Targeting the interaction between long noncoding RNA XR_001779380 and Prdm1 to enhance IFN-γ immunity in murine neonatal intestinal epithelial cells
ABSTRACT 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 ga...
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American Society for Microbiology
2025-07-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00773-25 |
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| author | Kehua Jin Ai-Yu Gong Shuhong Wang Gislaine A. Martins Juliane K. Strauss-Soukup Roberta M. O'Connor Xian-Ming Chen |
| author_facet | Kehua Jin Ai-Yu Gong Shuhong Wang Gislaine A. Martins Juliane K. Strauss-Soukup Roberta M. O'Connor Xian-Ming Chen |
| author_sort | Kehua Jin |
| collection | DOAJ |
| description | ABSTRACT 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. |
| format | Article |
| id | doaj-art-e204099083a84294847c4a11266e6db6 |
| institution | OA Journals |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | American Society for Microbiology |
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| spelling | doaj-art-e204099083a84294847c4a11266e6db62025-08-20T02:36:16ZengAmerican Society for MicrobiologymBio2150-75112025-07-0116710.1128/mbio.00773-25Targeting the interaction between long noncoding RNA XR_001779380 and Prdm1 to enhance IFN-γ immunity in murine neonatal intestinal epithelial cellsKehua Jin0Ai-Yu Gong1Shuhong Wang2Gislaine A. Martins3Juliane K. Strauss-Soukup4Roberta M. O'Connor5Xian-Ming Chen6Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USADepartment of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USADepartment of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USADepartments of Medicine and Biomedical Sciences, Research Division of Immunology Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California—Los Angeles, Los Angeles, California, USADepartment of Chemistry and Biochemistry, Creighton University College of Arts and Sciences, Omaha, Nebraska, USAVeterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, USADepartment of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mbio.00773-25Prdm1IFN-gammaantisense oligonucleotidesintestinal epitheliumneonatesLncRNAs |
| spellingShingle | Kehua Jin Ai-Yu Gong Shuhong Wang Gislaine A. Martins Juliane K. Strauss-Soukup Roberta M. O'Connor Xian-Ming Chen Targeting the interaction between long noncoding RNA XR_001779380 and Prdm1 to enhance IFN-γ immunity in murine neonatal intestinal epithelial cells mBio Prdm1 IFN-gamma antisense oligonucleotides intestinal epithelium neonates LncRNAs |
| title | Targeting the interaction between long noncoding RNA XR_001779380 and Prdm1 to enhance IFN-γ immunity in murine neonatal intestinal epithelial cells |
| title_full | Targeting the interaction between long noncoding RNA XR_001779380 and Prdm1 to enhance IFN-γ immunity in murine neonatal intestinal epithelial cells |
| title_fullStr | Targeting the interaction between long noncoding RNA XR_001779380 and Prdm1 to enhance IFN-γ immunity in murine neonatal intestinal epithelial cells |
| title_full_unstemmed | Targeting the interaction between long noncoding RNA XR_001779380 and Prdm1 to enhance IFN-γ immunity in murine neonatal intestinal epithelial cells |
| title_short | Targeting the interaction between long noncoding RNA XR_001779380 and Prdm1 to enhance IFN-γ immunity in murine neonatal intestinal epithelial cells |
| title_sort | targeting the interaction between long noncoding rna xr 001779380 and prdm1 to enhance ifn γ immunity in murine neonatal intestinal epithelial cells |
| topic | Prdm1 IFN-gamma antisense oligonucleotides intestinal epithelium neonates LncRNAs |
| url | https://journals.asm.org/doi/10.1128/mbio.00773-25 |
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