Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), remains one of the most threatening and devastating diseases worldwide, more especially in sub-Saharan Africa, Russia and Eastern Europe. With 10.4 million new cases and 1.7 million deaths caused by M. tb in 2017 [1], TB is the most deadly infectious disease worldwide (above HIV/AIDS). The diagnosis delay, inappropriate therapies, the HIV-AIDS pandemics and the emergence of multi-, extensively-, and totally-drug resistant (MDR, XDR and TDR) [2,3] strains are some of the main reasons for the global TB epidemic, despite the wide use of vaccination and antibiotherapy [4].

 

Infection with M. tb follows a relatively well-defined sequence of events [5,6]. When inhaled, M. tb reaches the lungs, where bacilli are phagocytosed by alveolar macrophages. Prognosis of the disease, i.e. active or dormant, will depend on the host’s ability to contain the bacilli at the site of infection. In most cases, mycobacteria grow exponentially until the emergence of an acquired immune response takes effect [5]. Concomitantly, and within weeks after M. tb infection, a granuloma is formed at the site of infection which allows the control of bacterial propagation in the lungs [7,8]. Within granulomas, some of the M. tb-infected macrophages differentiate into foamy cells characterized by the intracytosolic accumulation of neutral lipids in the form of lipid bodies (LB) [5,9]. In such foamy macrophages (FM), M. tb metabolizes host lipids contained in LB and accumulates the resulting neutral lipids, essentially triacylglycerols (TAG), in its own cytoplasm in the form of intracytoplasmic lipid inclusions (ILI) to serve as a source of carbon and energy [7,10-12]. Lipid-loaded mycobacteria were indeed shown to stop their replication, thus resulting in a state of persistent and non-dividing mycobacteria [6,10,13,14]. During the reactivation phase, these ILIs are hydrolyzed by M. tb and used to fuel the regrowth of the mycobacteria during their exit from the non-replicating state [10].

 

All these findings imply that assimilation of fatty acids from LB degradation, as well as TAG biosynthesis and hydrolysis are key aspects of the mycobacterial metabolism [15], and results from the presence of intracellular and secreted/membrane-anchored mycobacterial lipolytic enzymes capable of degrading LB and/or ILI, respectively.

 

From the past decade, it has been well established that such mycobacterial lipolytic enzymes, involved in the host-pathogen cross-talk, play critical roles in the physiopathology of the disease. Biochemical, clinical and cellular experiments have shown that they are involved in bacterial growth [10], virulence (reactivation and propagation) [16], dormancy [15], cell wall biosynthesis [16,17], as well as in lipid storage and degradation [6]. They have also been found to be powerful biomarkers of active disease [18,19]. These later interesting data could also open the way for using lipolytic enzymes as potential vaccinal tools.

 

In order to specifically study the physiological processes related to lipid accumulation/consumption which are critical to the M. tb infectious life-cycle for propagation of the infection, establishment of the dormancy state and reactivation of the disease, several in vitro and ex vivo models have been developed [6,12,20]. Consequently, exposure of in vitro growing pathogenic mycobacteria or mycobacterium-infected macrophages to inhibitors that specifically target such mycobacterial lipolytic enzymes may be particularly helpful to decipher the contribution of these enzymes to the physiology of M. tb growth and/or persistence. Accordingly, a better understanding of how bacilli can persist inside lipid-rich FM would bring important knowledge on the bacterial life cycle.

 

Several studies by us [21-27] and others [28-31] have highlighted the fact that inhibitors of such enzymes might turn out to be valuable anti-tuberculosis agents; arguing the fact that these enzymes are real mycobacterial drug targets [16,32]. This specific point is of major importance in a context where the treatment for TB disease consists in a multiple-drugs therapy for 6-9 months, which has to be often extended to prevent latent TB infection (i.e., persisting bacilli in dormant state) from turning into active TB disease. Such long treatment is in part responsible for the appearance of MDR strains, which prompted Zumla et al. to stated that “there is growing awareness of the need for drugs that can kill M. tuberculosis in its different physiological states” [33].

 

In this context, we aim at deciphering the physiological role of mycobacterial enzymes in lipid metabolism, notably focusing on the accumulation and consumption of lipids at key stages of the bacterial infection and using new anti-TB molecules targeting these lipolytic enzymes. Such knowledge will also provide major information on M. tb life cycle that should inspire new therapeutic strategies with the potential to eliminate actively growing and/or latent bacilli from infected individuals.

 

Above all, our research projects could provide new insights into the mechanism of latency and reactivation that are major issues for understanding the general development of TB.

​

​​​​​​​​​​​​​​​​​​​​​​​​​​