Viruses and miRNAs: More Friends than Foes

Abstract

There is evidence that eukaryotic miRNAs (hereafter called host miRNAs) play a role in the replication and propagation of viruses. Expression or targeting of host miRNAs can be involved in cellular antiviral responses. Most times host miRNAs play a role in viral life-cycles and promote infection through complex regulatory pathways. miRNAs can also be encoded by a viral genome and be expressed in the host cell. Viral miRNAs can share common sequences with host miRNAs or have totally different sequences. They can regulate a variety of biological processes involved in viral infection, including apoptosis, evasion of the immune response, or modulation of viral life-cycle phases. Overall, virus/miRNA pathway interaction is defined by a plethora of complex mechanisms, though not yet fully understood. This article review summarizes recent advances and novel biological concepts related to the understanding of miRNA expression, control and function during viral infections. The article also discusses potential therapeutic applications of this particular host-pathogen interaction.

Keywords: clinical perspectives; gene expression; microRNAs; viral microRNAs; virus life cycle.

FIGURE 1

Viruses interfere with host miRNA biogenesis. Primary miRNAs (pri-miRNAs) processing, first to precursor miRNAs (pre-miRNAs) and then to mature miRNAs, involves two ordered endonucleolytic cleavages. Following transcription by RNA polymerase II/III, the multiprotein complex containing Drosha processes the pri-miRNA into a ∼70 nt hairpin pre-miRNA. Through the interaction with exportin-5 and Ran-GTP, the pre-miRNA is transported into the cytoplasm where it undergoes a second round of processing catalyzed by Dicer. One strand of the resulting small RNA duplex, the mature miRNA, is loaded into the RNA induced silencing complex (RISC) which post-transcriptionally regulates the expression of target genes. Expression of viral proteins termed viral suppressor of RNA silencing inhibits the loading of miRNAs into the RISC complex (tomato bushy stunt virus p19 protein) or Ago2 activity (cucumber virus 2b protein). Multiple processes mediated by Epstein–Barr virus are responsible for miR-155 upregulation, among which chromatin remodeling, cell signaling regulation and transcription factor activation. Flaviviruses sfRNA and Vaccinia virus inhibit or reduce the expression of Dicer activity, respectively. Finally, several Herpesviruses encode viral sequences complementary to mature miRNAs miR-17 and miR-27, leading to their degradation or the inhibition of the miRNA-induced regulation of mRNA targets.

FIGURE 2

Host miRNAs directly improve RNA virus replication. Direct interaction of 3′ end- bovine viral diarrhea virus (BVDV), 3D-coding of region Coxsackie virus B3 (CVB3), and 5′-IRES of hepatitis C virus (HCV) RNAs with host miR-17, let-7, miR-10a-3p, and miR-122, respectively, increases viral replication (dark arrows). The unusual interaction between host miRNA and increasing amounts of viral RNA during replication implies a diminution of the interaction of the host miRNA with its cellular targets (“sponge effect”) (dark dotted inhibition arrows). MiR-10a-3p targets mRNAs implicated in temozolomide resistance (Ujifuku et al., 2010) indicating that miR-10a-3p is not only a passenger miRNA but has a functional role in the cells [image source for CVB3 (Luo et al., 2010) and HCV (Lindenbach and Rice, 2013)].

FIGURE 3

Host miRNA-146a favors viral replication. MiR-146a expression is increased upon vesicular stomatitis virus (VSV), Japanese encephalitis virus (JEV), and Dengue virus infection. In the case of VSV infection, miR-146a expression is increased in a RIG-I dependent manner. The RIG-I protein interacts with VSV RNA via its helicase domain, leading to the nuclear transcription of pri-miR-146a by NF-kB, and to an increasing amount of miR-146a. The proviral function of miR-146a is explained by the diminution of target mRNAs such as IRAK1, IRAK2, which are essential partners of the type I interferon response [image source for JEV adapted from Luca et al. (2012)].

FIGURE 4

Host miRNAs that favor viral replication via the inhibition of the Jak/STAT signaling pathway. Cellular miRNAs (miR-9041, miR-9850, miR-29a, and miR-373) are upregulated during DNA [White spot syndrome virus (WSSV)] or RNA (respiratory syncytial virus, HCV) viruses infections. The proviral function of miR-9041, miR-9850, miR-29a, and miR-373 is explained by the diminution of target mRNAs coding for key elements of the JAK/STAT signaling pathway, such as STAT, IFNAR, JAK1, IRF9. Consequently, the formation of the STAT-IRF9 complex is impaired and the activity of the ISRE (interferon-stimulated response element) promoter is reduced (dotted arrows) [image source for HCV (Lindenbach and Rice, 2013)].