Human Herpes Virus Type 7 (HHV-7)

Host DNA sensors TLR9, STING, and IFI16 are central signaling molecules that control innate immune responses to cytoplasmic nucleic acids. This study aimed to investigate how DNA sensing signals in natural killer (NK) cells are modified after infection with human herpesvirus (HHV)-6A, HHV-6B, or HHV-7. Researchers infected NK92 cell lines and primary NK cells with cell-free inocula of HHV-6A, HHV-6B, or HHV-7, and evaluated the expression of TLR9, STING, and IFI16 pathways 1, 2, 3, and 6 days after infection by real-time quantitative PCR, Western Blot, immunofluorescence, and flow cytometry. Virus presence (DNA) and transcription (RNA) analysis confirmed that NK92 and primary NK cells were rapidly infected by the three viruses. STING/STAT6 expression was upregulated in HHV-6A-infected NK cells. NK cells infected with HHV-6B and HHV-7 upregulated CCL3, IFN-α, TNF-α, IL-8, and IFN-γ, and slightly induced IL-4 and CCL4. NK cells infected with HHV-6A upregulated IL-4 and IL-13, and slightly induced IL-10, TNF-α, IFN-α, and IFN-γ. These results suggest that HHV-6B and HHV-7 actively control viral spread in vivo, mainly through the secretion of proinflammatory cytokines via TLR9. NK cells infected with HHV-6A, on the contrary, induced the STING/STAT6 pathway as an antiviral activation mechanism, but they were characterized by Th2-type responses and non-cytotoxic features, suggesting that HHV-6A-mediated immunosuppression may be a novel mechanism.

Here, researchers show that NK92 cells are tolerant to HHV-6A, HHV-6B, and HHV-7, with high viral loads at 3 days post-infection (d.p.i.) at a multiplicity of infection (m.o.i.) of 100 (Figure 1A). In Figures 1B,C, DNA and mRNA expression of U42, an immediate-early HHV-6 viral gene, increased during the 6 d.p.i. evaluated. Similarly, using primers specific for HHV-7 U42, both DNA and mRNA expression increased significantly. They chose the 3 d.p.i. time point for subsequent experiments because it coincides with high viral loads for HHV-6 and HHV-7. When researchers looked at viral late antigens at 3 d.p.i., in particular gp116 for HHV-6 and KR4 for HHV-7, their expression was observed (Figure 1D).

Figure 1. NK92 infection by HHV-6A, HHV-6B and HHV-7. (Bortolotti D, et al., 2020)