RNA-RNA interactions between Respiratory syncytial virus and miR-26 and miR-27 are associated with regulation of cell cycle and antiviral immunity

Abstract

Specific viruses can sequester or inhibit miRNAs through direct RNA-RNA interactions to enable their life cycle, but we still lack comprehensive understanding of the existence and functions of such interactions in respiratory virus infections. Here we optimise the CLEAR-CLIP protocol in A549 cells and show that Respiratory syncytial virus (RSV) directly binds miR-26, miR-27, and let-7. We show a significant global up-regulation of miR-26 targets upon RSV infection as well as up-regulation of miR-27 targets involved in cell cycle regulation and immune signalling. Through genome analysis of miRNA-target reads we further show that pseudogenes which overlap transcriptional regulatory regions are functional miRNA targets. We identify and validate an interaction between miR-27 and a pseudogene-derived lncRNA that overlaps an enhancer and show that this interaction regulates expression of Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). This work demonstrates that RSV directly interacts with host miRNAs to de-regulate host gene expression and provides biochemical support for the ability of miRNAs to directly regulate gene transcription linked to immune signalling.