is of significance to reduce mortality and morbidity associated with influenza.