In-vivo-tracking, immune control and autoimmunity in genetic models of murine endogenous retrovirus reactivation
Virology
Final Report Abstract
The goal of our DFG funded project was/is to get a glimpse of the in vivo biology of endogenous retroviruses (ERV). We hope that it will give us valuable insights on how epigenetic-, cell intrinsic restriction- and immune-mechanisms protect the genome against retroviral invasion. For our project, we proposed to generate and analyze new mouse strains containing transgenic endogenous retrovirus (ERVs) of the Moloney Murine leukemia type (Mo-MuLV). We were partially successful in obtaining two transgenic mouse strains, harboring a GFP-Env fusion protein and an IRES-GFP, to examine the immune response against a germline encoded replication and infection competent retrovirus. The mice express the novel ERV-GFPs in immune cells in an age- and cell type- specific manner. We could show that nucleic-acid sensing Toll-like receptors (Tlrs), in particular Tlr7 are essential for control of the ERV-GFP and the adaptive B cell immune response against the ERV. We used ex vivo GFP imaging techniques to demonstrate, which organs are affected by ERV reactivation/replication, especially in mice, which succumbed to leukemia. A number of theories exists, how silent proviral copies of retroviruses get activated. However, it is still unclear, if ERV based retroviremia in mice, which lack certain Tlrs or B cells, is due to the absence of an ERV recognizing and suppressing antibody response or is caused by increased proviral ERV reactivation by microbiota derived ligands. Although we do not have the results yet, we can address this by generation and analysis of germ-free ERV-GFP mice. A number of antiretroviral restriction factors have been described in humans and mice. In our model, we could show that transgenic human APOBEC3 suppresses the ERV-GFP in vivo. This is an important finding, which will allow to further study the mechanism of retroviral restriction in vivo. The most important and fundamental finding is related to the B cell response against the endogenous retrovirus. One of the basic paradigms in Immunology suggests that expression of GFP in normal GFP transgenic (reporter)-mouse strains should result in tolerance of the adaptive immune system against the neo-self antigen GFP. In stark contrast, our results show that in ERV-GFP transgenic mice a spontaneous formation of (auto-) antibodies against GFP takes place. This suggests that ERV activation in vivo is able to break B cell tolerance against germline encoded self-antigens. We are analyzing the pathogenic potential of the B cells and the mechanism of how ERVs could break B cell tolerance and its implication to our understanding of autoimmunity.
