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.