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

doi:10.1016/j.celrep.2019.11.021

Visualizing the Selectivity and Dynamics of Interferon Signaling In Vivo

Cell Rep. 2019 Dec 10;29(11):3539-3550.e4. doi: 10.1016/j.celrep.2019.11.021.

Authors

Affiliations

¹ 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.
² School of Medicine, Deakin University, Geelong, VIC 3216, Australia.
³ Bristol-Myers Squibb, Seattle, WA 98102, USA.
⁴ Laboratory Animal Sciences Program, National Cancer Institute, Frederick, MD 21702, USA.
⁵ Cytokine Biology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
⁶ Centenary Institute, The University of Sydney, NSW 2050, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia.
⁷ Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892-3202, USA.
⁸ 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. Electronic address: carl.feng@sydney.edu.au.

PMID: 31825834
DOI: 10.1016/j.celrep.2019.11.021

Abstract

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.

Keywords: Irgm1; epithelial cells; influenza; interferon receptor signaling; interferons; lung; viral infection.

MeSH terms

Alveolar Epithelial Cells / metabolism
Animals
Cells, Cultured
Female
GTP-Binding Proteins / genetics
GTP-Binding Proteins / metabolism
Hematopoietic Stem Cells / metabolism
Interferons / metabolism*
Male
Mice
Mice, Inbred C57BL
Orthomyxoviridae Infections / metabolism*
Signal Transduction*

Substances

Ifi1 protein, mouse
Interferons
GTP-Binding Proteins