Jin Kehua, Gong Ai-Yu, Wang Shuhong, Martins Gislaine A, Strauss-Soukup Juliane K, O'Connor Roberta M, Chen Xian-Ming
Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USA.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning, Hubei, China.
mBio. 2025 Jul 9;16(7):e0077325. doi: 10.1128/mbio.00773-25. Epub 2025 Jun 11.
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 , 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- 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. 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- 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 infection.
肠上皮细胞（IECs）是肠道宿主防御的第一线，干扰素信号在调节上皮细胞对细胞内病原体的固有防御中起着关键作用。然而，婴儿胃肠道中干扰素-γ介导的抗菌防御通常会降低，其潜在机制尚不清楚。我们之前观察到lncRNA XR_001779380可促进小鼠IECs中干扰素-γ刺激基因的转录。有趣的是，它与Prdm1（一种在新生儿而非成年肠道上皮中表达的DNA结合蛋白）相互作用，会减弱干扰素-γ刺激基因的转录，从而导致新生儿肠道中干扰素-γ介导的上皮细胞固有防御受到抑制。在本研究中，我们进一步研究了Prdm1在抑制小鼠新生儿IECs中干扰素-γ反应中的作用。此外，我们探索了开发特异性反义寡核苷酸来干扰XR_001779380与Prdm1的相互作用，以促进IECs中的干扰素-γ反应。我们的数据表明，Prdm1抑制干扰素-γ介导的基因转录，其诱导会抑制干扰素-γ刺激的细胞对一种顶复门寄生虫的固有防御，该寄生虫是全球幼儿感染性腹泻及腹泻相关死亡的主要原因。此外，设计用于阻断Prdm1与XR_001779380相互作用的反义寡核苷酸可促进小鼠新生儿IECs中的干扰素-γ反应，从而增强细胞对该寄生虫的固有防御。
与成年人相比，新生儿和婴儿肠道上皮的先天性抗菌防御通常会降低，导致感染易感性增加；然而，其潜在机制仍未完全了解。该寄生虫是全球儿童感染性腹泻及腹泻相关死亡的主要原因。Prdm1是一种DNA结合蛋白，在新生儿而非成年肠道上皮中表达。在我们之前的研究中，我们发现Prdm1招募XR_001779380形成Prdm1/Stat1/Pias1复合物。该复合物的形成导致新生儿IECs中干扰素-γ刺激基因的转录受到抑制。在本研究中，我们进一步研究了Prdm1表达对新生儿IECs中干扰素-γ刺激的细胞对该寄生虫固有防御的影响。我们还探索了针对Prdm1-RNA相互作用的基于RNA的治疗方法增强细胞对干扰素-γ反应的潜力。我们的研究结果支持靶向Prdm1与XR_001779380相互作用的反义寡核苷酸可促进干扰素-γ刺激基因的转录，并增强细胞对该寄生虫感染的固有防御。
