Targeting the interaction between long noncoding RNA XR_001779380 and Prdm1 to enhance IFN-γ immunity in murine...

Intestinal epithelial cells (IECs) serve as the front line of host defense in the intestine, with IFN signaling playing a critical role in regulating epithelial cell-intrinsic defense against intracellular pathogens. However, IFN-γ-mediated antimicrobial defense is usually reduced in the gastrointestinal tract in infants, and the underlying mechanisms remain unclear. We previously observed that the lncRNA XR_001779380 promotes IFN-γ-stimulated gene transcription in murine IECs. Interestingly, its interaction with Prdm1, a DNA-binding protein expressed in the neonatal but not adult intestinal epithelium, attenuates IFN-γ-stimulated gene transcription, thereby contributing to suppression of IFN-γ-mediated, epithelial cell-intrinsic defense in the neonatal intestine. In this study, we further investigated the role of Prdm1 in suppressing IFN-γ response in murine neonatal IECs. Additionally, we explored the development of specific antisense oligonucleotides to interfere with XR_001779380-Prdm1 interaction to promote IFN-γ response in IECs. Our data show that Prdm1 suppresses IFN-γ-mediated gene transcription, and its induction inhibits IFN-γ-stimulated cell-intrinsic defense against Cryptosporidium, an apicomplexan parasite and a leading cause of infectious diarrhea and diarrheal-related death in young children worldwide. Furthermore, antisense oligonucleotides designed to block Prdm1-XR_001779380 interaction can promote the IFN-γ response in murine neonatal IECs, leading to enhanced cell-intrinsic anti-Cryptosporidium defense.IMPORTANCECompared with adults, the innate antimicrobial defense of intestinal epithelium in neonates and infants is typically reduced, leading to increased susceptibility to infection; however, the underlying mechanisms remain incompletely understood. Cryptosporidium is a leading cause of infectious diarrhea and diarrheal-related death in children worldwide. Prdm1 is a DNA-binding protein that is expressed in neonatal, but not adult, intestinal epithelium. In our previous study, we found that Prdm1 recruits XR_001779380 to form the Prdm1/Stat1/Pias1 complex. Formation of this complex results in the suppression of IFN-γ-stimulated gene transcription in neonatal IECs. In this study, we further investigated the impact of Prdm1 expression on IFN-γ-stimulated cell-intrinsic anti-Cryptosporidium defense in neonatal IECs. We also explored the potential of RNA-based therapeutics targeting Prdm1-RNA interactions to enhance cellular response to IFN-γ. Our findings support that antisense oligonucleotides targeting the Prdm1-XR_001779380 interaction promote IFN-γ-stimulated gene transcription and enhance cell-intrinsic defense against Cryptosporidium infection.