Impact of protein prenylation inhibition on Mycobacterium leprae viability and IL-1β production in infected macrophages

ABSTRACT Leprosy is a chronic infectious disease caused by Mycobacterium leprae and M. lepromatosis. Brazil consistently ranks among the countries with the highest number of leprosy cases. Data from our group showed that M. leprae upregulates the mevalonate pathway (MP), contributing to the accumulation of cholesterol-ester-enriched lipid droplets in infected macrophages, and that the inhibition of this pathway by statins decreases bacterial intracellular viability. It has already been shown that part of the deleterious effect of statins on M. leprae survival is related to the reduced cholesterol levels, which M. leprae oxidizes to generate reductive power. According to the literature, statins, by inhibiting MP, increase the production of the inflammatory cytokine IL-1β through the negative modulation of the biosynthesis of the isoprenoid geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), which are responsible for protein prenylation. In the present study, we tested the hypothesis that part of the effect of statins on the intracellular viability of M. leprae comes from their impact on IL-1β production via decreased prenylation. We demonstrate that GGPP is essential in macrophage–M. leprae interaction since the MP inhibitors, pamidronate and GGTI-298, which inhibit the enzymes farnesyl pyrophosphate synthase and geranylgeranyl transferase-1, respectively, decreased the intracellular viability of M. leprae, measured by RT-qPCR. MP inhibitors increased IL-1β production by activating the inflammasome, but this effect was reversed with GGPP. IL-1β levels were inversely related to bacterial survival. In conclusion, our findings highlight the potential role of protein geranylgeranylation in M. leprae pathogenesis and suggest new therapy options for leprosy.IMPORTANCEMycobacterium leprae, the bacterium that causes leprosy, survives and replicates inside macrophages. Statins, which inhibit the mevalonate pathway, promote bacterial killing in macrophages by affecting cholesterol and isoprenoid production. Cholesterol is crucial for M. leprae survival in macrophages, which explains the microbicidal effect of statins on the bacteria. However, the role of isoprenoid inhibition in statin-induced bacterial killing has not been explored. Isoprenoid groups are added to about 2% of the mammalian proteins, ensuring their proper function. This study focused on geranylgeranyl pyrophosphate (GGPP) and found that inhibiting GGPP formation or protein prenylation in infected macrophages triggered IL-1β production, thereby controlling mycobacterial infection. The findings highlight the importance of protein prenylation in M. leprae and suggest new therapeutic strategies for leprosy.