Triple IFN pathway deficiency sensitizes mice to human respiratory virus infection independent of human viral receptor expression

Interferon (IFN) pathways form the innate barrier against viral invasion and partial deficiency in these pathways allows human virus infection. Whether a complete IFN pathway deficiency could confer the susceptibility to human viral infection independent of expressing the human viral receptor remains unknown. We develop an innate immunity severely deficient mouse model, designated AGL, which features one-step knock-out of the IFNAR, IFNGR and IFNLR. The AGL mice become susceptible to diverse representative human respiratory viruses, including adenovirus type 55 (HAdV-55; double-stranded DNA), human monkeypox virus (MPXV) clade IIb (double-stranded DNA), parainfluenza virus (PIV; negative-sense single-stranded RNA), and the clinically isolated SARS-CoV-2 delta variant (positive-sense single-stranded RNA). Our results suggest that the type III IFN pathway constitutes a backup layer of antiviral frontline beneath the type I and II IFN pathways. In addition, proof-of-concept studies testing MPXV and PIV antivirals highlight the translational value of AGL mice. The AGL mice, as a universal model, substantially enhance the ability to investigate both emerging and established viruses without the need for tailored mouse models.