OR09

1: Instituto de Biomedicina de Valencia (CSIC); 2: Instituto de Investigação e Inovação em Saúde; 3: Centro de Investigaciones Biológicas Margarita Salas; 4: Instituto de Biomedicina de Valencia, Spanish Research Council; 5: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; 6: Centro de Investigaciones Biológicas Margarita Salas, Spanish Research Council

Antimicrobial resistance is a major contributor to tuberculosis (TB)-related mortality. Host-pathogen interaction-based strategies may offer alternatives that circumvent resistance mechanisms. We investigated early events in Mycobacterium tuberculosis (Mtb) infection by RNA-seq, using both an in vitro culture model and an in vivo murine model resembling human infection. Two clinical Mtb isolates from L4.3/LAM sublineage, obtained from mild and severe TB patients respectively, were included. Despite their close genetic distance (302 bp), the isolates exhibited 1,798 differentially expressed genes under infection conditions. Notably, the severe TB-associated strain showed upregulation of trehalose biosynthesis genes (treY-treZ, treS), corroborated by metabolomic profiling in infected bone marrow derived macrophages. Given trehalose’s role in inducing autophagy via TFEB activation, we propose that this strain may leverage this pathway to reduce IL-1β production, a key compound in host immune response modulation by Mtb. Our findings highlight potential strain-specific strategies employed by Mtb during early infection. Moreover, targeting trehalose biosynthesis pathways may represent a promising avenue for therapeutic development. Ongoing studies include in vitro validation of candidate compounds identified through in silico screening.