Bacterial secretion systems
Dr Debnath Ghosal
+61 3 8344 8441
Bacteria harbour at least nine different types of secretion systems to transfer macromolecules across cellular envelope. These are sophisticated multi-protein nanomachines that secrete myriad substrates including proteins, nucleoprotein complexes and variety of small molecules and are central to pathogenesis of multiple human diseases. For example, many pathogenic bacteria utilise the Type III Secretion System (T3SS) to cause diseases such as typhoid (Salmonella), plague (Yersinia), dysentery (Shigella) etc.. Other human pathogens employ the Type IV Secretion System (T4SS) to mediate gastric cancer (Helicobacter), brucellosis (Brucella), typhus and spotted fevers (Rickettsia), as well as Legionnaires’ disease (Legionella).
The T4SS is also associated with the spread of antibiotic resistance, which currently presents a major threat to public health. Therefore, these molecular machines are attractive targets for drug developments to enrich our present repertoire of antibiotics. However, structural studies on these molecular machines are extremely challenging due to their large number of components, flexibility and tight integration into the bacterial cell envelope.
Recently, we used cryo-ET to decipher the in situ structure and molecular organisation of the intact Legionella T4SS, responsible for Legionnaires’ disease. Our work revealed that the T4SS has an envelope spanning channel and a large periplasmic "secretion chamber".
Fig. 1: 3D representation of the Dot/Icm complex showing a windowed secretion chamber (salmon, DotH; grey, DotD; green, DotK; and cyan, DotC), wings (yellow, DotF), a secretion channel (red, DotG) and the top-view of the complex. Cytoplasmic components are not shown.
Using a combination of genetic manipulation, immunofluorescence imaging and biochemical analysis, we also revealed the mechanism of polar targeting and biogenesis of this complex. This now sets the stage for investigating how this remarkable molecular machine is capable of secreting more than 300 different types of effectors and dissect its recondite modus operandi in the future.
This research project is available to Honours students to join as part of their thesis.
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