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HHV-6A/6B Infection of NK Cells Modulates the Expression of miRNAs and Transcription Factors Potentially Associated to Impaired NK Activity.

ABSTRACT: Natural killer (NK) cells have a critical role in controlling virus infections, and viruses have evolved several mechanisms to escape NK cell functions. In particular, Human herpesvirus 6 (HHV-6) is associated with diseases characterized by immune dysregulation and has been reported to infect NK cells. We recently found that HHV-6 in vitro infection of human thyroid follicular epithelial cells and T-lymphocytes modulates several miRNAs associated with alterations in immune response. Since miRNAs are key regulators of many immune pathways, including NK cell functions, we aimed to study the impact of HHV-6A and -6B in vitro infection on the intracellular mediators correlated to NK cell function. To this purpose, a human NK cell line (NK-92) was infected in vitro with HHV-6A or 6B and analyzed for alterations in the expression of miRNAs and transcription factors. The results showed that both viruses establish lytic replication in NK-92 cells, as shown by the presence of viral DNA, expression of lytic transcripts and antigens, and by the induction of an evident cytopathic effect. Notably, both viruses, although with species-specific differences, induced significant modifications in miRNA expression of miRNAs known for their role in NK cell development, maturation and effector functions (miR-146, miR-155, miR-181, miR-223), and on at least 13 miRNAs with recognized role in inflammation and autoimmunity. Also the expression of transcription factors was significantly modified by HHV-6A/6B infection, with an early increase of ATF3, JUN and FOXA2 by both species, whereas HHV-6A specifically induced a 15-fold decrease of POU2AF1, and HHV-6B an increase of FOXO1 and a decrease of ESR1. Overall, our data show that HHV-6A and -6B infections have a remarkable effect on the expression of miRNAs and transcription factors, which might be important in the induction of NK cell function impairment, virus escape strategies and related pathologies.

SUBMITTER: Rizzo R

PROVIDER: S-EPMC5671584 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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HHV-6A/6B Infection of NK Cells Modulates the Expression of miRNAs and Transcription Factors Potentially Associated to Impaired NK Activity.

Rizzo Roberta R Soffritti Irene I D'Accolti Maria M Bortolotti Daria D Di Luca Dario D Caselli Elisabetta E

Frontiers in microbiology 20171031

Natural killer (NK) cells have a critical role in controlling virus infections, and viruses have evolved several mechanisms to escape NK cell functions. In particular, Human herpesvirus 6 (HHV-6) is associated with diseases characterized by immune dysregulation and has been reported to infect NK cells. We recently found that HHV-6 <i>in vitro</i> infection of human thyroid follicular epithelial cells and T-lymphocytes modulates several miRNAs associated with alterations in immune response. Since ...[more]

PMID: 29163428

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Project description:Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscore the conclusion that HHV-6A and HHV-6B are distinct viruses of the β-herpesvirinae. Despite these viruses being implicated as causative agents in several nervous system disorders (e.g., multiple sclerosis, epilepsy, and chronic fatigue syndrome), the mechanisms of action and relative contributions of each virus to neurological dysfunction are unclear. Unresolved questions regarding differences in cell tropism, receptor use and binding affinity (i.e., CD46 versus CD134), host neuro-immunological responses, and relative virulence between HHV-6A versus HHV-6B prevent a complete characterization. Although it has been shown that both HHV-6A and HHV-6B can infect glia (and, recently, cerebellar Purkinje cells), cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we show that both viruses can infect different nerve cell types (i.e., glia versus neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. As demonstrated by immunofluorescence, HHV-6A and HHV-6B productively infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, neither virus appears to infect GAD67-containing cells (i.e., GABAergic neurons). As determined by qPCR, expression of immunological factors (e.g., cytokines) in cells infected with HHV-6A versus HHV6-B also differs. These data along with morphometric and image analyses of infected differentiated neural stem cell cultures indicate that while HHV-6B may have greater opportunity for transmission, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection end points. Cumulatively, results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, while neither virus productively infects GABAergic cells. Consistency between these in vitro data and in vivo experiments would provide new insights into potential mechanisms for HHV6-induced epileptogenesis.

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HHV-6A/6B Infection of NK Cells Modulates the Expression of miRNAs and Transcription Factors Potentially Associated to Impaired NK Activity.

Publications

HHV-6A/6B Infection of NK Cells Modulates the Expression of miRNAs and Transcription Factors Potentially Associated to Impaired NK Activity.

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