Phenotype, development and function of non-hematopoietic cells in tumor necrosis factor-deficient mice infected with Leishmania major

• Applicants: Professor Dr. Christian Bogdan; Privatdozentin Dr. Ulrike Schleicher
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Immunology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440931729

Leishmaniasis comprises a spectrum of chronic cutaneous, mucocutaneous or visceral infectious diseases that are caused by different species of the vector-borne protozoan parasite Leishmania. In both humans and mice interferon (IFN)-gamma-producing type 1 T helper cells (Th1) and tumor necrosis factor (TNF) are critical for controlling the infection. While there is consensus that TNF plays an important role as macrophage co-activator, the whole range of its protective activity in leishmaniasis is incompletely understood. This has become particularly evident in Leishmania major-infected C57BL/6 TNF-deficient mice, in which local cutaneous infection with L. major leads to progressive and ultimately fatal visceral disease despite a fully maintained Th1 immune response and an unaltered protein expression of type 2 nitric oxide (NO) synthase (NOS2).During our search for mechanisms underlying the disease-susceptibility of L. major-infected Tnf-/- mice we discovered in the spleen of these mice a striking expansion of non-hematopoietic cells exhibiting the surface phenotype of mesenchymal stromal or stem cells (MSC). In the present proposal we set out to test the hypothesis that these MSC-like cells are regulated by the cytokine milieu that prevails in TNF-deficient mice and directly or indirectly contribute to the non-healing course of L. major-infection in the absence of TNF. Specifically, we aim (1) to verify the stem cell potential and to further characterize the phenotype of the MSC-like cells, including their abundance in other visceral organs (liver and bone marrow); (2) to analyze the in situ localization of MSCs and to test whether MSC develop and proliferate in spleen and liver or originate from the bone marrow; (3) to investigate the function of the MSC-like cells in vitro and in L. major-infected Tnf-/- mice by testing their ability to act as host cells for the parasite, to express immunomodulatory factors and to alter the anti-leishmanial activity of macrophages and the course of infection in vivo; and (4) to examine the impact of the expansion of MSCs in Tnf-/- mice on the NADPH oxidase of phagocytes and the gene expression and development of cell populations in the myeloid and lymphoid compartment. We are confident that the proposed experiments will shed fresh light on the function of TNF during anti-infectious immune responses and open a new avenue of research in the exciting field of immune cell/mesenchymal cell interaction.

• DFG Programme: Research Grants