Dr. Yan Fu (Magdeburg / DE), Dr. Ehsan Vafadarnejad (Würzburg / DE), Iris Baars (Magdeburg / DE), Dr. Antoine-Emmanuel Saliba (Würzburg / DE), Prof. Dr. Thomas Schüler (Magdeburg / DE), Prof. Andreas J. Müller (Magdeburg / DE)
Abstract text
Introduction: Leishmania major (L. major) infection of the skin is marked by large heterogeneity in both pathogen physiological states and immune cell populations recruited to the infection site. Our previous work suggested that pathogen proliferation and cell-to-cell transfer is preferentially occurring in distinct phagocyte subpopulations. However, the link between pathogen physiology with the activation of infected host cells remains poorly understood.
Objectives: To investigate the dynamics of the recruitment, activation and deployment of cellular defence mechanisms of phagocytes recruited to the site of L. major infection in the context of differential pathogen proliferation rates.
Materials & Methods: Using an in vivo biosensor for L. major proliferation in combination with single cell RNAseq, we investigated transcriptional profiles of infected phagocytes isolated from infected skin dependently of the intracellular pathogen proliferation rate. Bone marrow chimeric mice, cell-specific depletion and cytokine blockade were used to characterize candidate cells and molecules with a possible impact on pathogen control using flow cytometry and multiparameter microscopy.
Results: We observed that fast versus slow L. major proliferation is linked to clearly defined infected cell populations with differential gene expression profiles. In particular, we identifed a distinct monocyte subpopulation, termed Lo3, which harboured low proliferating L. major and exhibited a hypoinflammatory phenotype. Furthermore, our data suggest that Interleukin-7 (IL-7), which is produced in the tissue upon induction of the immune response, acts as a feedback mechanism which restricts the immune response via the Lo3 monocytes. In particular, depletion of Lo3 monocytes, transient inhibition of IL-7, or absence of the IL-7 receptor on phagocytes drastically enhanced L. major clearance via an enforced T cell response.
Conclusion: L. major hijacks an immunoregulatory feedback mechanism which is mediated via IL-7 and hypoinflammatory monocytes which are specifically characterized by the infection of low proliferating pathogen. These cells seem to dampen the adaptive immune effector response and and perpetuate pathogen persistence in the tissue.