Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection.
Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection.
复制标题
DOI：
10.1371/journal.ppat.1003885
复制
发表时间：
2014-01
期刊：
影响因子：
6.7
通讯作者：
Gazzinelli RT
中科院分区：
文献类型：
--
作者：
Ataide MA;Andrade WA;Zamboni DS;Wang D;Souza Mdo C;Franklin BS;Elian S;Martins FS;Pereira D;Reed G;Fitzgerald KA;Golenbock DT;Gazzinelli RT
周期性发作和高热是疟疾的标志，与高水平的致热细胞因子（包括IL-1β）相关。在这份报告中，我们描述了疟疾中炎性小体相关基因表达和半胱天冬酶-1激活的特征。事实上，当我们感染小鼠时，疟原虫感染足以促进MyD 88介导的半胱天冬酶-1活化，这依赖于IFN-γ引发和炎性体组分ASC、P2 X7 R、NLRP 3和/或NLRP 12的表达。Pro-IL-1β的表达需要LPS的第二次刺激，并且还依赖于IFN-γ引发和功能性TNFR 1。由于疟原虫诱导的半胱天冬酶-1活化，小鼠在第二次微生物刺激后产生极高水平的IL-1β，并对脓毒性休克过敏。用IL-1受体拮抗剂进行治疗性干预可预防啮齿类动物的细菌诱导致死。与小鼠相似，我们观察到发热性疟疾患者外周血单核细胞中循环CD 14 + CD 16 −Caspase-1+和CD 14 dimCD 16 +Caspase-1+单核细胞的频率显著增加。这些细胞在用LPS刺激后容易产生大量IL-1β。此外，我们观察到存在的炎性小体复合物的单核细胞从疟疾患者含有NLRP 3或NLRP 12 pyroposomes。我们的结论是，NLRP 12/NLRP 3依赖的caspase-1激活可能是介导系统性IL-1β产生和对疟疾继发性细菌感染超敏反应的关键事件。恶性疟原虫和间日疟原虫每年共感染约2.5亿人，夺走近100万儿童的生命。对疟疾发病机制的广泛研究已达成共识，即临床表现通常是全身炎症的结果。重要的是，继发性细菌和病毒感染加强了这种炎症反应，成为严重疾病发展的重要辅助因素。疟疾综合征的特征之一是发作，其特征是与寄生虫血症高峰相关的高热。本研究对致热性细胞因子IL-1β的诱导机制及其在疟疾发病中的重要作用进行了探讨。我们的研究结果表明，先天免疫受体Toll样受体和炎性小体在诱导，加工和释放活性形式的IL-1β在疟疾中的关键作用。重要的是，我们提供的证据表明，细菌重叠感染进一步加强疟原虫诱导的全身炎症，导致大量IL-1β的释放和严重的疾病。因此，这项研究揭示了新的检查点，可以有针对性地预防全身性炎症和严重疟疾。
Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1β. In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria. Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN-γ-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1β expression required a second stimulation with LPS and was also dependent on IFN-γ-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1β upon a second microbial stimulus, and became hypersensitive to septic shock. Therapeutic intervention with IL-1 receptor antagonist prevented bacterial-induced lethality in rodents. Similar to mice, we observed a significantly increased frequency of circulating CD14+CD16−Caspase-1+ and CD14dimCD16+Caspase-1+ monocytes in peripheral blood mononuclear cells from febrile malaria patients. These cells readily produced large amounts of IL-1β after stimulation with LPS. Furthermore, we observed the presence of inflammasome complexes in monocytes from malaria patients containing either NLRP3 or NLRP12 pyroptosomes. We conclude that NLRP12/NLRP3-dependent activation of caspase-1 is likely to be a key event in mediating systemic production of IL-1β and hypersensitivity to secondary bacterial infection during malaria. Together Plasmodium falciparum and P. vivax infect approximately 250 million individuals, reaping life of near one million children every year. Extensive research on malaria pathogenesis has funneled into the consensus that the clinical manifestations are often a consequence of the systemic inflammation. Importantly, secondary bacterial and viral infections potentiate this inflammatory reaction being important co-factors for the development of severe disease. One of the hallmarks of malaria syndrome is the paroxysm, which is characterized by high fever associated with peak of parasitemia. In this study we dissected the mechanisms of induction and the importance of the pyrogenic cytokine, IL-1β in the pathogenesis of malaria. Our results demonstrate the critical role of the innate immune receptors named Toll-Like Receptors and inflammasome on induction, processing and release of active form of IL-1β during malaria. Importantly, we provide evidences that bacterial superinfection further potentiates the Plasmodium-induced systemic inflammation, leading to the release of bulk amounts of IL-1β and severe disease. Hence, this study uncovers new checkpoints that could be targeted for preventing systemic inflammation and severe malaria.
登录
查看更多内容
影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
以核酸感应 Toll 样受体为治疗靶点可预防实验性脑疟疾
DOI：
10.1073/pnas.1015406108
发表时间：
2011-03-01
影响因子：
11.1
作者：
Franklin, Bernardo S.;Ishizaka, Sally T.;Gazzinelli, Ricardo T.
通讯作者：
Gazzinelli, Ricardo T.
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
--
作者：
Jeru, Isabelle;Le Borgne, Gaelle;Amselem, Serge
通讯作者：
Amselem, Serge