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Michael Kolbe

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Structural Infection Biology

“The CSSB offers excellent conditions for an interdisciplinary research approach providing the infection biologists with state-of-the art instruments and ongoing development of new spectroscopic techniques.”

Michael Kolbe, CSSB Group Leader

Previous and current research

Bacterial Disease and Host-Pathogen Interactions
A major interest of the Kolbe group is the study of molecular machines from different pathogens and the host response to them. We focus on understanding how these macromolecular complexes assemble and work to facilitate bacterial infection. Water-borne bacterial pathogens like Salmonella or Shigella utilize a nanosyringe-like structure named Type 3 Secretion System (T3SS) to hijack human cells and prepare them for invasion. We study the structure and function of the T3SS and take a closer look at the atomic architecture of the T3SS throughout the infection process.

We seek to answer questions such as: How do structural switches in the secretion apparatus allow the recognition and secretion of effectors in a hierarchical manner? What kind of protein-protein interactions can drive bacterial invasion? How do bacteria promote the formation of vesicles and adapt to accommodate herein? We integrate high-end technologies like X-ray lasers and electron cryo-microscopes with other biophysical methodologies to examine the dynamic process of a bacterial infection at nanoscale resolution. The study of the structure and the molecular assembly mechanisms of vesicular trafficking induced by pathogenic bacteria in host cells will be a developing interest of the research group.

In addition, we have a strong interest in uncovering the strategies used by Gram-negative organisms to subvert the antibacterial response of human cells. Components of the tip of the T3SS nanomachine interact with host membranes to allow the translocation of bacterial effectors directly to the human cell. How the translocon components assemble and insert into host membranes to form pores is under investigation.

The group also focuses on the molecular interactions of T3SS effector proteins with host components and their signalling cascade that drives cellular subversion. A developing interest of the lab is to understand, at the atomic level, how innate immune receptors sense the presence of bacterial components, such as T3SS effectors or bacterial pigments, when they gain access to the cell cytosol leading to immune activation. Three-dimensional structural analysis and binding assays of key components of the T3SS pathway and their host interacting partners will allow us to design molecular drugs for the treatment of Gram-negative bacterial infections.

Our overarching goal is to integrate interdisciplinary approaches such as cellular microbiology, computational modelling and structural biology methodologies to advance our understanding of the assembly of macromolecular structures at near atomic resolution and to determine which approaches can also be applied to other biological pathways beyond infectious diseases.

Future perspective
Our underlying biological goal is to understand in-depth the process by which Type 3 Secretion Systems orchestrate the sequential order of effector translocation and trigger controlled subversion of a target cell. In addition, we aim to explore the potential for therapeutic targeting of the type 3 secretion pathway involved for either bacterial invasion or immune activation depending on the disease state.
Selected Publications

Selected Publications
Moura-Alves P et al, (2014) Aryl hydrogen receptor senses bacterial pigmented virulence factors and orchestrates antibacterial defenses, Nature, 512: 387-392

Dohlich K, Brotcke Zumsteg A, Goosmann C, Kolbe M, (2014) A Substrate-Fusion Protein is Trapped inside the Type III Secretion System Channel in Shigella flexneri, PLoS Pathogens, e003881

Loquet A, et al. (2012) Atomic model of the type III secretion system needle, Nature, 486: 276-279

Poyraz O, et al. (2010) Protein refolding is required for assembly of the type three secretion needle. Nat. Struct. Mol. Biol., 17: 788-792

Lunelli, M, Lokareddy, RK, Zychlinsky, A, Kolbe, M, (2009) IpaB-IpgC interaction defines binding motif for type III secretion translocator. Proc. Natl. Acad. Sci., 106: 9661-9666



Picture: © Marta Mayer
Drucker