Date Published: April 8, 2016
Publisher: Public Library of Science
Author(s): Jennifer Paijo, Marius Döring, Julia Spanier, Elena Grabski, Mohammed Nooruzzaman, Tobias Schmidt, Gregor Witte, Martin Messerle, Veit Hornung, Volkhard Kaever, Ulrich Kalinke, Edward Mocarski.
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.
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]. These strategies allow HCMV to establish latency and to silently spread to naïve individuals. Currently 60–100% of the world population is latently infected with HCMV . In immunocompromised hosts, e.g., transplant recipients, HCMV reactivation may cause serious disease, while congenital infection can lead to abortion or dramatic disabilities in the infant, such as deafness and mental retardation [4,5].
The knowledge of diverse mechanisms applying for primary human immune cell sensing of human-specific viruses, such as HCMV, is of major importance to better understand complex virus/host interactions. Here we report that in primary human monocyte-derived DC and MΦ cGAS was essential for HCMV sensing and subsequent IFN-I induction. The degree of cGAS-dependent cGAMP formation correlated with the susceptibility of different monocyte-derived cell subset to HCMV infection. In line with this observation, pDC that were not readily HCMV infected mounted IFN-I responses in a TLR9-dependent manner, although they expressed abundant amounts of cGAS and STING.