Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression

Abstract

Dicer is essential for plant, Caenorhabditis elegans, and Drosophila antiviral responses because of its role in generating small interfering RNA (siRNA) from viral genomes. We show that because of impaired miRNA production, mice with a variant Dicer1 allele (Dicer1(d/d)) were more susceptible to vesicular stomatitis virus (VSV) infection. We did not detect VSV genome-derived siRNA in wild-type cells or any alteration of interferon-mediated antiviral responses by Dicer1 deficiency. Rather, we found that host miR24 and miR93 could target viral large protein (L protein) and phosphoprotein (P protein) genes, and a lack of miR24 and miR93 was responsible for increased VSV replication in Dicer1(d/d) cells. Our data suggest that host miRNA can play a role in host interactions with viruses.

MicroRNAs in the regulation of TLR and RIG-I pathways

“…120,123,124 Cellular miRNAs are highly induced or regulated by viral infection, and can affect both the viral replication and host anti-viral immunity. Repression of Dicer increases the replication of HIV-1, VSV and influenza A virus, [125][126][127] suggesting that cellular miRNAs play a role in the restriction of viral biology. Individual miRNAs that target viral genes responsible for this restriction have been identified.…”

“…128 Hypersusceptibility to VSV infection in Dicer1-deficient mice is due to impaired miR-24 and miR-93 expression, which target VSV L and P proteins. 125 Furthermore, human miR-32 has been shown to repress replicationessential viral proteins and restrict the retrovirus primate foamy virus type 1 replication. 129 However, miR-122, which is specifically expressed and highly abundant in human liver, targets 59-UTR of HCV RNA.…”

Everything you wanted to know about small RNA but were afraid to ask

“…135 Mice homozygous for an unusual hypomorph allele of Dicer1 show increased susceptibility to infection by vesicular stomatitis virus (VSV). 136 VSV mutated to ablate putative binding sites for host miR-24 and miR-93 has increased virulence, suggesting that these host microRNAs could work in a Dicer1-dependent manner to limit the course of the viral infection. 136 In another twist, several cellular microRNAs have been shown to bind HIV-1 encoded transcripts, limiting production of the viral proteins, but ironically contributing to the ability of the retrovirus to remain latent and undetected by the immune system in quiescent CD4-positive T cells.…”

Silencing suppressors: viral weapons for countering host cell defenses

“…Although a single specific viral-derived siRNA corresponding to the structured Rev responsive element has been detected in human immunodeficiency virus-1 (HIV-1) infected cells (Bennasser et al, 2005), this observation could not be reproduced by another laboratory (Lin and Cullen, 2007). The second reason is that many viruses, such as influenza A virus and vaccinia virus, replicated to similar, or even lower, viral titers in Dicer −/− macrophages (Otsuka et al, 2007). On the other hand, although whether viruses encode miRNAs during the infection process has been controversial, increasing evidence suggests that miRNAs which are encoded by host cells can regulate the replication of the virus.…”

“…Song et al reported that host miR-323, miR-491 and miR-654 inhibit the replication of the H1N1 influenza virus in MDCK cells by binding and degrading PB1 (a subunit of influenza virus RNA polymerase) (Song et al, 2010). Otsuka et al have reported that host miR-24 and miR-93 can target viral large protein and phosphoprotein genes, and that a lack of miR-24 and miR-93 is responsible for increased vesicular stomatitis virus (VSV) replication (Otsuka et al, 2007). These data suggest that RNAi is probably part of the innate immune system in mammals.…”