Institute of Clinical Microbiology, Immunology and Hygiene
Friedrich-Alexander-University (FAU) Erlangen-Nürnberg University Hospital Erlangen
The role of innate lymphoid cells in cutaneous and visceral leishmaniasis
Non-cytotoxic innate lymphoid cells (ILCs) are a newly discovered family of immune cells with lymphoid morphology that originate from a common precursor, lack recombination-dependent antigen receptors and lineage-markers, and consist of at least three different groups (ILC1, ILC2 and ILC3) defined by their transcription factor(s) and cytokine expression profiles. ILCs have been identified as important sentinel cells at barrier surfaces that regulate the innate as well as the adaptive arm of the immune response during homeostasis and inflammation. However, their exact role during infections with intracellular microorganisms is still poorly defined. In particular, we do not yet understand (a) the division of function between natural killer (NK) cells (also termed cytotoxic ILCs) and ILC1s and the interplay between ILC1s and ILC2s; (b) the full range of signals (e.g. host-derived vs. microbial; cytokines vs. inorganic milieu factors) that activate ILCs in situ and (c) to which extent ILCs are involved in the initiation of protective vs. counter-protective immune responses to intracellular infectious pathogens.
In this project we will use our mouse models of cutaneous and visceral leishmaniasis (elicited by infection with the protozoan parasites Leishmania [L.] major and L. infantum, respectively) to test the hypothesis that ILC1s are instrumental to the initial control of Leishmania parasites and pave a protective immune response, whereas ILC2s help the parasites to establish themselves in the host and to cause a chronic, progressive infections. Specifically, we aim (1) to analyse the prevalence of activated ILC1s and ILC2s in the infected tissues; (2) to characterize the cellular, cytokine and receptor signals required for the activation of ILC1s and ILC2s; (3) to investigate the impact of key environmental cues (e.g. oxygen content / hypoxia and nitric oxide) on the activation and proliferation of ILC1s and ILC2s and (4) to study the function of ILC1s and ILC2s in vivo using adoptive cell transfers and various depletion strategies including transgenic mouse models. We believe that these analyses will help to further define the regulation and function of ILCs, provide the basis for the respective studies with Leishmania-infected human tissue samples and open new avenues for immune intervention.
Schleicher U., Paduch K., Debus A., Obermeyer S., Konig T., Kling J.C., Ribechini E., Dudziak D., Mougiakakos D., Murray P.J., Ostuni R., Korner H. and Bogdan C. TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection. Cell Rep 2016, 15:1062-75.
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Bogdan C. Nitric oxide synthase in innate and adaptive immunity: an update. Trends Immunol. 2015 Mar;36(3):161-78.
Bogdan C. Natural killer cells in experimental and human leishmaniasis. Front Cell Infect Microbiol. 2012, 2:69. Epub 2012 May 29.
Prajeeth CK, Haeberlein S, Sebald H, Schleicher U, and Bogdan C. Leishmania-infected macrophages are targets of NK cell-derived cytokines, but not of NK cell cytotoxicity. Infect Immun 2011, 90: 551-562
Haeberlein S, Sebald H, Bogdan C*, Schleicher U*. IL-18, but not IL-15, contributes to the IL-12-dependent induction of NK cell effector functions by Leishmania infantum in vivo. Eur J Immunol. 2010, 40(6):1708-17. (* shared senior authorship)
Liese J, Schleicher U, and Bogdan C. TLR9 signaling is essential for the innate NK cell response in murine cutaneous leishmaniasis. Eur J Immunol. 2007 Dec;37(12):3424-34.
Schleicher, U., Liese, J., Knippertz, I., Kurzmann, C., Hesse, A., Heit, A., Fischer, J., Weiss, S., Kalinke, U., and Bogdan, C (2007). TLR9- and CD11chigh cell-dependent, but plasmacytoid dendritic cell-independent NK cell activation in visceral leishmaniasis. The Journal of Experimental Medicine Apr 16;204(4):893-906.