PORTEFEUILLE

With the advent of genome engineering and synthetic biology, we chave the ability assemble cellular systems naturally found in the microbial world. For example, we can repurpose sensing and effecting systems into a single bacterial machine in order to perform a variety of complex tasks in a defined context. Consequently, engineering and programming bacteria into “smart therapeutics” that patrol a host to detect and treat diseases now appears as a realistic endeavor. Such strategies may help us treat a variety of conditions including cancer, infectious diseases or immune disorders.
However, a major obstacle in developing successful bacterial therapies is the lack of specificity of their action as they may target both healthy and sick tissues. Here, we propose to design and engineer a mechanosensitive bacterial therapy (mBaT). mBats consist in a bacterial chassis system able decorated with adhesive structures that help direct ist attachment to specific diseased tissue. Then, mBats are programmed with the ability to inject effector proteins into host cells upon contact. To produce this, we assemble specifica dhesion components at the surface of the bacterium and combine this with effecting components allowing the bacterium to eradicate tumor cells by translocation of toxic effectors. Altogether, mBaTs has the potential to become a highly specific cell-based treatment of tumors.

Most therapeutic approaches to treat diseases consist in developping moleculas that act on specific receptors or markers of disease tissue. Here, we go beyond the current paradign of disease treatment by repruprposing microbial systems to generate a cell-based therapeutic. mBats are autonomous, meaning that they can target the diseased tissue without guidance.

We have succesfully developped a toolbox allowing for the design and implementation of receptor display at the surface of a bacterium. As such, the system can be repruprosed on many bacteria and can be used to tune the specificity of many other cell-based therapeutics. We are currently implementing this adhesion system in pathogens susceptible to eradicate a targeted tissue. In particular, we are currently leveraging engineered mBats to specifically target breast cancer cells growing within healthy cells, thereby representing an early proof of concept. In addition, engineering mBats stimulated further ideas in using display strains to treat other types of diseases. For example, we will seek to adapt this system to the treatment of infectious diseases by stimulating contact between a bacterium and a foreign pathogen, thus initiating its degradation. Altogteher, our approach will stimulate the community in engineering contact-stimulated cell ased therapeutics.

“Control of bacterial adhesion to target mammalian cells using VHH display”, X. Pierrat, A. Cont, J. Wong and A. Persat, manuscript in preparation;
“Mechanomicrobiology: how bacteria sense and respond to forces”. Y. Dufrene and A. Persat, Nature Reviews Microbiology 18