PGL I expression in live bacteria allows activation of a CD206/PPARγ cross-talk that may contribute to successful Mycobacterium leprae colonization of peripheral nerves.
PGL I expression in live bacteria allows activation of a CD206/PPARγ cross-talk that may contribute to successful Mycobacterium leprae colonization of peripheral nerves.
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DOI：
10.1371/journal.ppat.1007151
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发表时间：
2018-07
期刊：
影响因子：
6.7
通讯作者：
Pessolani MCV
中科院分区：
文献类型：
--
作者：
Díaz Acosta CC;Dias AA;Rosa TLSA;Batista-Silva LR;Rosa PS;Toledo-Pinto TG;Costa FDMR;Lara FA;Rodrigues LS;Mattos KA;Sarno EN;Bozza PT;Guilhot C;de Berrêdo-Pinho M;Pessolani MCV
麻风分枝杆菌是一种专性胞内杆菌，可感染雪旺细胞，导致周围神经损伤，是麻风最严重的症状。在本研究中，我们使用表达酚糖脂I(PGL I)的重组牛分枝杆菌，重新探讨了这种糖脂在麻风杆菌-SC相互作用中的作用。我们证明了PGL I对于细菌黏附和SC内化是必不可少的。我们还发现，产生活体分枝杆菌的PGLI以过氧化体增殖物激活受体γ(PPARγ)依赖的方式诱导感染细胞内吞甘露糖受体(MR/CD206)的表达。值得注意的是，阻断甘露糖识别减少了细菌的进入和存活，表明这一替代识别途径在细菌神经发病中发挥了作用。此外，检测到CD206和核受体PPARγ之间的活跃串扰，导致脂滴(LD)和前列腺素E2(PGE2)的形成，这两种物质以前被描述为细菌发病的基本角色。最后，该途径被证明能诱导IL-8的分泌。综上所述，我们的研究提供了证据，表明活的麻风杆菌通过PGL I识别进入细胞内调节SC表型，有利于细胞内细菌的持久性以及伴随的炎症介质的分泌，而炎症介质最终可能参与神经炎症。神经损伤是麻风病最严重的症状，麻风病是一种古老的疾病，在几个国家仍然是一个主要的健康问题。神经损伤是由于麻风分枝杆菌的能力，麻风杆菌入侵干细胞，周围神经系统的神经胶质细胞。了解麻风杆菌-干细胞相互作用的分子基础对于创造旨在治疗并最重要的是预防麻风神经病的新工具至关重要。这项研究证明了PGL I，一种富含麻风杆菌的特殊细胞壁脂，在建立感染中的关键作用。PGL I不仅是启动细菌对干细胞的黏附和随后侵袭的先决条件，而且也是改变细胞表面蛋白以允许细菌通过替代途径进入的先决条件。PGL I诱导的这些新的侵袭途径涉及对其他细菌细胞表面糖脂的识别，这些糖脂反过来又引起感染细胞的功能变化，包括宿主细胞衍生的脂类的积累，这有利于细菌的生存。这些途径还促进炎症介质的分泌，这可能会导致神经损伤。在一个以翻译为导向的研究时代，深入探索这些受体可能会导致开发出有吸引力的策略，以确保旨在预防神经病变的治疗药物的靶向细胞内递送。
Mycobacterium leprae, an obligate intracellular bacillus, infects Schwann cells (SCs), leading to peripheral nerve damage, the most severe leprosy symptom. In the present study, we revisited the involvement of phenolic glycolipid I (PGL I), an abundant, private, surface M. leprae molecule, in M. leprae-SC interaction by using a recombinant strain of M. bovis BCG engineered to express this glycolipid. We demonstrate that PGL I is essential for bacterial adhesion and SC internalization. We also show that live mycobacterium-producing PGL I induces the expression of the endocytic mannose receptor (MR/CD206) in infected cells in a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent manner. Of note, blocking mannose recognition decreased bacterial entry and survival, pointing to a role for this alternative recognition pathway in bacterial pathogenesis in the nerve. Moreover, an active crosstalk between CD206 and the nuclear receptor PPARγ was detected that led to the induction of lipid droplets (LDs) formation and prostaglandin E2 (PGE2), previously described as fundamental players in bacterial pathogenesis. Finally, this pathway was shown to induce IL-8 secretion. Altogether, our study provides evidence that the entry of live M. leprae through PGL I recognition modulates the SC phenotype, favoring intracellular bacterial persistence with the concomitant secretion of inflammatory mediators that may ultimately be involved in neuroinflammation. Nerve damage is the most severe symptom of leprosy, an ancient disease that continues to be a major health problem in several countries. Nerve damage is due to the ability of Mycobacterium leprae, the etiologic agent, to invade SCs, the glial cells of the peripheral nervous system. Understanding the molecular basis of M. leprae–SC interaction is essential for the creation of new tools aiming to treat and, above all, prevent leprosy neuropathy. This study demonstrates the critical role of PGL I, an M. leprae-abundant specific cell wall lipid, in establishing infection. PGL I is not only a prerequisite in initiating bacterial adhesion to and subsequent invasion of SCs, but also for changing the repertoire of cell surface proteins to allow for the entrance of bacteria via alternative pathways. These new invasive pathways induced by PGL I involve recognition of other bacterial cell surface glycolipids that, in turn, evoke functional changes in the infected cell, including the accumulation of host cell-derived lipids, which favor bacterial survival. These pathways also promote the secretion of inflammatory mediators that may contribute to nerve damage. In an era of translational-oriented research, exploring these receptors in depth could lead to the development of attractive strategies to ensure the targeted intracellular delivery of therapeutics aiming to prevent neuropathy.
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影响因子：
5.3
作者：
Alter A;de Léséleuc L;Van Thuc N;Thai VH;Huong NT;Ba NN;Cardoso CC;Grant AV;Abel L;Moraes MO;Alcaïs A;Schurr E
通讯作者：
Schurr E
DOI：
10.1091/mbc.1.10.731
发表时间：
1990-09-01
期刊：
CELL REGULATION
影响因子：
--
作者：
ENGVALL, E;EARWICKER, D;SANES, JR
通讯作者：
SANES, JR
影响因子：
3.2
作者：
HUNTER, SW;BRENNAN, PJ
通讯作者：
BRENNAN, PJ
影响因子：
5.6
作者：
Cheng H;Meng J;Wang G;Meng Y;Li Y;Wei D;Fu C;Deng K;Shen A;Wang H;Dai S
通讯作者：
Dai S
影响因子：
4
作者：
Arbues, Ainhoa;Malaga, Wladimir;Astarie-Dequeker, Catherine
通讯作者：
Astarie-Dequeker, Catherine