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MicroRNA profiling of extracellular vesicles isolated from rhesus macaques vaccinated with DNA/ALVAC/gp120 vaccine

ABSTRACT: We contrasted innate and adaptive immune responses elicited by the DNA/ALVAC/gp120/alum vaccine in non-human primates differing in age. We performed several analyses. MicroRNA profiling in Extracellular Vesicles (EVs) isolated from plasma collected prior and 1 week following vaccination identified 109 miRNAs that differed significantly between age groups at the end of immunization. Several miRNAs correlated with risk of virus acquisition in young and old animals, but none remained significant following correction for FDR. In young animals, we identified 3 miRNAs which were modified by vaccination and correlated with decreased risk of SIV acquisition (unadjusted p-values). Of these three miRNAs, two, miR-139-5p and miR-29b-1-5p, were increased by vaccination, whereas one, mir 98, decreased by vaccination. MiR-139-5p has several validated targets, including: CXCR4, important for egress of CXCR4+ cells and monocytes from bone marrow and HIV entry in target T-cells; the cAMP-specific PDE4D gene which decreases CREB1-mediated transcription by degrading cAMP; and the IGF-1/AKT/Glut1 gene receptor, central for glucose utilization and cellular metabolism. The validated target of miR-29b-1-5p is the NF-kB pathway. Mir-98 has several validated targets, inhibits IL-10 production, modulates M1-M2 polarization of macrophages towards the M1 phenotype, and its CCL2-induced downregulation increases IL-6 production. These data suggest the importance of CREB1-mediated transcription in vaccine efficacy, identified in the study, is likely assisted by miR-139-5p targeting the cAMP-degrading PDE4D gene, and downregulation of the NF-kB pathway, targeted by miR-29b-1-5p.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE188575 | GEO | 2023/01/06

REPOSITORIES: GEO

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Project description:To investigate the potential role of miRNAs in disease mechanisms, we conducted a thorough analysis by comparing the entire miRNome of 18 vEDS dermal fibroblasts to those of 18 control cells. To improve statistical reliability, we sequenced each sample from both groups as biological replicates. By applying a log2 fold change threshold of greater than 1 or less than -1, and an adjusted p-value of less than 0.05, we identified 137 DE-miRNAs in patient vs. control fibroblasts. Among these, 71 miRNAs exhibited decreased expression, while 66 miRNAs were upregulated. To explore the functional relationship between DE-miRNAs and the altered gene expression profile of vEDS cells, we conducted an extensive review of the literature and consulted several bioinformatics databases. Our search involved utilizing data from four miRNA-target prediction databases (microT-CDS, Targetscan, miRTarBase, and miRwalk) in addition to relevant literature sources providing information on the functional roles of these miRNAs. We thus focused our research on a specific subset of DE-miRNAs, known as miR-15b-5p, miR-16-5p, miR-21-3p, miR-24-3p, miR-29a-3p, miR-29b-3p, miR-138-5p, miR-145-5p, and miR-195-5p, which may play a biological role in dysregulated molecular mechanisms underlying disease pathogenesis. Our initial emphasis was on miR-29a-3p and miR-29b-3p due to their involvement in regulating critical cellular processes such as ECM remodeling into the vascular network, autophagy, cell proliferation, and apoptosis. To study how miR-29a-3p and miR-29b-3p contribute to the dysregulated cellular processes observed in patient cells, we performed GO and pathway enrichment analyses on their predicted target DEGs. GO analysis revealed that both these miRNAs may disturb fundamental biological functions, such as regulation of transcription by RNA polymerase II, negative gene expression regulation, miRNA-mediated gene silencing, translation regulation, heterochromatin organization, and ECM organization. This comphrensive transcriptome analysis of a large cohort of dermal fibroblasts from patients with vEDS reveals deregulated biological functions potentially involved in the disease pathogenesis. Taken together, the abnormal expression of several miRNAs suggests the presence of epigenetic control in vEDS cells, which could influence the transcriptional regulation of numerous target DEGs and related biological processes, potentially influencing disease mechanisms. This work was supported by Fondazione Telethon and the “Associazione con Giacomo contro vEDS”, (Grant number: GSA21F001, Seed Grant Fall 2021 vEDS) to Nicola Chiarelli.

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MicroRNA profiling of extracellular vesicles isolated from rhesus macaques vaccinated with DNA/ALVAC/gp120 vaccine

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