Oral Presentation Lorne Infection and Immunity 2023

IFNλ1 utilises interferon alpha/beta receptor 2 to induce signalling and anti-viral defence in lung epithelial cells (#7)

Nicky de Weerd 1 , Julian Vivian 2 , Tony Matthews 1 , Amina Ismail 1 , Tatiana Soares da Costa 3 , Jodee Gould 1 , Jamie Gearing 1 , Natalia Sampaio 1 , Daniel Garama 1 , Daniel Gough 1 , Eveline de Geus 1 , Qian Zhang 4 , Jean-Laurent Casanova 4 , Rune Hartmann 5 , Meredith O'Keeffe 6 , Charles Rice 4 , Paul Hertzog 1
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. St Vincent's Institute, Fitzroy, VIC, Australia
  3. Waite Research Institute, The University of Adelaide, Urrbrae, South Australia, Australia
  4. St Giles Laboratory of Human Genetics of Infectious Disease, The Rockefeller Institute, New York, USA
  5. Aarhus University, Aarhus, Denmark
  6. Monash Biomedical Discovery Institute, Clayton, VIC, Australia

Type I and type III interferons (IFNs) together regulate the early response to viral infection including SARS-CoV-2. Despite displaying structural and functional similarities, type I and type III IFNs operate via different heterodimeric receptor complexes. Type I IFNs (IFNα, IFNβ, etc) bind ubiquitously expressed IFN alpha/beta receptor (IFNAR)1 and IFNAR2. In contrast, type III IFNs (IFNλ1-4) bind a unique high affinity receptor, IFN lambda receptor (IFNLR)1 which displays restricted cellular expression and a widely expressed low affinity receptor shared with the Interleukin(IL)10 cytokine superfamily (IL10R2).

Here we report that the type I IFN receptor IFNAR2 is required for mediating the anti-viral properties of the type III IFN, IFNλ1 on lung epithelial cells. Using microscale thermophoresis, we observed high affinity binding of IFNλ1 to the extracellular domain of IFNAR2; a characteristic not displayed by IFNλ3 or IFNλ4. We used direct protein-protein interactions and mass spectrometry to show that IFNAR2 co-operates with IFNLR1 to bind IFNλ1, forming a novel ternary protein complex. Furthermore, IFNλ1, but not IFNλ3, utilise IFNAR2 on the surface of lung epithelial cells for efficient expression of interferon regulated genes (IRGs) including key anti-viral genes such as MX2, OAS2, BST2, STAT1, STAT2, IFITM1 and IFITM3. Finally, we demonstrate that IFNλ1, but not IFNλ3, requires IFNAR2 on lung epithelial cells to upregulate cell-surface levels of the viral restriction factor IFITM3 and to efficiently protect cells from viral infection.

Our data shows that IFNλ1 binds IFNAR2 to form a novel protein complex that is required for efficient IFNλ1-mediated gene induction and anti-viral activity in lung epithelial cells.