Integrative analysis of miRNA-RBP-splicing interactions during respiratory syncytial virus infection

Abstract

Introduction: Respiratory syncytial virus (RSV) is a major cause of severe acute lower respiratory tract infections (ALRI), with incomplete elucidation of its pathogenesis and intricate host-virus crosstalk constraining the development of effective therapies. The post-transcriptional interplay among microRNAs (miRNAs), RNA-binding proteins (RBPs), and alternative splicing (AS) is a critical, yet underexplored host response layer.

Methodology: We integrated and analyzed three public datasets (GSE231784, GSE231788, and GSE155151) of RSV-infected A549 cells, screened differentially expressed miRNAs, identified conserved differentially expressed RBPs, used SUVA to detect AS events, and constructed a miRNA-RBP-AS network to find core axis. This integrated bioinformatics approach enabled systematic dissection of multi-layered post-transcriptional regulation during RSV infection.

Results: Our analysis revealed that RSV infection substantially alters host post-transcriptional regulation, with 86 conserved differentially expressed RBPs and 94 conserved AS events identified. A potential miRNA-RBP-AS axis was uncovered via regulatory network construction. Crucially, this axis suggests that the downregulation of let-7 family miRNAs (e.g., let-7f-2-3p, let-7a-3p) is strongly associated with the upregulation of the RBP genes SAMD4A and ENOX1. The expression of these RBPs, in turn, correlates with the AS of host genes that are implicated in viral replication and immunity, such as TNIP1 and NR5A2.

Conclusions: These findings propose that RSV may exploit this post-transcriptional crosstalk to modulate host immunity and facilitate viral replication. Through bioinformatics analysis, this study provides a novel, system-level map of RSV-host interactions and identifies the let-7-SAMD4A/ENOX1-TNIP1/NR5A2 axis as a promising new target for future antiviral strategies, though this requires further experimental validation.