Dissecting pathogen persistence- versus clearance-promoting functions of monocyte-derived cell populations during L. major infection

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Tissue damage and infection results in the massive recruitment of immune cells from the bloodstream. Among these recruited cells, the monocytes give rise to a versatile system of phagocytes which can take up and neutralize pathogens, activate the adaptive immune system, but also induce tissue repair. Despite intense investigation in a variety of disease models, it has remained unclear how the different functions of specific monocyte subsets are induced after recruitment to the tissue, and how these functions contribute to the control of infections. This question is especially important for the infection with intracellular pathogens such as L. major, for which monocyte-derived cells can serve both as niches for intracellular growth of the pathogen, but also as effector cells fighting the infection.In our previous work, we have identified distinct subsets of monocyte-derived cells that harbour L. major with different intracellular proliferation rates, exhibit characteristic gene expression patterns, and are differentially engaged by effector T cells. How such differences relate to distinct effects of the individual monocyte-derived subsets, i.e. to what extent they promote intracellular survival and persistence of the pathogen, or pathogen clearance by activating the immune system, is unclear yet.The objective of the proposed research is therefore to investigate the following questions:(1) How are the monocyte-derived cell subsets are recruited to, and activated at, the site of L. major skin infection? To achieve this, we will employ fluorescent reporter systems that allow us to track in vivo the recruitment and activation of monocytes to the site of infection.(2) How do the different subsets interact with T cells and modulate T cell effector functions? For this, we will investigate by intravital 2-photon microscopy in vivo, and by live cell imaging and RNA sequencing ex vivo, the capacity of different monocyte-derived cell subsets to interact with and activate effector T cells.(3) How do candidate genes shown to be specifically expressed in distinct monocyte-derived cell subsets impact on the role of these subsets in promoting pathogen persistence versus clearance? To investigate this question, we will apply mixed bone marrow chimeric models combined with partial cell depletion to address cell-intrinsic versus cell extrinsic effects of candidate gene deficiencies on pathology and infection course.The proposed research should critically contribute to our understanding of the mechanisms and dynamics of how different monocyte-derived cell subsets impact on the course of infection. Given the widespread involvement of monocytes in a variety of infectious, inflammatory and malignant diseases, elucidating the mechanisms that control such immunostimulatory versus immunomodulatory functions could guide novel therapeutic strategies targeting this balance specifically in monocytes.