Background:The mammalian antiviral response is regulated by virus-induced changes in cellular gene expression. Results: Cellular miRNAs are induced by influenza virus to regulate antiviral response genes including IRAK1 and MAPK3. Conclusion: Influenza virus infection alters the miRNA profile of human cells to regulate innate immune signaling. Significance: The miRNA response to influenza virus identifies new pathways of cell regulation that modulate the mammalian innate antiviral response.

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The mammalian antiviral response relies on the alteration of cellular gene expression, to induce the production of antiviral effectors and regulate their activities. Recent research has indicated that virus infections can induce the accumulation of cellular microRNA (miRNA) species that influence the stability of host mRNAs and their protein products. To determine the potential for miRNA regulation of cellular responses to influenza A virus infection, small RNA profiling was carried out using next generation sequencing. Comparison of miRNA expression profiles in uninfected human A549 cells to cells infected with influenza A virus strains A/Udorn/72 and A/WSN/33, revealed virus-induced changes in miRNA abundance. Gene expression analysis identified mRNA targets for a cohort of highly inducible miRNAs linked to diverse cellular functions. Experiments demonstrate that the histone deacetylase, HDAC1, can be regulated by influenza-inducible miR-449b, resulting in altered mRNA and protein levels. Expression of miR-449b enhances virus and poly(I:C) activation of the IFNβ promoter, a process known to be negatively regulated by HDAC1. These findings demonstrate miRNA induction by influenza A virus infection and elucidate an example of miRNA control of antiviral gene expression in human cells, defining a role for miR-449b in regulation of HDAC1 and antiviral cytokine signaling.

Dopaminergic amacrine (DA) cells play multiple and important roles in retinal function. Neurotrophins are known to modulate the number and morphology of DA cells, but the underlying regulatory mechanisms are unclear. Here we investigate how neurotrophin-3 (NT-3) regulates DA cell density in the mouse retina. We demonstrate that overexpression of NT-3 up-regulates DA cell number, and leads to a consequent increase in the density of DA cell dendrites. To examine the mechanisms of DA cell density increase, we further investigate the effect of NT-3 overexpression on retinal apoptosis and mitosis during development. We find that NT-3 does not affect the well-known wave of retinal cell apoptosis which normally occurs during the first two weeks after birth. Instead, overexpression of NT-3 promotes additional mitosis of DA cells at postnatal day 4, but does not affect cell mitosis before birth, the peak period of amacrine cell genesis in wildtype retinas. We next show that retinal explants cultured from birth to day 7 without extra NT-3 produced by lens exhibit similar number of DA cells as in wildtype, further supporting the notion that postnatal overexpression of lens-derived NT-3 affects DA cell number. Moreover, the additional mitosis after birth in NT-3 overexpressing mice does not occur in calretinin-positive amacrine cells or PKC-positive rod ON bipolar cells. Thus, the NT-3 triggered wave of cell mitosis after birth is specific for the retinal DA cells.

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