MicroRNA expression and virulence in pandemic influenza virus-infected mice - PubMed (original) (raw)
MicroRNA expression and virulence in pandemic influenza virus-infected mice
Yu Li et al. J Virol. 2010 Mar.
Abstract
The worst known H1N1 influenza pandemic in history resulted in more than 20 million deaths in 1918 and 1919. Although the underlying mechanism causing the extreme virulence of the 1918 influenza virus is still obscure, our previous functional genomics analyses revealed a correlation between the lethality of the reconstructed 1918 influenza virus (r1918) in mice and a unique gene expression pattern associated with severe immune responses in the lungs. Lately, microRNAs have emerged as a class of crucial regulators for gene expression. To determine whether differential expression of cellular microRNAs plays a role in the host response to r1918 infection, we compared the lung cellular "microRNAome" of mice infected by r1918 virus with that of mice infected by a nonlethal seasonal influenza virus, A/Texas/36/91. We found that a group of microRNAs, including miR-200a and miR-223, were differentially expressed in response to influenza virus infection and that r1918 and A/Texas/36/91 infection induced distinct microRNA expression profiles. Moreover, we observed significant enrichment in the number of predicted cellular target mRNAs whose expression was inversely correlated with the expression of these microRNAs. Intriguingly, gene ontology analysis revealed that many of these mRNAs play roles in immune response and cell death pathways, which are known to be associated with the extreme virulence of r1918. This is the first demonstration that cellular gene expression patterns in influenza virus-infected mice may be attributed in part to microRNA regulation and that such regulation may be a contributing factor to the extreme virulence of the r1918.
Figures
FIG. 1.
The infections of H1N1 influenza viruses r1918 and Tx/91 induce distinct cellular microRNA expression patterns in mouse lungs. (a) Distinct cellular microRNA expression patterns in r1918- and Tx/91-infected mouse lungs. The columns correspond to the expression patterns of differentially expressed microRNAs between r1918- and Tx/91-infected mouse lungs on days 1, 3, and 5. The y axis indicates the number of differentially expressed microRNAs. The microRNAs satisfied a cutoff ANOVA P value of ≤0.01 of direct comparison and the absolute fold change between r1918 and Tx/91 of ≥1.5. Red represents microRNA with increased expression in r1918- or Tx/91-infected samples, relative to mock-infected samples. Green represents microRNA with decreased expression in r1918- or Tx/91-infected samples, relative to mock-infected samples. (b) Correlation coefficient of microRNA expression changes derived from microRNAs arrays and TaqMan qRT-PCR assays. Each spot represents one microRNA per time point measurement. The x axis represents the fold change in r1918-infected samples relative to Tx/91-infected samples derived from microRNA arrays. The y axis represents the fold change in r1918-infected samples relative to Tx/91-infected samples derived from TaqMan qRT-PCR assays. The overall correlation coefficient is represented by the _R_2 value. A total of 8 microRNAs from the three days were tested. One spot represents three biological duplicates.
FIG. 2.
A total of 18 microRNAs demonstrate various expression patterns between r1918-infected and Tx/91-infected lungs. All fold changes shown here are relative to mock-infected lungs. A red bar indicates an r1918 infection, and a blue bar indicates a Tx/91 infection.
FIG. 3.
Schematic representation of the strategy for assessing the functional associations of the differentially expressed microRNAs. A rectangular shape represents the type of microRNA, gene, or pathway. A diamond shape represents the type of database. An oval shape represents the type of analysis.
FIG. 4.
miR-200a is implicated in the type I interferon signaling pathway. (Top) Type I interferon signaling pathway comprised of miR-200a targets; (bottom) expression changes of miR-200a and its targets associated with the type I interferon pathway in r1918-infected samples. Red represents microRNA or targets that have increased expression in r1918-infected samples, relative to Tx/91-infected samples. Green represents microRNA or targets that have decreased expression in r1918-infected samples, relative to Tx/91-infected samples.
FIG. 5.
miR-223 is implicated in the CREB signaling pathway. (Top) CREB pathway comprised of miR-223 targets; (bottom) expression changes of miR-223 and its targets associated with the CREB pathway in r1918-infected samples. Red represents microRNA or targets that have increased expression in r1918-infected samples, relative to Tx/91-infected samples. Green represents microRNA or targets that have decreased expression in r1918-infected samples, relative to Tx/91-infected samples.
FIG. 6.
The r1918 might potentially regulate the cellular microRNA expression at multiple levels.
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