cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells

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.

cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection

“…However, near-complete depletion of IFI16 mRNA levels in HUVECs not only failed to diminish HMCV-induced IRF3 activation but also, in fact, significantly enhanced it (Fig. 3F), which is consistent with recently reported results showing that IFI16-deficient THP-1 monocytes produce increased levels of IFN-␤ after infection with HCMV (35). Taken together, these results definitively show that HCMV infection of primary endothelial cells activates a cytosolic DNAsensing pathway involving a cGAS-STING-TBK1-IRF3 axis, leading to the transcription of innate antiviral genes, including IFN-I and IFN-I-inducible genes.…”

Restriction of Human Cytomegalovirus Replication by ISG15, a Host Effector Regulated by cGAS-STING Double-Stranded-DNA Sensing

“…With this in mind, host signaling pathways necessary for HCMV-induced ISG15 accumulation and conjugation were examined. For HCMV, engaging the cytoplasmic dsDNA sensor cGAS is responsible for activating the critical adaptor protein STING and triggering antiviral responses (34,35). To determine if ISG15 accumulation was cGAS dependent, NHDFs transfected with control NS siRNA or cGAS-specific siRNAs were infected with HCMV, and ISG15 abundance was measured by immunoblotting.…”

Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

“…Recent studies have revealed that the cGAS/STING-mediated cytosolic DNA-sensing signal pathway is important for cellular innate responses and intrinsic resistance to DNA virus infection (11)(12)(13). However, so far little is known about the countermeasures by DNA viruses, including herpes simplex virus 1 (HSV-1), against the cGAS/STINGmediated DNA sensing signal pathway.…”