miRNA Regulation of NK Cells Antiviral Response in Children With Severe and/or Recurrent Herpes Simplex Virus Infections

Abstract

Severe and/or recurrent infection with Herpes simplex virus (HSV) is observed in a large group of patients treated in clinical immunology facilities. Atypical and prolonged HSV infection is the most common clinical manifestation of disturbed NK cell development and functions, yet the molecular basis of these disorders is still largely unknown. Since recent findings indicated the importance of miRNA in regulating NK cell development, maturation and functions, the aim of our study was to investigate miRNA expression pattern in NK cells in patients with severe and/or recurrent infections with HSV and analyze the role of these miRNAs in NK cell antiviral response. As a result, miRNA expression pattern analysis of human best known 754 miRNAs revealed that patients with severe and/or recurrent HSV infection had substantially upregulated expression of four miRNAs: miR-27b, miR-199b, miR-369-3p and miR-491-3p, when compared to healthy controls. Selective inhibition of miR-27b, miR-199b, miR-369-3p and miR-491-3p expression in NK-92 cells resulted in profound upregulation of 4 genes (APOBEC3G, MAP2K3, MAVS and TLR7) and downregulation of 36 genes taking part in antiviral response or associated with signaling pathways of Toll-like receptors (TLR), NOD-like receptors, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and type I IFN-related response. Additionally, flow cytometry analysis revealed that miR-369-3p and miR-491-3p inhibitors downregulated NK cell intracellular perforin expression, while the expression of granzyme B and IFNγ remained unchanged. Taken together, our study suggests a novel mechanism which may promote recurrence and severity of HSV infection, based on miRNAs-dependent posttranscriptional regulation of genes taking part in antiviral response of human NK cells.

XIST-microRNAs/mRNA Network in Circulating CD4⁺ T Cells of the Patients with Hepatocellular Carcinoma

“…Nuclear translocation of NF-κB is likewise reduced by miR-369-3p [29]. In viral infections, inhibiting the expression of miR-369-3p dramatically reduces the expression of antiviral response genes, including CCL3, CCL5, CTSS, CXCL11, and IRF3 [30]. In addition, miR-494-3p has a function in macrophage polarization and activation via activating Wnt signaling to modulate M1/M2 polarization [31].…”

Exploring the Regulatory Role of XIST-microRNAs/mRNA Network in Circulating CD4+ T Cells of Hepatocellular Carcinoma Patients

“…The nuclear translocation of NF-κB is likewise reduced by miR-369-3p [32]. In viral infections, inhibiting the expression of miR-369-3p dramatically reduces the expression of antiviral response genes, including CCL3, CCL5, CTSS, CXCL11, and IRF3 [33]. In addition, miR-494-3p has a function in macrophage polarization and activation via activating Wnt signaling to modulate M1/M2 polarization [34].…”

Natural Killer Cell‐Derived Extracellular Vesicles as Potential Anti‐Viral Nanomaterials

“…[17] miR-369-3p was evaluated as it was previously reported to regulate inflammation by suppressing the expression of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-𝛼). [18,[39][40][41] Quantitative RT-qPCR showed a significantly higher expression of miR-27a, 27b, 491-5p, and 369-3p in NK-EVs than control A549-EVs (n = 3, p < 0.05, p < 0.001; Figure 3A). Importantly, when LPS-treated A549 cells were incubated with NK-EVs, treated cells showed an approximately sixfold increase in expression of the anti-viral miRNA than the non-treated and A549-EV treated cells after 48 h (Figure 3D; n = 3, p < 0.001, p < 0.0001).…”