Projects Mucosal Infection Immunology

Immunometabolism in intestinal infections

Targeting the intracellular metabolism of immune cells is a promising novel strategy for immunomodulation. Our previous work suggested that intracellular de novo fatty acid synthesis represents an important metabolic checkpoint for the reciprocal differentiation of Th17 versus regulatory T cells. One focus of our work is to understand the impact of central metabolic processes on intestinal immune responses under in vivo conditions. We use established as well as newly generated genetic mouse models that allow for the deletion of the key metabolic enzymes in specific immune- and non-immune cells such as T-cells, ILCs and intestinal epithelial cells. We also assess the potential of pharmacologic modulation of metabolic pathways and translate these findings into the human system. 

Publications

Effector T cells such as Th17 depend for their development on the “glycolytic-lipogenic pathway”. The enzyme Acetyl-CoA Carboxylase 1 (ACC1) catalyzes the rate-limiting step in de novo cellular fatty acid syntheses. Inhibition of this enzyme disrupts fatty acid synthesis and inhibits Th17 cell development.

Immune cell function in intestinal infections

It has been a long-standing focus of our research group to analyze the immune response in gut inflammation and infection with gut-specific bacterial pathogens. In particular, we study the role of dendritic cells for the induction of protective innate lymphoid cell (ILC)- and T cell-mediated immune responses in the intestine. Another focus is on the identification and functional characterization of epigenetic signature genes in ILC lineages, which will be an important step for the discovery of key pathways and molecular mechanisms in ILC differentiation and function in intestinal infection and inflammation. C. difficile is one of the most important causes of healthcare acquired infectious diarrhea. Using a newly established murine infection model, we aim to identify and to characterize processes associated with C. difficile infection, including the role of specific immune cell subpopulations or the impact of specific environmental and host-derived factors on the integrity of the intestinal barrier during acute/relapsing infection.

Publications

Live in vivo imaging of mice infected with Citrobacter rodentium. Pictures were taken 9 days after infection with a modified C. rodentium mutant expressing bioluminescent signal and imaged on an IVIS-Spectrum with combined computed tomography.

Immunometabolism in mucosal infection and inflammation

Raud, B., D.G. Roy, A.S. Divakaruni, T.N. Tarasenko, R. Franke, E.H. Ma, B. Samborska, W.Y. Hsieh, A.H. Wong, P. Stuve, C. Arnold-Schrauf, M. Guderian, M. Lochner, S. Rampertaap, K. Romito, J. Monsale, M. Bronstrup, S.J. Bensinger, A.N. Murphy, P.J. McGuire, R.G. Jones, T. Sparwasser, and L. Berod, Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation. Cell Metab, 2018. 28(3):  504-515 e7.

Raha, S., B. Raud, L. Oberdorfer, C.N. Castro, A. Schreder, J. Freitag, T. Longerich, M. Lochner, T. Sparwasser, L. Berod, C. Koenecke, and I. Prinz. 2016. Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease. Eur J Immunol, 2016. 46:2233-2238.

Almeida, L.*, M. Lochner*, L. Berod*, and T. Sparwasser. 2016. Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol. 28(5):514-524. (*equal contribution)

Lochner, M., L. Berod, and T. Sparwasser. 2015. Fatty acid metabolism in the regulation of T cell function. Trends Immunol 36:81-91. 

Berod, L., C. Friedrich, A. Nandan, J. Freitag, S. Hagemann, K. Harmrolfs, A. Sandouk, C. Hesse, C.N. Castro, H. Bahre, S.K. Tschirner, N. Gorinski, M. Gohmert, C.T. Mayer, J. Huehn, E. Ponimaskin, W.R. Abraham, R. Muller, M. Lochner*, and T. Sparwasser*, De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med, 2014. 20(11): 1327-33. (*equal contribution)

Funding: DFG (LO1415/7-1) 

Immune cell function in mucosal infection and inflammation

Mamareli P., F. Kruse, C. Friedrich, N. Smit, T Strowig, T Sparwasser, and Lochner M, Epithelium-specific MyD88 signaling, but not DCs or macrophages, control acute intestinal infection with Clostridium difficile. Eur J immunol, 2019. 49(5):747-757

Friedrich, C., P. Mamareli, S. Thiemann, F. Kruse, Z. Wang, B. Holzmann, T. Strowig, T. Sparwasser, and M. Lochner, MyD88 signaling in dendritic cells and the intestinal epithelium controls immunity against intestinal infection with C. rodentium. PLoS Pathog, 2017. 13(5):  e1006357.

Yang, B.H., S. Hagemann, P. Mamareli, U. Lauer, U. Hoffmann, M. Beckstette, L. Foehse, I. Prinz, J. Pezoldt, S. Suerbaum, T. Sparwasser, A. Hamann, S. Floess, J. Huehn, and M. Lochner, Foxp3+ T cells expressing RORγt represent a stable regulatory T cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol, 2016. 9(2):444-57.

Wang, Z., C. Friedrich, S.C. Hagemann, W.H. Korte, N. Goharani, S. Cording, G. Eberl, T. Sparwasser, and M. Lochner, Regulatory T cells promote a protective Th17-associated immune response to intestinal bacterial infection with C. rodentium. Mucosal Immunol, 2014. 7(6): 1290-301.

Sawa, S., M. Lochner, N. Satoh-Takayama, S. Dulauroy, M. Berard, M. Kleinschek, D. Cua, J.P. Di Santo, and G. Eberl, RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol, 2011. 12(4): 320-6. 

Lochner, M., C. Ohnmacht, L. Presley, P. Bruhns, M. Si-Tahar, S. Sawa, and G. Eberl, Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells. J Exp Med, 2011. 208(1): 125-34.

Funding: DFG (LO1415/8-1), Niedersachsen R2N, Niedersachsen CDinfekt