Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis.
Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis.
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DOI：
10.1186/s12974-016-0770-9
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发表时间：
2017-01-03
影响因子：
9.3
通讯作者：
van de Beek D
中科院分区：
文献类型：
--
作者：
Kasanmoentalib ES;Valls Seron M;Ferwerda B;Tanck MW;Zwinderman AH;Baas F;van der Ende A;Schwaeble WJ;Brouwer MC;van de Beek D
肺炎球菌脑膜炎是细菌性脑膜炎中最常见和最严重的形式。死亡率很高，大约一半的幸存者会产生长期后遗症。疾病结局与蛛网膜下腔促炎反应的严重程度相关。补体系统介导关键的炎症过程，在动物研究中被认为是肺炎球菌脑膜炎疾病严重程度的调节剂。我们研究了诊断性腰椎穿刺脑脊液（CSF）样本中甘露糖结合凝集素相关丝氨酸蛋白酶（MASP-2）水平，该水平可用于我们前瞻性全国队列研究中792例肺炎球菌脑膜炎发作中的307例（39%），以及这些水平与临床结局之间的相关性。随后，我们使用Masp 2 −/−小鼠研究了MASP-2在我们的实验性肺炎球菌脑膜炎小鼠模型中的作用，并评估了MASP-2特异性单克隆抗体在野生型（WT）小鼠中辅助治疗的潜力。细菌性脑膜炎患者脑脊液中的MASP-2水平与不良功能结局相关。与这些人类数据一致，与WT小鼠相比，患有肺炎球菌脑膜炎的Masp 2缺陷小鼠具有较低的细胞因子水平和增加的存活率。用MASP-2特异性单克隆抗体的辅助治疗导致补体活化减少和疾病严重程度降低。MASP-2导致患有肺炎球菌脑膜炎的人和小鼠的不良疾病结局。MASP-2特异性单克隆抗体可用于减弱肺炎球菌脑膜炎中的炎症反应。本文的在线版本（doi：10.1186/s12974-016-0770-9）包含补充材料，可供授权用户使用。
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the pro-inflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. We investigated mannose-binding lectin-associated serine protease (MASP-2) levels in cerebrospinal fluid (CSF) samples derived from the diagnostic lumbar puncture, which was available for 307 of 792 pneumococcal meningitis episodes included in our prospective nationwide cohort study (39%), and the association between these levels and clinical outcome. Subsequently, we studied the role of MASP-2 in our experimental pneumococcal meningitis mouse model using Masp2 −/− mice and evaluated the potential of adjuvant treatment with MASP-2-specific monoclonal antibodies in wild-type (WT) mice. MASP-2 levels in cerebrospinal fluid of patients with bacterial meningitis were correlated with poor functional outcome. Consistent with these human data, Masp2-deficient mice with pneumococcal meningitis had lower cytokine levels and increased survival compared to WT mice. Adjuvant treatment with MASP-2-specific monoclonal antibodies led to reduced complement activation and decreased disease severity. MASP-2 contributes to poor disease outcome in human and mice with pneumococcal meningitis. MASP-2-specific monoclonal antibodies can be used to attenuate the inflammatory response in pneumococcal meningitis. The online version of this article (doi:10.1186/s12974-016-0770-9) contains supplementary material, which is available to authorized users.