Mycoplasma – Structural Characterization of Host Cell Interaction Determinants

• Applicant: Professor Dr. Achilleas Frangakis
• Subject Area: Structural Biology
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274962763

Mycoplasmas are among the smallest and simplest prokaryotes capable of self-replication, with a genome which may be as small as 600 kbases. They are significant pathogens that may induce clinically relevant manifestations. In the previous funding period we used cryo- electron microscopy to solve the structure of the main adhesion complex of Mycoplasma pneumoniae and Mycoplasma genitalium, the Nap, that is responsible for the adhesion of the pathogens to host cells and indispensable for manifesting the infection. In addition, we studied numerous mutants of M. genitalium by cryo-electron tomography, which allowed for explaining the mechanism of adhesion and motility. Here we apply for funding to continue this study using two avenues: (i) Using single-particle cryo-electron microscopy to solve the structure of the intracellular part of the Nap (Napic), for which we have evidence that it is responsible for triggering the adhesion release mechanism, and of further immunodominant and/or abundant Mycoplasma surface proteins (specifically P116/MG075 and MPN474/MG328). The structures will complement our previous structures of the main adhesin and should provide us with a complete mechanistic understanding of the adhesion. Mechanistic understanding of the adhesion has the potential for facilitating development of new therapeutics against these pathogens that are notoriously difficult to control with current antibiotics. (ii) Using cryo- electron tomography and a focused-ion-beam approach, we would like to investigate the direct interaction of the Mycoplasmas with host cells to understand how the infection manifests. In particular, we would also like to visualize the adhesion of Mycoplasmas to epithelial cilia, which apparently causes ciliary dysfunction during the infection. For both of the above avenues we have already done significant prior work, both independently and as members of a vibrant collaborative community. Finally, the motivation for our work is reinforced by recent studies that have reported a critical role of Mycoplasma pneumoniae for the clinical outcome of viral infections of the respiratory tract.

• DFG Programme: Research Grants