AUTOPHAGTUBERCULOSIS · MOLECULAR MECHANISMS OF AUTOPHAGY REGULATION IN TUBERCULOSIS

MOLECULAR MECHANISMS OF AUTOPHAGY REGULATION IN TUBERCULOSIS

*Background: Despite being an ancient infectious disease, tuberculosis remains the leading cause of mortality by single bacterial infection around the world, with approximately 1.5 million deaths every year. Nearly one third of the world population is infected with the causative agent of tuberculosis, Mycobacterium tuberculosis (M.tb). Among those infected 1 in 10 will develop the active disease. Although BCG vaccine can prevent some serious cases of tuberculosis, overall it remains largely inefficient. To make matter worse, we see emergence of multi- and extensively-drug resistant strains (MDR, XDR) and an increase in rate of co-infection with HIV which both contribute to high incidence of tuberculosis infection in large populations. Not to forget, that in addition to placing a huge burden on human health and well-being, TB has also a dramatic negative socioeconomic impact in areas where it strikes. Furthermore, with population migration and traveling, TB-MDR and TB-XDR, once found only in Asia, Africa or East-European have now reached Western-Europe Hospitals, challenging local health-system. Therefore, the development of new drugs and/or therapeutics to combat M.tb has become a high priority for the control and eradication of the disease. A better understanding of the pathogenesis and of M.tb interaction with the host is crucial for achieving that goal. Autophagy is a ubiquitous cellular process whereby cytoplasmic components are degraded by lysosomes. In addition to its function in cell homeostasis, autophagy plays major roles in immune system in particular in killing of intracellular invaders such as M.tb. Yet, recent studies have highlighted M.tb ability to counteract this process in macrophages, a privileged cellular niche for M.tb replication. How M.tb keeps at bay autophagy and its role in bacterial survival and replication inside macrophages remain to be fully investigated. *Objective and achievement: The main objective of AUTOPHAGTUBERCULOSIS was to progress in our understanding of autophagy and mycobacteria interaction in macrophages, particularly M.tb, using microbiological, biochemical and fluorescence microscopy approaches. Our principal results indicate that host autophagic responses to mycobacteria are plural in terms of mechanisms and intensities, and vary during the course of infection. Depending on the species, at least two types of autophagic processes appear to be triggered by mycobacteria: one dependent of phagosomal membrane damage and ubiquitin coating and a second independent which needs to be completely characterized. In addition, we uncovered that several non-proteinaceous components of mycobacterial cell envelope play a major role in the modulation of these responses. Finally, using different arrays probing signaling pathways and gene expression, we identified several potential host factors modulated by M.tuberculosis that might be implicated in autophagy regulation. The data obtained during CIG period will be submitted for publication in the coming year. *Scientist integration: Dr I.Vergne has a permanent position as a tenured CNRS Research Associate (http://www.cnrs.fr/index.php) since November 2010 at the institute IPBS (http://www.ipbs.fr/). The Marie Curie Career Integration Grant allowed Dr I.Vergne to successfully integrate the host organization. Indeed, during the CIG period Dr Vergne was able to development her career and transfer her knowledge through several activities: -Creation and development of a French Autophagy Society (http://cfatg.org/en/) http://www.tandfonline.com/doi/pdf/10.4161/auto.25168 -Organization of First Joint Meeting of Nordic, Spanish & French Autophagy Networks (http://cfatg.org/wp-content/uploads/2014/01/Flyer-IAC-2014.pdf) -Reviewing of manuscripts for scientific journals, grant applications for funding agencies and thesis. -Presenter: invited seminars, session chairs and posters at national and international meetings. -Teaching and supervision of PhD and master students from Toulouse University (http://en.univ-toulouse.fr/our-strengths) -Publication of two reviews: 1.Manipulation of the endocytic pathway and phagocyte functions by Mycobacterium tuberculosis lipoarabinomannan: http://www.ncbi.nlm.nih.gov.gate1.inist.fr/pmc/articles/PMC4290680/ 2.Autophagy in Mycobacterium tuberculosis and HIV infections: http://www.ncbi.nlm.nih.gov.gate1.inist.fr/pmc/articles/PMC4451423/ -Secure additional grant funding (French foundation and European Commission/Horizon2020, TBVAC2020. Finally she developed several important collaborations with research groups at the Institute and National Universities. *Impact: Autophagy is a field of intensive research that has been growing exponentially since early 2000. The rapid rising interest in this field is due to the pleiotropic functions of autophagy in the eukaryotic cells and its association with a wide range of debilitating human pathologies: cancer, neurodegenerative diseases, myopathies, and metabolic disorders, inflammatory and infectious diseases. Thus, autophagy modulation as emerged as a potential and novel therapeutic strategy to combat several diseases. However, before developing such strategies, one needs to fully decipher the role and the regulation of this pathway in each pathological setting. Despite important progresses made by scientists around the world, many questions remain to be answered, in particular regarding the regulation of autophagy by intracellular pathogens such as M.tb. Unlocking the complex interplay between the etiologic agent of Tuberculosis and host autophagy will be a decisive step towards developing innovative therapeutics against this deadly pathogen. This basic scientific research project has generated new knowledge on the complex dialog between the pathogen and host defences. Further investigation will undoubtedly help unveiling novel potential drug targets for boosting autophagy in infected host and could open-up novel avenues for future development of original anti-TB treatment based on host immune responses.

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