Integrative Deep Sequencing of the Mouse Lung Transcriptome Reveals Differential Expression of Diverse Classes of Small RNAs in Response to Respiratory Virus Infection

Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
mBio (Impact Factor: 6.79). 10/2011; 2(6). DOI: 10.1128/mBio.00198-11
Source: PubMed


We previously reported widespread differential expression of long non-protein-coding RNAs (ncRNAs) in response to virus infection. Here, we expanded the study through small RNA transcriptome sequencing analysis of the host response to both severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza virus infections across four founder mouse strains of the Collaborative Cross, a recombinant inbred mouse resource for mapping complex traits. We observed differential expression of over 200 small RNAs of diverse classes during infection. A majority of identified microRNAs (miRNAs) showed divergent changes in expression across mouse strains with respect to SARS-CoV and influenza virus infections and responded differently to a highly pathogenic reconstructed 1918 virus compared to a minimally pathogenic seasonal influenza virus isolate. Novel insights into miRNA expression changes, including the association with pathogenic outcomes and large differences between in vivo and in vitro experimental systems, were further elucidated by a survey of selected miRNAs across diverse virus infections. The small RNAs identified also included many non-miRNA small RNAs, such as small nucleolar RNAs (snoRNAs), in addition to nonannotated small RNAs. An integrative sequencing analysis of both small RNAs and long transcripts from the same samples showed that the results revealing differential expression of miRNAs during infection were largely due to transcriptional regulation and that the predicted miRNA-mRNA network could modulate global host responses to virus infection in a combinatorial fashion. These findings represent the first integrated sequencing analysis of the response of host small RNAs to virus infection and show that small RNAs are an integrated component of complex networks involved in regulating the host response to infection.

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    • "H3K3me3, Figure 4). Given virus infection and other inflammatory diseases have been shown to affect the expression of snoRNA’s and other non coding RNAs [33,34], these findings suggest that SNORA12 is a component of the antiviral or inflammatory processes within the airway epithelium. "
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    • "Predicted target genes of these miRNAs encoded cell death and inflammatory factors involved in influenza pathogenesis, which suggest that their regulation could play crucial roles in influenza virulence (Li et al., 2011). In mice, 45 miRNAs were differentially expressed in lung samples from different mouse strains during severe acute respiratory syndrome coronavirus (SARS-CoV) (MA15) or influenza virus (PR8) infection and expression of 6 miRNAs was confirmed to change after VN1203 infection (Peng et al., 2011). These miRNAs, such as miR155 that was previously implicated in lymphocyte function (Vigorito et al., 2007), represent potential important regulators of the host response and provide an interesting target to validate in studies focused on understanding their mechanisms. "
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    • "ular interest since it is known to be directly regulated by p53 and involved in the regulation of p53 - mediated cell death ( Hermeking , 2010 ) . Interestingly , we have previously shown , by a transcriptional profiling approach , that members of the p53 pathway , including p53 transcriptional targets , are strongly downregulated upon infection ( Terrier et al . , 2011 ) . The absence or presence of miR - 34c in influenza - infected cells , at levels below the detection threshold , could play a role in p53 - mediated cell death upon infection and requires further investigation . This hypothesis is reinforced by the downregulation of miR - 34a , another member of the miR - 34 family , observed in infec"
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