Abstract
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and affecting 23% of the population worldwide. WHO has declared tuberculosis as world emergency since 1993. Yet, tuberculosis remained the deadliest infectious disease until the COVID-19 pandemic and cause 1.4 million deaths in 2019. The fight against the disease is slowed because of the poor efficiency of current vaccination which protects infants, but not adults, against the disease. Moreover, Mtb has the ability to circumvent the host immune response to its own benefits, which limits the efficiency of current antibiotherapies. Therefore, a strong interest arises for strategies aimed at enhancing trained immunity to optimize the immunization offered by current TB vaccines and for the host directed therapies as a mean to support the antibiotherapy. Macrophages are Mtb main host cells. Macrophages are professional phagocytes that usually trigger a protective inflammatory response against infection by pathogens. Unfortunately, Mtb is able to hijack this response and uses macrophage as its niche, ensuring long term infectionIn order to shed light on mechanisms underlying Mtb ability to reroute macrophage inflammatory response, I characterized, with a transcriptomic approach, the inflammatory response triggered by TB models used for drug discovery. I also identified, in a human macrophage model, the inflammatory response genes whose expressions were to Mtb virulence. As miRNAs are most mRNA post transcriptional repressors, I focused on miR-132-3p as a potential candidate to regulate macrophage defense during Mtb infection. By loss of function experiments, using RNA interference, I showed that miR-132-3p inhibition allows reduction of Mtb load in vitro, within human macrophages and in vivo in a murine TB model. Using measurement of macrophage immunometabolism and quantification of polarization marker genes, my results showed that miR-132-3p interferes with macrophage defense likely by regulating their polarization.My work provides insight on the means deployed by Mtb to hijack the macrophage inflammatory response and opens new research avenues on pertinent miR-132-3p regulated pathways that could be targeted for the development of host directed therapies.