Induction of a long non-coding RNA, lncRNA-Chr1:1226, by Cryptosporidium infection primes intestinal epithelial cells for IFN-γ-mediated host antimicrobial gene transcription

Abstract

Abstract Cryptosporidium, a protozoan parasite that infects the intestinal epithelium and other mucosal surfaces in animals and humans, is an important opportunistic pathogen in AIDS patients and a common cause of diarrhea in young children in developing countries. Intestinal epithelial cellular defense is key to innate mucosal anti-Cryptosporidium defense but underlying molecular mechanisms are still obscure. Here, we identified several long non-coding RNAs (lncRNAs) that are predominantly expressed in intestinal epithelial cells. Several of such epithelial-enriched lncRNAs, such as lncRNA-Chr1:1226, were upregulated in cells following C. parvum infection. Induction of lncRNA-Chr1:1226 in infected intestinal epithelial cells was controlled by TLR4/NF-κB/Cdc42 signaling and epithelial specific transcription factor Eif3. Induction of lncRNA-Chr1:1226 promoted IFN-γ-mediated epithelial antimicrobial defense, through facilitating STAT1/SWI/SNF-associated chromatin remodeling to promote IFN-γ-mediated transcription of defense genes in intestinal epithelial cells. We observed that IFN-γ-mediated antimicrobial defense was suppressed in neonatal intestinal epithelium. Expression of PRDM1 in the neonatal intestinal epithelium might contribute to suppression of IFN-γ-mediated antimicrobial gene transcription. Furthermore, PRDM1 interacted with lncRNA-Chr1:1226 and PIAS1 to attenuate SWI/SNF-mediated antimicrobial transcription induced by IFN-γ in intestinal epithelium of neonates. Our data demonstrate that lncRNAs, particularly epithelial lncRNAs, may be key regulators in IFN-γ-mediated epithelial defense.