Periodic Reporting for period 1 - ESX-4 T7SS (Structure/function of a prototypic type VII secretion system from a fast-growing pathogenic mycobacteria) Reporting period: 2019-04-01 to 2021-03-31 Summary of the context and overall objectives of the project Mycobacteria are pathogens responsible for many infamous and widely spread diseases, like tuberculosis or leprosis. At the start of this project, no potent vaccines were available against mycobacteria and with the rise of multiple multi-drug resistant strains of mycobacteria, new drugs were needed. Though concerning, the World Health Organization (WHO) was still, with extensive efforts, optimistically hoping to eradicate TB by 2035. At the end of this study, however, the WHO stated that due to the COVID pandemic, their efforts in eradicating the century old disease were predicted to experience at least a 7-year set-back. This project aimed at studying a secretion system, specific to mycobacteria, called the Type VII Secretion system (T7SS). T7SS allows the bacteria to import important nutrients, while exporting virulent factors that lets the bacteria evade the human immune system. Therefore, this makes this study of T7SS so attractive: if we could design a drug that would block the import of essential nutrient for the bacteria, we could starve it to death; or we could attempt to block the secretion of the virulent factors and let our immune system take care of the bacteria. During this project, information was gathered on the 3D structure of the T7SS complex machinery and, in collaboration with laboratories from Germany and France, more information was gathered on the factors secreted by T7SS and their impact on our immune system. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Since the beginning of this project, substantial efforts were made toward the 3D resolution of the Mycobacterium abscessus ESX-4 type VII secretion system. Therefore, the complex, and its multiple copies of the five different proteins that composes it, was successfully purified and promising results toward its structure resolution were obtained. Invaluable information was also gathered on two of the five proteins composing the secretion system. Finally, extensive information, in collaboration with the research center of Borstel (Germany), and the University of Versailles and the IRIM institute of Montpellier (France), were obtained on the virulent factors secreted by Mycobacterium abscessus ESX-4. A literature review of the progress made in the field was also recently accepted by Microbiology, a Microbiology Society journal. This review was written in collaboration with members of all four laboratories. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Beyond the state-of-the-art and the release of the literature review, we are expecting to release another paper within the year on the secreted factors. It will provide additional information on the behavior of Mycobacteria abscessus and its interaction with the human immune system, helping clinician better understand the bacteria and better care for their patient. Model of ESX-4 imbedded within the complex membrane of Mycobacterium abscessus.
