Respiratory Syncytial Virus Regulates Human MicroRNAs by Using Mechanisms Involving Beta Interferon and NF-κB

Respiratory syncytial virus (RSV) is the most common viral cause of severe lower respiratory tract illness in infants and children. The virus replicates in polarized epithelial cells in the airway and, to a lesser extent, infects airway antigen-presenting cells, such as dendritic cells (DCs). RSV possesses a number of expressed genes that antagonize the effect of type I interferons and other related host factor pathways that inhibit replication efficiency. Virus infection alters host gene transcription and the translation of host transcripts through specific antagonism of the function of host proteins, through induction of RNA stress granules, and through induction of altered patterns of host gene expression. In healthy cells, microRNAs (miRNAs) regulate gene expression by targeting the noncoding region of mRNA molecules to cause silencing or degradation of transcripts. It is not known whether or not RSV infection alters the level of microRNAs in cells. We profiled the pattern of expression of host cell microRNAs in RSV-infected epithelial cells or DCs and found that RSV did alter microRNA expression but in a cell-type-specific manner. The studies showed that let-7b was upregulated in DCs, while let-7i and miR-30b were upregulated in epithelial cells in a process that required viral replication. Interestingly, we found that the RSV nonstructural genes NS1 and NS2 antagonized the upregulation of let-7i and miR-30b. RSV appears to manipulate host cell gene expression through regulation of expression of miRNAs related to the interferon response. The data suggest a new mechanism of virus-host cell interactions for paramyxoviruses.