Marc’s main research goals are to understand the regulation, function and assembly of virulence factors of pathogenic bacteria. In particular, his research focuses on the Gram-negative, gastrointestinal pathogen Salmonella enterica. The incidence of foodborne outbreaks caused by Enterobacteriaceae, including Salmonella enterica, remains substantial and constitutes a significant socioeconomic burden in Europe and worldwide. To efficiently colonize their host, Salmonella employ multiple virulence factors, including flagella and needle-like injectisome devices, whose assembly and function both require a conserved type-III protein secretion system. In order to elucidate the underlying regulatory principles, function and assembly mechanisms of these virulence factors, Marc and his team combine quantitative single-cell and superresolution microscopy analyses, biochemical approaches, genetic engineering and biophysical modeling.
Re-constructing the coordinated self-assembly of a bacterial nanomachine
Life has evolved diverse protein machines and bacteria provide many fascinating examples. Despite being unicellular organisms of relatively small size, bacteria produce sophisticated nanomachines with a high degree of self-organization. The motility organelle of bacteria, the flagellum, is a prime example of complex bacterial nanomachines. Flagella are by far the most prominent extracellular structures known in bacteria and made through self-assembly of several dozen different kinds of proteins and thus represent an ideal model system to study sub-cellular compartmentalization and self-organization. In the ERC-funded project BacNanoMachine, we employ quantitative single-cell analyses, biochemical and genetic engineering tools, in order to deconstruct the assembly of the flagellum in living bacteria and to identify the underlying rules that govern its biogenesis in time and space.
Molecular mechanisms of type-III protein secretion
Protein export via type-III secretion systems is essential for construction of the bacterial flagellum, as well as for the assembly and function of the virulence-associated injectisome systems of many Gram-negative pathogens. While isolated components have been studied, purified type-III secretion systems lack their integral membrane components, and thus mechanistic insights on export apparatus assembly, substrate translocation and energy coupling are lacking. The goal of our DFG-funded project is to obtain a mechanistic understanding of the molecular quality control mechanisms that orchestrate assembly of the core components of the type-III protein secretion apparatus.
Evolutionary optimization and environmental control of bacterial motility
Most bacteria swim in liquid environments by rotating one or several flagella. However, the biosynthetic resources required to assemble and operate flagella are significant and the large external filament is a major antigen recognized by the host’s immune system. Accordingly, complex regulatory systems control flagella synthesis in many bacteria, which, in combination with the intrinsic noise of gene expression and the stochastic re-distribution of flagella during cell division, result in large fluctuations in terms of flagellation patterns within a bacterial population. In an interdisciplinary consortium funded by the VolkswagenStiftung, we combine genetic engineering with single-cell microscopic tracking techniques and mathematical models of chemotactic behavior in order to determine how fluctuations in the flagellation pattern influence bacterial motility in varying environments.
Genetic engineering of bacteria for pharmaceutical and biotechnological applications
In collaboration with Siegfried Weiss at Hannover Medical School, we investigate the immunogenicity of genetically engineered and conditionally attenuated Salmonella for use in bacteria-mediated tumor therapy. We further engineer synthetic bacteria that exploit the flagellar protein export system for the secretion of recombinant polypeptides into the culture supernatant, readily available for subsequent applications, or for targeted secretion into eukaryotic cells.
For more details on research projects in Marc Erhardt's lab: click here.