The mechanism behind a novel protein secretion system in Salmonella Typhi

• Applicant: Dr. Tobias Geiger
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258606529

Typhoid toxin is an essential virulence factor of Salmonella enterica serovar Typhi (S. Typhi), and it is most likely responsible for the most lethal symptoms associated with typhoid fever. Although its structure, its host cellular receptors or its effects on the host are well described, very little is known about the initial mechanism by which typhoid toxin is secreted from the bacteria. Recently an interesting discovery has been made, showing that typhoid toxin is secreted by a novel protein secretion mechanism which appears to be a recent evolutionary adaptation from endolysin/holin pair systems utilized by phages to exit infected bacteria. It depends on a cell-wall degrading muramidase (TtsA) and most likely, on a yet unidentified accessory protein of the holin family. It is the objective of my research project to characterize this novel protein secretion system, to identify all of its components and to gain a mechanistic insight into many aspects of its function. Since adapted from phage endolysin/holin pair systems, screening for potentially associated holins will be the first task. Further on, I will utilize an unbiased genetic screen to identify alternative or additional components. The identification of the holin and/or additional secretion factors will provide the basis for a thorough mechanistic characterization, such as examination of potential protein interactions with typhoid toxin, TtsA itself or new-found proteins, revealed by the genetic screens. These experiments will also provide evidence for the specificity of this mechanism for typhoid toxin secretion. The discovered protein secretion system is not a unique feature of S. Typhi, as indicated by the existence of holin/amidase pairs encoded immediately adjacent to toxins or large extracellular enzymes in various pathogenic bacteria. Thus, this work has the potential to establish new paradigms about how large protein complexes such as toxins or extracellular enzymes are secreted from bacterial cells. In the process, knowledge gained by these studies may also lead to the development of novel therapeutic strategies to combat infectious diseases.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Jorge Galán, Ph.D.