Junior Scientists

Our reseach focuses on the cellular and molecular interactions between the microbiome, the gastrointestinal (GI) mucosa and the mucosal immune system in humans.

We are interested in how microbiota modulate innate and adaptive immune pathways and how they influence the intestinal and hematopoietic stem cell niches in cancer, stem cell transplantation and immunotherapy. We aim to identify microbiome signatures that contribute to positive clinical outcomes, how bacteria and their bacterial products mediate protection of mucosal barriers and the molecular mechanisms by which they do so. The advent of immunotherapy has been practice-changing and as these therapies gain an ever greater hold in hematology-oncology, we aim to identify which microbiome signatures predict their efficacy and why.

Our clinical aims are first, to develop microbiome-based therapeutic approaches that can provide resistance to intensive chemotherapy, radiotherapy and immune reactions after cellular therapy. Second, we are motivated to translate microbiome analytics to a clinical diagnostics, to better steer antibiotic therapy, screen antibiotic resistance genes and identify patient candidates for FMT.

Publications

Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, Tam AJ, McAllister F, Fan H, Wu X, Ganguly S, Lebid A, Metz P, Van Meerbeke SW, Huso DL, Wick EC, Pardoll DM, Wan F, Wu S, Sears CL, Housseau F.
Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.

Cell Host Microbe. 2018Feb 14;23(2):203-214.e5.
Thiele Orberg E, Fan H, Tam AJ, Dejea CM, Destefano Shields CE, Wu S, Chung L, Finard BB, Wu X, Fathi P, Ganguly S, Fu J, Pardoll DM, Sears CL, Housseau F.
The myeloid immune signature of enterotoxigentic Bacteroides fragilis-induced murine colon tumorigenesis.
Mucosal Immunol. 2017 Mar;10(2):421-433.

Summary: Metabolites fuel adaptive immunity

T cells protect us against pathogen infections in a diverse set of tissues. In these tissues, they are exposed to largely different metabolic conditions and diverse metabolites. This is especially relevant in the gut, where bacterial metabolites can rapidly change in composition and mediate effector T cell function. How the availability of these molecules affects T cell differentiation from naïve cells into effector cells is largely unknown. In this project, we focus on understanding how the nutrient and metabolite composition in gut-associated and peripheral tissues changes during various conditions and determines T cell function. We aim to identify natural, as well as pharmacological metabolite candidates with the potential to modulate T cell function.

Previous Publications:

Kumar, A., Katz, L.S., Schulz, A.M., Kim, M., Honig, L.B., Li, L., Davenport, B., Homann, D., Garcia-Ocaña, A., Herman, M.A., Haynes, C.M., Chipuk, J.E., and Scott, D.K. Activation of Nrf2 is required for normal and ChREBPα-augmented glucose-stimulated β-cell proliferation. Diabetes. doi: 10.2337/db17-0943.

Fiorese, C.J.*, Schulz, A.M.*, Lin, Y.F., Rosin, N., Pellegrino, M.W., Haynes, C.M. (2016) The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr Biol. 26(15):2037-43. *contributed equally.

Lin, Y.F., Schulz, A.M., Pellegrino, M.W., Lu, Y., Shaham, S., Haynes, C.M. (2016) Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial UPR. Nature. doi: 10.1038/nature17989.

Schulz, A.M. & Haynes, C.M. (2015) UPR^mt-mediated cytoprotection and organismal aging. Review article. Biochim Biophys Acta. doi10.1016/j.bbabio.2015.03.008.

Schulz, A.M., Stutte, S., Hogl, S., Luckashenak N., Dudziak, D., Leroy, C., Forné, I., Imhoff, A., Müller, S.A., Brakebusch, C.H., Lichtenthaler, S.F., Brocker, T. (2015) Cdc42-dependent actin dynamics control maturation and secretory activity of dendritic cells. J Cell Biol. 211(3):553-67.

Luckashenak, N.*, Wähe, A.*, Breit, K., Brakebusch, C., Brocker, T. (2013) Rho-family GTPase Cdc42 controls migration of Langerhans cells in vivo. J Immunol. 190:27-35. *contributed equally   

Wähe, A., Kasmapour, B., Schmaderer, C., Liebl, D., Sandhoff, K., Nykjaer, A., Griffiths, G., Gutierrez, M.G. (2010) Golgi-to-phagosome transport of acid sphingomyelinase and prosaposin is mediated by sortilin. J Cell Sci. 123:2502-11. Including Cover Image

Current and previous funding:

German Research Foundation (DFG, SFB1371, seed funding)

German Research Foundation (DFG, Individual research grant #419162346)

European Union’s Horizon 2020 Research and Innovation Program (Marie-Curie COFUND Fellowship, Eurotech Postdoc)

German Research Foundation (Research and Return Fellowship) – Completed

In Germany, considerable moves were made towards the support of bacteriophage (phage) therapy in the last months, including completed case series, an early clinical study, and a practicability test of the magistral approach according to the Belgian model. Embedded in the German phage task group, we are motivated to enhance international and German cross-disciplinary teamwork and to provide patients with safe, certified and tailor-made adjunct phage therapy.

In addition to deciphering the safest and most realistic way of phage therapy, we seek to enhance a bioanalytical filtration method for tailored fecal microbiota transplantation (FMT). FMT has shown curative potential in various disorders in the digestive tract. Thus, interest in FMT is growing particularly on the side of patients despite several reported adverse events. Adverse events by FMT are based on the complex composition of the material including pathogenic and facultative pathogenic bacteria and viruses. Patients suffering from intestinal Graft versus Host Disease (GvHD) or inflammatory bowel disease (IBD) can be expected to profit from major advantages of a filter-based enrichment method such as monolithic affinity filtration. This technically advanced enrichment system is enhanced to a purification device, which could offer unique benefits in GvHD-situations and IBD. There is special focus on phage-based coatings and the optimal arrangement of filters using series circuits.

Team (co-supervision with Prof. Li Deng and PD Dr. Michael Seidel):
-          Eggl, Anja (study nurse)
-          Hering, Svenja (doctoral student)
-          Marinkovic, Vanessa (study nurse)
-          Trommler, Julian (master student)
-          Wesch, Chris (doctoral student)
-          Winkler Corinna (doctoral student)
-          Geier, Raffaela (bachelor student, successfully completed)

Third party funding:
-          German Research Foundation (DFG, SFB 1371, seed funding)
-          Else Kröner-Fresenius-Stiftung (EKFS, Forschungskolleg "Mikrobielle Trigger als Auslöser von Krankheiten", Clinician scientist)
-          Federal Ministry of Education and Research (BMBF, PI: Prof. Li Deng)
-          German Center for Infection Research (DZIF, Translational medicine program, PI: Prof. Li Deng)
-          Commission for Clinical Research (KKF, Clinician scientist)

For questions to bacteriophage therapy, please don’t hesitate to contact silvia.wuerstle@tum.de. / Bei Fragen zur Therapie mit Bakteriophagen, wenden Sie sich bitte an silvia.wuerstle@tum.de.