Impaired IFN?-Signaling and Mycobacterial Clearance in IFN?R1-Deficient Human iPSC-Derived Macrophages.

ABSTRACT: Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFN?) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFN? is the macrophage-activating factor, macrophages from these patients have never been studied. We demonstrate the generation of heterozygous and compound heterozygous (iMSMD-cohet) induced pluripotent stem cells (iPSCs) from a single chimeric patient, who suffered from complete autosomal recessive IFN?R1 deficiency and received bone-marrow transplantation. Loss of IFN?R1 expression had no influence on the macrophage differentiation potential of patient-specific iPSCs. In contrast, lack of IFN?R1 in iMSMD-cohet macrophages abolished IFN?-dependent phosphorylation of STAT1 and induction of IFN?-downstream targets such as IRF-1, SOCS-3, and IDO. As a consequence, iMSMD-cohet macrophages show impaired upregulation of HLA-DR and reduced intracellular killing of Bacillus Calmette-Guérin. We provide a disease-modeling platform that might be suited to investigate novel treatment options for MSMD and to gain insights into IFN? signaling in macrophages.

SUBMITTER: Neehus AL 

PROVIDER: S-EPMC5768914 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature