Immunological sensing of cytomegalovirus (CMV)
About this project
Currently 60-100% of the world´s population is latently infected with HCMV. This represents a major health challenge because in immunocompromised individuals virus reactivation can lead to severe morbidity and mortality. Nevertheless, in immunocompetent individuals primary HCMV infection is mostly unnoticed and the virus developed sophisticated means to escape immunity and to persist in a latent state. We aim to better understand how HCMV is sensed by the immune system and how antiviral immune mechanisms are induced. Therefore, we focus especially on sensing of CMV by myeloid cells in the human and murine model and on the induction of type I interferons which can exhibit pro- and anti-viral effects on CMV infection. We discovered that in human monocyte derived myeloid cells sensing of HCMV infections depends on productive infection and is mediated via the cGAS/STING axis (Paijo et al., 2016). More recently we found that during the early phase of MCMV infection IFN-β responses are induced in Kupffer cells within the liver. Notably, under such conditions MCMV is also sensed by the cGAS/STING axis (Tegtmeyer et al., 2019). Interestingly, hepatocyte-derived MCMV does not infect other cells of the body until day 5 of infection, whereas from day 8 on hepatocyte-derived MCMV disseminates to the salivary gland (Tegtmeyer et al., 2019). This dissemination is dependent on the viral component MCK2 and is mediated by MCMV infected myeloid cells. In the future we will in depth analyze which myeloid cell subsets contribute to MCMV dissemination (AFR-DFG German French project).
Recently, we found that monocyte-derived cells only express type I IFN when stimulated by cell-free HCMV, or upon encounter of HCMV-infected cells that already produce cell-free virus. Nevertheless, also in the absence of cell-free virus, i.e., upon co-culture of infected epithelial/endothelial cells with monocyte-derived macrophages (moMΦ) or dendritic cells (moDC), antiviral responses are induced that limit HCMV spread (Becker et al., 2018). This observation together with our recently improved understanding of antigen presentation by human dendritic cells (Döring et al., 2019) is applied to develop improved methods for the generation of HCMV-specific T cell products for the use in patients with severe HCMV infection (Forschergruppe 2830, P04).
By applying single cell sequencing to HCMV infected human dendritic cells we aim to elucidate the delicate balance between the host response and evasion strategies deployed by HCMV. The objective is to better understand how HCMV establishes latent infection in myeloid cells (SFB 900, B2).