Deregulation of Type I IFN-Dependent Genes Correlates with Increased Susceptibility to Cytomegalovirus Acute Infection of Dicer Mutant Mice

Abstract

Regulation of gene expression by microRNAs (miRNAs) is now considered as an essential mechanism for cell development and homeostasis. Indeed, numerous studies have reported that modulating their expression, maturation, or activity can affect cell survival, identity or activation. In particular, miRNAs are key players in the tight regulation of signaling cascades, and as such, they appear as perfectly suited immunomodulators. Several immune-related processes, including inflammation, have recently been demonstrated to require specific miRNAs. In addition, the discovery of herpesvirus-encoded miRNAs has reinforced this assumption. To decipher the potential roles of miRNAs in innate antiviral immune response, we developed an in vivo model based on the inoculation of mouse cytomegalovirus (MCMV) in mice. Furthermore, we exploited a mouse line carrying a hypomorphic mutation in the Dicer gene to visualize the impact of impaired miRNA biogenesis upon the anti-MCMV response. Our data indicate that miRNAs are important actors in mounting an efficient response against herpesviruses. We suggest that a rapid and transient interferon response following viral infection requires miRNA-dependent repressor release. In addition, our in vivo efforts identified several miRNA targets, thus providing a conceptual framework for future analyzes on the regulation of specific actors involved in the Type I interferon pathway.

Reciprocal Inhibition between Intracellular Antiviral Signaling and the RNAi Machinery in Mammalian Cells

“…Similar results of slightly less magnitude were observed without IFN pretreatment (data not shown). Recent in vivo work shows that Dicer hypomorphic mice controlled viral infection better than wild type mice at early times post-infection (Ostermann et al, 2012). This observation could be explained by the effects of miR-17/93 (or similar-functioning miRNAs) on ISG expression.…”

“…PKR, RNaseL) requires detection of intracellular pathogen associated molecular patterns (PAMPs) by a pattern recognition receptor (PRR). The translation of at least some ISG transcripts is regulated post-transcriptionally by miRNAs (Cloonan et al, 2008; Gregersen et al, 2010; Lee et al, 2012; Ostermann et al, 2012). Here, we test the hypothesis that antiviral signaling in mammalian cells alters the RNAi response, thereby altering expression of components of the IFN response.…”

MicroRNA miR-27 Inhibits Adenovirus Infection by Suppressing the Expression of SNAP25 and TXN2

“…For many viruses, the mechanism of infection is positively or negatively regulated by miRNA-mediated posttranscriptional silencing (4,5,42,43); however, it has remained to be elucidated whether miRNAs regulate Ad infection. The aim of this study was to examine whether Ad infection is regulated by miRNA-mediated posttranscriptional silencing and to identify miRNAs and their target genes involved in Ad infection.…”

“…Several previous reports demonstrated that host miRNAs inhibited viral infection via various mechanisms (2)(3)(4)(5). Triboulet et al showed that a host miR-17/92 cluster directly suppressed expression of the cellular p300/CREB-binding protein (CBP)-associated factor (PCAF), leading to inhibition of HIV-1 replication (3).…”

“…Various types of viruses encode inhibitors of general or specific miRNAs in order to circumvent miRNA-mediated inhibition of virus infection (2,(6)(7)(8)(9)(10)(11)(12). Moreover, knockdown of cellular factors involved in miRNA-mediated posttranscriptional gene silencing, including Dicer, also reduces miRNA expression levels, leading to enhancement of infection with various types of viruses, including mouse cytomegalovirus (MCMV) and VSV (2,4,5). Thus, numerous miRNAs that regulate virus infection have been reported, but the mechanisms of miRNA-mediated regulation of virus infection have not been clarified completely.…”