Kliniken & Institute … Institute Zentrum für… Medizinische… Forschung Research Hildebrand

Research Group Hildebrand

Group Leader: Dr. Dagmar Hildebrand

Research interests

The center of our research is infection and immunity.

We are studying innate immune cell-mediated mechanisms that regulate T cell responses to infection.

A focus of my lab is the connection between activation and termination of the immune response against bacterial infection. In the human system, we analyze infection-induced signaling cascades, involved in modulating myeloid cell phenotype and the consequences for adaptive immunity.

Another focus of our research is the impact of Escherichia coli heterogeneity on invasiveness and immunity. We try to identify virulence factors of intestinal multi-resistant Escherichia coli strains that facilitate endogenous bloodstream infection.

Endogenous Escherichia coli bloodstream infection - involved virulence factors

In this project we investigate virulence factors responsible for endogenous bloodstream infections with resistant (3MRGN) gram-negative Escherichia coli strains.

Gram-negative E.coli are considered as commensals that colonize the gut lumen without invading the tight barrier of intestinal epithelial cells. Naturally, E.coli don`t induce an immune response but facilitate tolerance. However, some intestinal E.coli strains become invasive. They cross the endothelial barrier, enter the blood stream and can cause severe immune reactions. Infected endothelial cells mediate a switch from a tolerogenic to an inflammatory milieu that facilitates clearance of the infection but also dampens barrier function.

Why some E.coli strains induce an endogenous infection and others do not is largely unknown.

In this study we are looking for bacterial factors that facilitate invasion and investigate the mediated modulation of intestinal epithelial cells and immune cells. We establish genome (whole genome sequencing) and gene expression (RNA-Seq) profiles of 3MRGN E.coli isolates from gut and blood of hospital patients in comparison to commensal strains. The respective strains are utilized in invasion assays and immunological approaches in in vitro infection models.

In cooperation with Sebastien Boutin, Dennis Nurjadi and Sabrina Klein we focus on the following questions

  • Which virulence factors of intestinal E.coli facilitate an endogenous infection?
  • Are the factor encoding genes transferred to other bacterial strains and increase their virulence?
  • Does resistance correlate with virulence?
  • How do invasive E.coli strains modulate intestinal epithelia cells and the gut-associated immune system?

Medical student: Johannes Lars Krall    

Notch signalling and the immune system

Positive feedback loop between Notch and STAT3 ​​​​​​​1+1A) LPS stimulates IL-6 through TLR4-mediated NF-κB signaling. 2) IL-6 binds to IL-6 receptor (IL-6R) and induces activation of STAT3. 3) STAT3 induces expression of DLL1. 4) Transmembrane DLL1 binds to Notch receptor on neighboring cells. NICD translocates to the nucleus, induces gene transcription and NF-κB accumulation in the nucleus. IL-6 production is enhanced. 5) Enhanced IL-6 receptor signaling stabilizes STAT3 activation. 6) STAT3-dependent expression of immune suppressive PD-L1 is increased. Hildebrand et al., 2018 Front. Cell. Infect. Microbiol

In this project we investigate the impact of Notch signalling on the immune response towards infection.

The highly conserved Notch signalling cascade is mostly known for participating in immune regulation through controlling lineage decisions of developing immune cells. The pathway depends on transmembrane Notch ligands (Jagged-1, Jagged-2, Delta-like 1 (DLL1), DLL3, DLL4) binding to Notch receptors (Notch1-4) on neighboring cells. Upon ligand binding, proteolytic processing events occur, which mediate shedding of the extracellular domain and translocation of Notch intracellular domain (NICD) to the nucleus and Notch target gene expression.  Similar to their receptors, Notch ligands also undergo enzymatic cleavage upon receptor-binding.

In previous studies, we investigated the mechanism behind DLL1 expression in E. coli-infected human primary monocytes and demonstrated a bidirectional interaction between Notch signalling and Signal transducer and activator of transcription (STAT3) that facilitates remodeling of myeloid cells into an immuno-suppressive phenotype.

Our present work focuses on Notch ligand-mediated remodeling of the immune system during infection. In particular, we are interested in T cell activation, metabolism and formation of memory T cells.

Master student: Selina Börsig   

Group members

 Johannes Lars Krall, MD student

  Selina Börsig, Master student

  Aline Sähr, Technician

Selected publications

Hildebrand D, Decker SO, Koch C, Schmitt FCF, Ruhrmann S, Schneck E, Sander M, Weigand MA, Brenner T, Heeg K, Uhle F
“Host-Derived Delta-Like Canonical Notch Ligand 1 as a Novel Diagnostic Biomarker for Bacterial Sepsis—Results From a Combinational Secondary Analysis”
Front. Cell. Infect. Microbiol., 23 July 2019

Hildebrand D, Metz-Zumaran C, Jaschkowitz G, Heeg K
“Silencing SOCS1 via Liposome-Packed siRNA Sustains TLR4-Ligand Adjuvant.”
Front Immunol. 2019 Jun 4;10:1279. doi: 10.3389/fimmu.2019.01279.

Hildebrand D, Uhle F, Sahin D, Krauser U, Weigand MA, Heeg K
“The Interplay of Notch Signaling and STAT3 in TLR-Activated Human Primary Monocytes.”
Front Cell Infect Microbiol. 2018 Jul 10;8:241. doi: 10.3389/fcimb.2018.00241.

Hildebrand D, Eberle ME, Wölfle S,  Egler F, Sahin D, Sähr A, Bode KA, Heeg K
“Hsa-miR-99b/let-7e/miR-125a cluster regulates pathogen recognition receptor-stimulated suppressive APCs “
Front. Immunol. 2018 May 9:224 doi: 10.3389/fimmu.2018.01224

Giesbrecht K, Eberle M, Wölfle S, Sahin D,  Sähr A, Oberhardt V, Menne Z, Bode K, Heeg K, Hildebrand D
” IL-1β as mediator of resolution that reprograms human peripheral monocytes towards a suppressive phenotype.“
Front. Immunol. 2017 Aug 3;8:899.