Viral and cellular microRNAs as determinants of viral pathogenesis and immunity

Abstract

MicroRNAs (miRNAs) have recently emerged as key posttranscriptional regulators of gene expression in multicellular eukaryotes. It is increasingly clear that miRNAs of both viral and cellular origin can positively or negatively influence viral replication. Viral miRNAs can directly alter host physiology, including components of the immune system, and host miRNAs can directly alter the virus life cycle. Here, we discuss what is known about how viral and cellular miRNAs influence viral replication and pathogenic potential through their regulation of viral mRNAs or by reshaping cellular gene expression.

Figure 1. Potential mechanisms of viral miRNA function

(A) dsDNA virus-derived miRNAs may target viral transcripts that are transcribed antisense to the miRNA precursor for degradation by RISC (green circle). (B) Viral miRNAs may inhibit translation of viral transcripts carrying imperfect matches to the miRNA. (C) Viral miRNAs may engage in novel interactions with host mRNAs (red) or function as orthologs of cellular miRNAs and therefore inhibit the normal mRNA targets of the orthologous host cell miRNA (purple).

Figure 2. Potential effect of cellular miRNAs on virus replication

Cellular miRNAs (purple) may bind viral RNAs and thereby directly promote viral replication, as in the case of miR-122, which promotes HCV RNA replication. Cellular miRNAs may mediate the recognition of viral mRNAs (red) by RISC (green circle) and thereby limit virus replication. In this case, viral mRNAs would likely be under evolutionary pressure to avoid matches to cellular miRNAs abundantly expressed in their physiological host cells. Finally, cellular miRNAs might indirectly promote or limit virus replication through regulation of their endogenous mRNA targets. In this case, viruses could benefit from re-shaping the cellular miRNA environment.

Figure 3. Viral miRNAs with cellular orthologs

Seed alignments of viral miRNAs with their known or candidate cellular orthologs (homologous bases are in red) are shown. KSHV miR-K12-11 functions as an ortholog of cellular miR-155 (Gottwein et al., 2007; Skalsky et al., 2007). Other potential orthologs of viral miRNAs referred to in the text are listed. Nucleotides that distinguish hsa-miR-18a from hsa-miR-18b are in black and bold. miRNAs are designated as in miRBase (http://microrna.sanger.ac.uk/). Abbreviations: hsa, homo sapiens (human); gga, gallus gallus (chicken); mmu, mus musculus (mouse); mghv, murine gammaherpesvirus 68 (MHV68).