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Visualization of Bacterial Secretion Systems

Gram-negative bacteria use secretion systems for nutrient acquisition, virulence, and the transport of proteins, drugs, and toxins out of the cell or into host cells. We exploit a cutting-edge direct electron detector and high-throughput cryo-electron tomography (cryo-ET) to visualize high-resolution 3D structures of these complex nanomachines - specifically Type III (T3SS or injectisome) and Type IV (T4SS) secretion systems - which inject effector proteins from the bacterium into eukaryotic host cells and mediate the transport of macromolecules across cell membranes. In Shigella flexneri, we revealed the intact injectisome, including cytoplasmic sorting platform, and its interaction with host cells (Hu et al, PNAS 2015). And currently, we are investigating T4SS in the disease-causing pathogens Legionella pneumophila and Coxiella burnetii. By combining advanced cryo-ET with genetic and biochemical approaches, we aim to determine the structure and assembly of the Dot/Icm machine, an essential virulence determinant. Our work stands to elucidate how the Dot and Icm proteins contribute to machine assembly and function at the molecular level, enabling this incredibly versatile apparatus to translocate into host cells a repertoire of over 300 different proteins with distinct biochemical functions and diverse structural properties.