Visualizing the Selectivity and Dynamics of Interferon Signaling In Vivo
Sebastian A. Stifter,
Nayan Bhattacharyya,
Andrew J. Sawyer,
Taylor A. Cootes,
John Stambas,
Sean E. Doyle,
Lionel Feigenbaum,
William E. Paul,
Warwick J. Britton,
Alan Sher,
Carl G. Feng
Affiliations
Sebastian A. Stifter
Immunology and Host Defense Group, Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia; Centenary Institute, The University of Sydney, NSW 2050, Australia
Nayan Bhattacharyya
Immunology and Host Defense Group, Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia; Centenary Institute, The University of Sydney, NSW 2050, Australia
Andrew J. Sawyer
Immunology and Host Defense Group, Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia; Centenary Institute, The University of Sydney, NSW 2050, Australia
Taylor A. Cootes
Immunology and Host Defense Group, Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia; Centenary Institute, The University of Sydney, NSW 2050, Australia
John Stambas
School of Medicine, Deakin University, Geelong, VIC 3216, Australia
Sean E. Doyle
Bristol-Myers Squibb, Seattle, WA 98102, USA
Lionel Feigenbaum
Laboratory Animal Sciences Program, National Cancer Institute, Frederick, MD 21702, USA
William E. Paul
Cytokine Biology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Warwick J. Britton
Centenary Institute, The University of Sydney, NSW 2050, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia
Alan Sher
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892-3202, USA
Carl G. Feng
Immunology and Host Defense Group, Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia; Centenary Institute, The University of Sydney, NSW 2050, Australia; Corresponding author
Summary: Interferons (IFN) are pleiotropic cytokines essential for defense against infection, but the identity and tissue distribution of IFN-responsive cells in vivo are poorly defined. In this study, we generate a mouse strain capable of reporting IFN-signaling activated by all three types of IFNs and investigate the spatio-temporal dynamics and identity of IFN-responding cells following IFN injection and influenza virus infection. Despite ubiquitous expression of IFN receptors, cellular responses to IFNs are highly heterogenous in vivo and are determined by anatomical site, cell type, cellular preference to individual IFNs, and activation status. Unexpectedly, type I and II pneumocytes, the primary target of influenza infection, exhibit striking differences in the strength and temporal dynamics of IFN signaling associated with differential susceptibility to the viral infection. Our findings suggest that time- and cell-type-dependent integration of distinct IFN signals govern the specificity and magnitude of IFN responses in vivo. : Stifter et al. generated an Irgm1 reporter mouse sensitive to induction by all three types of IFNs. They show that cellular responses to IFNs are highly heterogenous in vivo. Furthermore, different types of IFNs act in a cell-type-dependent manner to convey synergistic, antagonistic, or non-redundant signaling during influenza infection. Keywords: interferons, interferon receptor signaling, viral infection, influenza, lung, epithelial cells, Irgm1
