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.
Highlights
Natural killer (NK) cells belong to the innate immune system and are essential effector cells in the control of virus infections (Cooper et al, 2001)
Human herpesvirus 6A and 6B (HHV-6A and 6B), as all viruses belonging to the Herpesviridae family, have developed several mechanisms to control and inactivate the immune response in order to establish a lifelong infection in their hosts
Infected NK-92 cells appeared damaged and less able to form clusters compared to uninfected controls, with more pronounced effects in the case of HHV-6A, compared to HHV-6B (Figure 1B)
Summary
Natural killer (NK) cells belong to the innate immune system and are essential effector cells in the control of virus infections (Cooper et al, 2001). HHV-6A/B and NKs: miRNAs and Transcription Factors (Vivier et al, 2008) Their relevance is supported by the observation that individuals with defects in the NK cell component of the innate immunity are more susceptible to virus infection (Orange, 2002), including herpesviruses (Fleisher et al, 1982; Biron et al, 1989), and more prone to develop symptomatic disease following infection. Reactivations in the adult have been associated to the development of multiple symptomatic diseases often characterized by immune dysregulation (multiple sclerosis, Sjögren’s syndrome, autoimmune thyroiditis, and others) (Caselli and Di Luca, 2007) Both viruses are considered lymphotropic, showing an elective tropism for CD4+ T-lymphocytes and being able to infect several different cell types of the immune system, including NK cells (Lusso et al, 1993; Caselli and Di Luca, 2007)
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