Characterizing host microRNA: virus interactions of Orthoavulavirus javaense

Authors: Bakre, Abhijeet; Mears, Megan

Submitted to: Viruses
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/5/2024
Publication Date: 11/7/2024
Citation: Bakre, A.A., Mears, M.C. 2024. Characterizing host microRNA: virus interactions of Orthoavulavirus javaense. Viruses. 16(11):1748. https://doi.org/10.3390/v16111748.
DOI: https://doi.org/10.3390/v16111748

Interpretive Summary: Virulent strains of Orthoavulavirus javaense (OAVJ) cause Newcastle disease in many avian species but are of special concern for the poultry industry. We hypothesized that virulent viruses encode mechanisms to delay / inhibit the immune response in birds enabling them to spread rapidly within and between species. MicroRNAs which are highly conserved small regulatory RNAs also found in the chicken genome, regulate both viral sensing and the immune response to infection. To identify how virulent OAVJs may alter microRNA function we analyzed the potential interactions between the OAVJ nucleic acid (viral RNA) and chicken microRNAs. Through computational analysis we identified potential examples where viral RNA sequences could stop (sponges) or enhance (mimic) the function of these chicken microRNAs. We studied the distribution of these viral RNA motifs amongst different genes in the OAVJ genome(s) as well as between viruses of different virulence. Data showed an abundance of the mimic motifs in virulent viruses versus an abundance of the sponges in the low virulence viruses. Abundance of either the sponge / mimic motifs was independent of length of viral gene. Experimental data validated binding of one such sponge motif in the viral RNA with a chicken microRNA 27b in a sequence dependent manner leading to changes in viral gene expression. The selective abundance of the mimics vs sponges in high virulence vs low virulence OAVJ viruses observed here suggests that virulent OAVJs may have selectively preserved these mimics to increase fitness.

Technical Abstract: Post transcriptional gene regulation mediated by microRNAs (miRNAs) relies on sequence complementarity between the miRNA seed site and a complementary sequence in the target gene transcripts). This complementarity can completely inhibit or reduce translation into protein. We hypothesized that viruses employ sequence complementarity / similarity with host miRNAs to inhibit or increase miRNA mediated regulation of host gene expression specifically during viral infection(s). In this study, we focus on Orthoavulavirus javaense (OAVJ), the causative of Newcastle disease, a poultry disease with significant economic impact.computational analysis of OAVJ genomes from low virulence(lentogenic) versus virulent (velogenic) viruses was carried out to identify viral signature motifs that potentially either mimic or complement host miRNA seed sequences. Data show that OAVJ genomes harbor viral seed mimics (vSMs) or viral seed sponges (vSSs) and can mimic host miRNAs or inhibit their regulation of host genes disrupting cellular pathways. Analysis showed that velogens encode a statistically significant higher number of vSMs and a lower number of vSSs relative to lentogens. The number of vSMs or vSSs did not correlate with gene length. Analysis of secondary structure flanking these vSMs and vSSs show structural features common to miRNA precursors. Inhibition or upregulation of vSS-miR-27b-5p altered P gene expression in a sequence dependent manner. These data demonstrate that viral transcripts can interact with host miRNAs to alter the outcomes of infection.