Priority Research Area Infections

Infection Immunology

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Th1/Th17-mediated formation of protective granulomas

Interferon-gamma (IFN-γ) and interleukin (IL)-17A are two prototype T helper (Th) 1 and Th17 cytokines, respectively, that play a critical role in protection against infections with intracellular pathogens. As we have previously shown, mice lacking IL-23 or IL-17A production are highly susceptible to infection identifying an IL-23-dependent Th17 immune reaction as an important effector arm of protective immune responses (Hölscher 2001 J Immunol 167:6957; Schulz 2008 Int Immunol 20:1129; Werninghaus 2009 J Exp Med 206:89; Hernandez 2015 Nat Immunol). On the other hand, Th17 cells also play an essential role in the development of chronic inflammatory diseases, especially those mediated by T effector cells. For example, Th17 cells have been shown to promote the pathogenesis of various inflammatory and autoimmune diseases (Hölscher 2005 Curr Opin Investig Drugs 6:489; Paus 2009 J Am Soc Nephrol 20: 969; Gelderblom 2012 Blood 120: 3793). This proverbial function of Th17 cytokines as a “double-edged sword” is highlighted by our studies of TB in IL-27 receptor-alpha (Rα)-deficient mice. In these animals, an enhanced inflammatory immune response to Mtb infection results in a better control of mycobacterial growth but also lead to immunopathology and premature death (Hölscher 2005 J Immunol 167:6957). We could now show that these opposed effects are exclusively mediated by an elevated expression of IL-17A. Of importance, however, is that the increased levels of IL-17A lead to the formation of highly structured „protective“ granulomas (Fig. 2). The exact mechanisms how these granulomas are induced by IL-17A and which mechanism expressed in these lesions in fact promote protection is not clear at the moment. Moreover, given that an increased expression of IL-17A fosters protective immune responses, a controlled increase in IL-17A or of downstream effects may represent an immunomodulatory approach for host directed therapy. Nevertheless, further detailed analysis of regulatory and of IL-17A-dependent cell type-specific mechanisms that mediate its protective effect are imperative. References: Sodenkamp 2011 Eur J Cell Biol 90:505; Sodenkamp 2012 Immunobiol 217:996; Heitmann 2013 Immunobiol 218:506; Erdmann 2013 Immunobiol 6:910; Behrends 2013 PLoS One 8:e57379; Berod 2014 PLoS One 9:e102804; Böhme 2016 Immunol; Erdmann 2016 Sci Rep; Stüve 2018 Front Immunol; Erdmann 2018 Muc Immunol.

 

Abbildung 2. Schützendes IL-17A-abhängiges GranulomFigure 2. Protective IL-17A-dependent granuloma
 
 

 

Th2-dependent development of damaging granulomas

Until today, factors influencing the course of Mtb infection are only incompletely defined. One important reason is the fact that genetically or immunologically tractable mouse models do not exist that displays the characteristic features of granulomas in TB patients: centrally necrotizing lesions, a strict stratification of a fibrous capsule that separates the necrotizing granuloma from the adjoining tissue, foamy macrophages found adjacent to the fibrous capsule within the necrotic lesion, and most importantly hypoxia. Because lipid-containing foamy macrophages and necrosis-related hypoxia might be key factors in the pathogenesis of post-primary TB and eventually the distribution and success of Mtb, the Infection Immunology research group developed a mouse model in which Mtb infection results in granuloma necrosis strongly resembling the pathology of human TB (Fig. 3). In these IL-13-overexpressing (tg) mice, arginase-1-expressing alternatively activated macrophages, which have previously shown by us to promote susceptibility to intracellular pathogens (Herbert 2004 Immunity 20:623, Hölscher 2006 J Immunol 176:1115, Schreiber 2009 J Immunol 183:1301), drive the typical pathology with centrally necrotizing granulomas, a fibrous rim and foamy macrophages. Because IL-13 signals through the IL-4 receptor-alpha (α) we performed genetic analysis in humans and found a mutation in this receptor chain in humans that was linked to the degree of pathology in TB patients. These genetic association study further supports our assumption that IL-13/IL-4Rα-dependent mechanisms are involved in mediating tissue pathology of human TB. As the pathology observed in Mtb-infected IL-13tg mice display many features of post-primary TB in humans, this mouse model is an ideal tool to study the progression of TB and to determine factors important for the clinical outcome. References: Heitmann 2014 J Pathol; Hölscher 2016 Mediators Inflamm; Herrtwich 2016 Cell; Schmok 2017 Front Immunol.

 

Abbildung 3. IL-13/IL-4Rα-induzierte zerstörendes, zentral nekrotisierendes GranulomFigure 3. IL-13/IL-4Rα-mediated damaging, centrally necrotizing granuloma
 

 

Evaluation of antibiotics in optimized preclinical models

Drug resistant Mtb strains represent the major threat for the global control of TB and new anti-TB drugs are urgently needed. Drug development against multidrug-resistant (MDR)-TB requires preclinical testing in optimized models that mimic pathobiological aspects of human TB. Within the German Centre for Infection Research (DZIF), the Infection Immunology research group has implemented in collaboration with other scientists a preclinical test station (TTU-TB “New Drugs and Regimen”) which further develops existing models of in vitro and in vivo drug testing to advance several selected compounds, or therapeutic modalities, from “candidate” to “potential regimen for human use” status. One important aspects of the DZIF infrastructure TTU-TB „MycoDrug and Trials“ executed by the Infection Immunology research group is to further develop the animal model of IL-13tg mice (see above) for the in vivo analysis of anti-mycobacterial compounds under more physiological conditions resembling the pathology of human post-primary TB. Based on proof of principle studies with standard antibiotics IL-13tg mice will further serve as a “close to human” model to proof the efficacy of novel anti-mycobacterial compounds under physiological conditions in vivo.