da Silva Rocha Matheus, Rodrigues Pereira Antônio Marcos, Freire Dos Santos Plínio Marcos, Alves Dias André, Pontes Pereira Melissa, Sammarco Rosa Patrícia, Bertoluci Daniele F F, Belisle John T, Ramalho Costa Fabricio da Mota, de Macedo Cristiana Santos, Vidal Pessolani Maria Cristina, Berrêdo-Pinho Marcia
Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
Divisão de Pesquisa e Ensino, Instituto Lauro de Souza Lima, São Paulo, Brazil.
J Bacteriol. 2025 Aug 27:e0018525. doi: 10.1128/jb.00185-25.
Leprosy is a chronic infectious disease caused by and . Brazil consistently ranks among the countries with the highest number of leprosy cases. Data from our group showed that 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 survival is related to the reduced cholesterol levels, which 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 comes from their impact on IL-1β production via decreased prenylation. We demonstrate that GGPP is essential in macrophage 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 , 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 pathogenesis and suggest new therapy options for leprosy.
, 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 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 and suggest new therapeutic strategies for leprosy.
麻风病是一种由[细菌名称]引起的慢性传染病。巴西一直是麻风病病例数最多的国家之一。我们团队的数据显示，[细菌名称]上调甲羟戊酸途径（MP），导致感染的巨噬细胞中富含胆固醇酯的脂滴积累，并且他汀类药物对该途径的抑制会降低细菌的细胞内存活率。已经表明，他汀类药物对[细菌名称]生存的部分有害作用与胆固醇水平降低有关，胆固醇被氧化以产生还原力。根据文献，他汀类药物通过抑制MP，通过对类异戊二烯香叶基香叶基焦磷酸（GGPP）和法尼基焦磷酸（FPP）生物合成的负调节来增加炎症细胞因子IL-1β的产生，而GGPP和FPP负责蛋白质异戊二烯化。在本研究中，我们测试了以下假设：他汀类药物对[细菌名称]细胞内存活率的部分影响来自它们通过减少异戊二烯化对IL-1β产生的影响。我们证明GGPP在巨噬细胞相互作用中至关重要，因为分别抑制法尼基焦磷酸合酶和香叶基香叶基转移酶-1的MP抑制剂帕米膦酸盐和GGTI-298降低了通过RT-qPCR测量的[细菌名称]的细胞内存活率。MP抑制剂通过激活炎性小体增加IL-1β的产生，但这种作用被GGPP逆转。IL-1β水平与细菌存活率呈负相关。总之，我们的研究结果突出了蛋白质香叶基香叶基化在[细菌名称]发病机制中的潜在作用，并为麻风病提出了新的治疗选择。
引起麻风病的[细菌名称]在巨噬细胞内生存和复制。抑制甲羟戊酸途径的他汀类药物通过影响胆固醇和类异戊二烯的产生促进巨噬细胞中的细菌杀伤。胆固醇对[细菌名称]在巨噬细胞中的生存至关重要，这解释了他汀类药物对细菌的杀菌作用。然而，类异戊二烯抑制在他汀类药物诱导的细菌杀伤中的作用尚未得到探索。类异戊二烯基团被添加到约2%的哺乳动物蛋白质中，以确保它们的正常功能。本研究聚焦于香叶基香叶基焦磷酸（GGPP），发现抑制感染巨噬细胞中GGPP的形成或蛋白质异戊二烯化会触发IL-1β的产生，从而控制分枝杆菌感染。这些发现突出了蛋白质异戊二烯化在[细菌名称]中的重要性，并为麻风病提出了新的治疗策略。
