STAT1 gain of function mutation impairs immune response to viral infections

Abstract The coordinated effort of the immune system in host defense is dependent upon proper release and interpretation different cytokine signals. Several examples monogenic diseases targeting JAK-STAT pathway reveal there still a critical need to understand basic principles signaling output. For example, patients with STAT1 gain-of-function (GOF) mutations exhibit type 1/IFN-gamma bias that antagonizes 3/IL-17 response important for controlling fungal infection, yet also, paradoxically, chronic sometimes lethal viral infections. Using novel conditional knock STAT1-GOF mouse model, we demonstrate mice respond poorly infections are easily controlled by WT mice, such as MCMV LCMV-Armstrong. High-dimensional flow cytometry scRNA-seq an impaired NK CD8 T cell effector not simply due exhaustion phenotype. Instead, unexpected defect IFN-gamma production early during innate response, leading storm, immunopathology, adaptive response. scATAC/RNA-seq uncovers altered usage STAT complexes misinterpretation innate-stimulating cytokines. These results provide insight into why interferonopathies or elevated interferons highlight importance properly tuning R.L.P. was supported Postdoctoral Research Associate (PRAT) fellowship from National Institute General Medical Sciences (NIGMS), award number 1Fi2GM137942-01