Subproject B06

Mechanism of induction and effector function in T-cell-mediated ileitis following oral infection with Toxoplasma gondii.

Prof. Dr. rer. nat. Stefan Bereswill

Bereswill Bild

Leader of the Subproject A07

CharitéUniversitätsmedizin Berlin

CBF: Campus Benjamin Franklin

Charité Center Diagnostic Laboratory and Preventive Medicine CC 5

Institute of Microbiology and Hygiene - Molecular Diagnostics / AG Gastrointestinal Microbiology

Postal address:

Hindenburgdamm 27

12203 Berlin

t: +49 30 450 524 228 +49 30 450 524 002

Dr. med. Markus M. Heimesaat

heimesaat portrait klein

Project Leader of the Subproject B06

CharitéUniversitätsmedizin Berlin

CBF: Campus Benjamin Franklin

Charité Center Diagnostic Laboratory and Preventive Medicine CC 5

Institute of Microbiology and Hygiene

Postal address:

Hindenburgdamm 27

12203 Berlin

t: +49 30 8445 3739

Following peroral infection with Toxoplasma (T.) gondii susceptible mice develop an acute Th1-type immunopathology of the small intestine (pan-ileitis). This inflammatory scenario is mediated by pro-inflammatory cytokines such as IL-12, IL-18, TNF, NO and IFN-ϒ. We have previously shown that an IL-23-dependent upregulation of IL-22 was essential for ileitis development whereas IL-17 was dispensable. In addition, we have identified IL-23 as a key regulator of the matrix-modulating molecule gelatinase A (MMP-2), which is also directly involved in the immunopathogenesis following oral T. gondii infection.

So far neither upstream regulators and downstream effectors of IL-22, nor the potential cellular sources of IL-22 and MMP-2 are known. Thus, in the upcoming period of grant support we will investigate IL-22-dependent (downstream) effects on immune and matrix effector molecules and analyze IL-22-regulating (upstream) mechanisms. For this purpose we aim to identify the cellular sources of IL-22 and MMP-2, and, in addition, investigate the role of the intestinal microbiota for the differentiation of these cells or molecules.

Actual results point towards a so far unknown IL-22-dependent regulation of the pro-inflammatory cytokine IL-18 in the inflamed ileum following T. gondii infection. Given that we have also shown a MyD88-dependent IL-22 expression within the terminal ileum, MyD88 might exert so far unknown regulating properties within the IL18-signalling pathway and/ or the IL-23-/ IL-17 axis. We therefore hypothesize a feedback loop between IL-22 and IL-18 involved in ileitis development. A compromised integrity of the small intestinal epithelial barrier is essential in the pathogenesis of T. gondii-induced ileitis. In ex vivo ileum biopsies of IL-22 deficient mice a significantly higher transepithelial resistance could be measured as compared to Wildtype controls. The IL-22- and MMP-2-dependent regulation of the epithelial barrier function in the small intestine will be another central focus of our work during the next period of support. The studies will contribute to our understanding of the molecular mechanisms involved in the IL-22-dependent immunopathogenesis of intestinal inflammation and to identify potential novel molecular targets for treatment of inflammatory diseases.

Head of office

Birgit Röders

Birgit Roeders

Charité – Universitätsmedizin Berlin

CBF: Campus Benjamin Franklin

Charité Center Internal Medicine with Gastroenterology and Nephrology CC 13

Postal address:

Hindenburgdamm 30

12203 Berlin

t: +49 30 8445 2820

f: +49 30 8445 2820