Abstract
Human cytomegalovirus (HCMV) infections of healthy individuals are mostly unnoticed and result in viral latency. However, HCMV can also cause devastating disease, e.g., upon reactivation in immunocompromised patients. Yet, little is known about human immune cell sensing of DNA-encoded HCMV. Recent studies indicated that during viral infection the cyclic GMP/AMP synthase (cGAS) senses cytosolic DNA and catalyzes formation of the cyclic di-nucleotide cGAMP, which triggers stimulator of interferon genes (STING) and thus induces antiviral type I interferon (IFN-I) responses. We found that plasmacytoid dendritic cells (pDC) as well as monocyte-derived DC and macrophages constitutively expressed cGAS and STING. HCMV infection further induced cGAS, whereas STING expression was only moderately affected. Although pDC expressed particularly high levels of cGAS, and the cGAS/STING axis was functional down-stream of STING, as indicated by IFN-I induction upon synthetic cGAMP treatment, pDC were not susceptible to HCMV infection and mounted IFN-I responses in a TLR9-dependent manner. Conversely, HCMV infected monocyte-derived cells synthesized abundant cGAMP levels that preceded IFN-I production and that correlated with the extent of infection. CRISPR/Cas9- or siRNA-mediated cGAS ablation in monocytic THP-1 cells and primary monocyte-derived cells, respectively, impeded induction of IFN-I responses following HCMV infection. Thus, cGAS is a key sensor of HCMV for IFN-I induction in primary human monocyte-derived DC and macrophages.
Highlights
Human cytomegalovirus (HCMV) is a highly host-adapted, opportunistic β-herpesvirus that copes amazingly well with the host’s immune response due to a plethora of different evasion mechanisms [1,2]
In this study we found that plasmacytoid dendritic cells (pDC) as well as monocytederived dendritic cells (DC) and macrophages express cyclic GMP/AMP synthase (cGAS) and stimulator of interferon genes (STING)
To address the role of the cGAS/STING pathway in HCMV infected primary human immune cells, in a first step we studied cGAS and STING expression of pDC, monocyte-derived DC (moDC), GM-CSF MF, and M-CSF MF
Summary
Human cytomegalovirus (HCMV) is a highly host-adapted, opportunistic β-herpesvirus that copes amazingly well with the host’s immune response due to a plethora of different evasion mechanisms [1,2]. While the cellular source and the underlying recognition platform of the first IFN-I wave are still poorly defined, it was shown previously that the second IFN-I wave is primarily contributed by plasmacytoid dendritic cells (pDC) [21,22], which are known for their extraordinary IFN-I production capacity [23,24] This IFN-I response is highly dependent on endosomally-located TLR9 [25], which recognizes double-stranded hypomethylated CpG-rich DNA and signals via the adaptor molecule MyD88 [26]. Patients suffering from primary MyD88 deficiency did not show increased susceptibility to infection with herpesviruses [31,32] questioning the central function of pDC in the pathogenesis of HCMV in humans and suggesting the involvement of other cells and recognition platforms in the production of protective IFN-I
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