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.
Highlights
Severe and/or recurrent infections with Herpes simplex virus (HSV) are observed in a considerable group of patients treated in clinical immunology facilities
The aim of the study was to investigate 1) miRNA expression pattern in natural killer (NK) cells in patients with severe and/or recurrent HSV infections, and to describe 2) which miRNAs might be associated with increased susceptibility to prolonged and severe HSV infection, and 3) define the genes associated with antiviral response which expression is altered by studied miRNAs, in order to predict the possible new mechanism of NK cell deficiency leading to propagation of HSV infection
To evaluate the miRNAs expression pattern in NK cells of patients with severe and/or recurrent HSV infection and healthy control subjects, we performed real-time PCR quantification of the best known 754 human miRNAs in NK cells isolated from peripheral blood of all analyzed individuals
Summary
Severe and/or recurrent infections with HSV are observed in a considerable group of patients treated in clinical immunology facilities. In a large group of patients suffering from severe and/or recurrent HSV infection who exhibit normal NK cell numbers and NK cell cytotoxic activity, the molecular basis of their disorder is still largely unknown. NK cells can secrete a number of cytokines and chemokines, such as interferon g (IFN-g), crucial in antiviral response; TNF, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 5 (IL-5), IL-13, macrophage inflammatory protein (MIP-1) and RANTES [6]. The release of these cytokines activates Th1 response, macrophagemediated killing of intracellular pathogens and up-regulates major histocompatibility complex (MHC) class I molecules expression. NK cells can provide a co-stimulatory signal to T and B lymphocytes, through CD40L and OX40L [8]
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