Trained immunity of mononuclear phagocytes during viral infection and immunisation
Most of our knowledge about haematopoiesis was derived under homeostatic conditions (Amon et al., 2019; Papaioannou et al., 2021; Heidkamp et al., 2016) and only little is known about the dynamic integration of environmental cues or inflammation. In general, vast numbers of myeloid cells – including monocytes, macrophages and dendritic cells – are rapidly recruited to the site of inflammation. This requires an increased output and mobilisation of myeloid cells from the bone marrow and the so-called emergency haematopoiesis (Guilliams et al., 2018). Of note, the attenuated vaccine Bacille-Calmette-Guerin (BCG) was found to induce long-lasting functional changes in the myeloid compartment leading to an increased cytokine release upon infection with unrelated pathogens at a later timepoint. This is known as trained immunity in innate cells associated with transcriptional and epigenetic changes in hematopoietic stem cells and their progenies (Zhang et al., 2022; Kong et al., 2021; Cirovic et al., 2020; Arts et al., 2018; Goodridge et al., 2016). We here hypothesise that the myeloid progenitor pool is reacting to viral infections and other common vaccinations with changes in magnitude, differentiation pathways and cellular function.
To investigate which changes in mononuclear phagocytes and their precursors are mediated by acute versus chronic or latent viral infections as well as vaccinations with attenuated viruses or inactivated whole-pathogens, we are performing infections and vaccinations in mice. Bone marrow, lymph nodes and spleen will be analysed for the frequency and phenotype of mononuclear phagocytes and their precursors using multicolour flow cytometry, single cell RNASeq (scRNAseq) and single cell ATACSeq (scATACseq) (Amon et al., 2022; Clausen et al., 2022; Kong et al., 2021). Furthermore, purified precursors will be transferred into naïve mice to explore their role in trained immunity. These experimental setups will allow to systematically study the influence of vaccinations and infections on the mononuclear phagocyte (precursor) pool. Next, the doctoral candidate will analyse how the observed (imprinted) changes within the mononuclear phagocyte (precursor) pool shape subsequent immune responses to “new” (before unknown, antigen-unrelated) infections and vaccinations. To analyse the induction of trained immunity, we will study the function of the mononuclear phagocyte pool by analysis of the immune response upon targeted antigen delivery to dendritic cell subsets, as well as heterologous vaccinations/infections (Clausen et al., 2022; Lehmann et al., 2017; Dudziak et al., 2007). We will investigate precursor differentiation and frequencies, cytokine release, as well as induction of T cell and B cell responses. These experiments will help to stratify the investigated infections and vaccinations into different categories according to their beneficial or detrimental effect on the immune systems responses. Further, they will help to understand the changes induced by chronic and latent infections, which is important to support the immune system to not only fight the infections but to also reverse potential detrimental effects, e.g. by pharmacological interventions.