Abstract
ObjectivesThe host DNA sensor proteins TLR9, STING, IFI16 are central signaling molecules that control the innate immune response to cytosolic nucleic acids. Here we propose to investigate how Natural killer (NK) cell infection by human herpesvirus (HHV)-6A, HHV-6B or HHV-7 is able to modify DNA sensor signaling in NK cells.MethodsWe infected the NK92 cell line and primary NK cells with cell-free inocula of HHV-6A, HHV-6B or HHV-7 and evaluated TLR9, STING, and IFI16 pathway expression by Real-Time PCR, Western Blot, immunofluorescence and flow cytometry for 1, 2, 3, and 6 days post-infection. We evaluated NK cell cytokine-producing by Real-Time PCR and enzyme immunosorbent assay.ResultsNK92 and primary NK cells were promptly infected by three viruses, as demonstrated by virus presence (DNA) and transcription (RNA) analysis. Our data show STING/STAT6 up-modulation in HHV-6A infected NK cells. NK cells infected with HHV-6B and HHV-7 up-regulated CCL3, IFN-alpha, TNF-alpha, IL-8 and IFN-gamma and slightly induced IL-4, and CCL4. HHV-6A infected NK cells up-regulated IL-4 and IL-13 and slightly induced IL-10, TNF-alpha, IFN-alpha, and IFN-gamma.ConclusionFor the first time, we demonstrate that HHV-6A, HHV-6B, and HHV-7 infections have a differential impact on intracellular DNA sensors. HHV-6B and HHV-7 mainly lead to the active control of in vivo viral spreading by pro-inflammatory cytokine secretion via TLR9. HHV-6A infected NK cells conversely induced STING/STAT6 pathway, as a mechanism of anti-viral activation, but they were characterized by a Th2 type response and a non-cytotoxic profile, suggesting a potential novel mechanism of HHV-6A-mediated immunosuppression.
Highlights
Three herpesviruses gaining medical interest are the human herpesvirus-6 (HHV-6) A and B and human herpesvirus-7 (HHV-7)
We showed that NK92 cells are permissive to HHV-6A, HHV-6B, and HHV-7, with a high viral amount 3 days post infection (d.p.i.) using 100 multiplicity of infection (m.o.i.) (Figure 1A)
When we looked at viral late antigens at 3 d.p.i., in particular gp116 for HHV-6 and KR4 for HHV-7, we observed their expression (Figure 1D)
Summary
Three herpesviruses gaining medical interest are the human herpesvirus-6 (HHV-6) A and B and human herpesvirus-7 (HHV-7). They are members of the Herpevirales order, Herpesviridae family, Betaherpesvirinae subfamily, and Roseolavirus genus. HHV-6, as HHV-6A and HHV-6B are commonly called when they are not separated into two species, has a wide cell tropism inducing a lifelong latent infection in humans HHV-6A/B replicate preferentially in CD4+ T lymphocytes and utilize distinct cell surface receptors: HHV-6A uses CD46, a regulator of complement activation expressed on all nucleated cells, while HHV-6B uses CD134 ( called OX40), a member of the tumor necrosis factor (TNF) receptor superfamily. HHV-6 infects CD8+ T lymphocytes, NK cells, astrocytes, microglial cells oligodendrocytes, liver cells, human fibroblasts, epithelial cells, endothelial in vitro cells (De Bolle et al, 2005).
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