Abstract
Licensed live attenuated vaccines have been developed to prevent varicella zoster virus (VZV) infection, which causes chickenpox and shingles. The genomic sequences of both clinical- and vaccine-derived VZV strains have been analyzed previously. To further characterize the molecular signatures and complexity of wildtype (clinical) versus attenuated (vaccine-derived) VZV-mediated host cellular responses, we performed high-throughput next generation sequencing to quantify and compare the expression patterns of mRNAs and microRNAs (miRNAs) in primary human dermal fibroblasts (HDFs) infected with wildtype (YC01 low passage) and attenuated (YC01 high passage, SuduVax, and VarilRix) VZV strains. 3D-multidimensional scaling of the differentially expressed genes demonstrated the distinct grouping of wildtype and attenuated strains. In particular, we observed that HDFs infected with attenuated strains had more differentially expressed genes (DEGs) involved in the retinoic-acid inducible gene–I-like receptor and interferon-mediated signaling pathways compared with wildtype strains. Additionally, miRNA expression patterns were profiled following the infection of HDFs with VZV. Small RNA sequencing identified that several miRNAs were upregulated, including miR-146a-5p, which has been associated with other herpesvirus infections, whereas let-7a-3p was downregulated in both wildtype and attenuated VZV-infected cells. This study identified genes and miRNAs that may be essential in VZV pathogenesis.
Highlights
Varicella zoster virus (VZV), a member of the Alphaherpesvirinae family, is the primary causative agent of chickenpox [1]
These data indicate a good sample cluster based on gene expression pattern similarity, whilst a clear difference was observed between the wildtype and attenuated varicella zoster virus (VZV)-infected human dermal fibroblasts (HDFs)
The wildtype and attenuated VZV-infected samples were distinctly distributed in the 3D-Multidimensional Scaling (MDS) plot and attenuated strains (YC01-high, SuduVax, and VarilRix) were most closely related, suggesting that the samples clustered best according to their respective virus types
Summary
Varicella zoster virus (VZV), a member of the Alphaherpesvirinae family, is the primary causative agent of chickenpox (varicella) [1]. Pathogens 2019, 8, 183 preparation (19,000 PFU vs 1350 PFU) ZostaVax (Merck) is routinely used to prevent herpes zoster [3,4] These vaccines were attenuated from a wildtype virus (pOka) isolated from a small child with primary varicella [5]. We conducted a comparative genomic analysis of VZV single nucleotide polymorphisms (SNPs) and identified 24 vaccine-specific sites that were commonly found in all vaccine strains, including SuduVax, VariVax, and VarilRix [12]. These nonsynonymous mutations were found in ORFs 0, 6, 31, 39, 55, 62, and 64 in all three vaccine strains. Our work provides a global overview of virus type-specific mRNA and miRNA profiles, and gives an insight into the effect of vaccine-type VZV mutations on host immune signaling and the microRNA network
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