THE TRANSCRIPTIONAL REGULATOR FasR IS REQUIRED FOR THE SURVIVAL AND REPLICATION OF Mycobacterium tuberculosis.

BIGI, FABIANA; BLANCO, FEDERICO; GAGO, GABRIELA; VAZQUEZ, CRISTINA

Buenos Aires

Congreso; Reunión Conjunta Sociedades de Biociencias de Argentina- LIII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular (SAIB); 2017

SAIB

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis,has the capacity of surviving within infected host and persistsfor long time. This is due to its distinctive cell wall, which plays acrucial role in the pathogenesis, virulence and survival in macrophages,its intracellular niche. The main component of the cell envelopeis the mycolic acids (MA) that together with peptidoglycanform the cell wall skeleton and contributes to the reduced cell wallpermeability and acid fastness characteristic of Mtb. The biosynthesisof MA depends on the action of two different types of fatty acidsynthases (FAS): FAS-I and FAS-II. The FAS-II complex elongatesfatty acyl-CoAs previously synthesized by FAS-I to generate verylong precursors of MA. Recently it has been described FasR, a transcriptionalactivator from Mtb that binds specifically to fas promoterto regulate its expression and the biosynthesis of MA precursors.Evidence shows that FasR is important for bacterial growth. Here,we investigate the role of FasR in the Mtb infection. To address theeffect of FasR in vivo, we infected BalbC mice with Mtb wild-type(WT), the mutant MtbFasR or with the FasR complemented strain(MtbFasR::FasR) during 60 days. Our results show that FasR isrequired for the survival and replication of Mtb in the lung of infectedmice. Next we evaluated the impact of FasR on Mtb infectionof human macrophages (THP-1). After 120 and 144 h of infection,the total CFU of mycobacteria significantly decreased in cells infectedwith MtbFasR, showing that the intracellular survival of Mtb inmacrophages depends on FasR. We also analyse the function ofFasR in the phagosome maturation, determined by the acquisitionof Lysotracker and LAMP-3 (late endo/lysosomal markers). Interestingly,the absence of FasR increased the phagosome maturationcompared to cells infected with WT or complemented strain. Weconclude that FasR is an essential regulator for the virulence of Mtb.Key words: Mycobacterium tuberculosis, FasR, phagosome