将 MASP1 添加到凝集素途径-麻风病关联谜题中：来自基因多态性和蛋白水平的提示。
Adding MASP1 to the lectin pathway-Leprosy association puzzle: Hints from gene polymorphisms and protein levels.
机构信息
Laboratory of Molecular Immunopathology, Department of Clinical Pathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil.
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil.
出版信息
PLoS Negl Trop Dis. 2020 Apr 2;14(4):e0007534. doi: 10.1371/journal.pntd.0007534. eCollection 2020 Apr.
BACKGROUND
Deposition of complement factors on Mycobacterium leprae may enhance phagocytosis. Such deposition may occur through the lectin pathway of complement. Three proteins of the lectin pathway are produced from the gene MASP1: Mannan-binding lectin-associated serine protease 1 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44). Despite their obvious importance, the roles played by these proteins have never been investigated in leprosy disease.
METHODOLOGY
We haplotyped five MASP1 polymorphisms by multiplex sequence-specific PCR (intronic rs7609662G>A and rs13064994C>T, exon 12 3'-untranslated rs72549262C>G, rs1109452C>T and rs850314*G>A) and measured MASP-1, MASP-3 and MAp44 serum levels in 196 leprosy patients (60%, lepromatous) and 193 controls.
PRINCIPAL FINDINGS
Lower MASP-3 and MAp44 levels were observed in patients, compared with controls (P = 0.0002 and P<0.0001, respectively) and in lepromatous, compared with non-lepromatous patients (P = 0.008 and P = 0.002, respectively). Higher MASP-3 levels were present in controls carrying variants/haplotypes associated with leprosy resistance (rs13064994T, rs1109452_rs850314CG within GT_CCG and rs850314A: OR = 0.5-0.6, Pcorr = 0.01-0.04). Controls with rs1109452T, included in susceptibility haplotypes (GT_GTG/GT_CTG: OR = 2.0, Pcorr = 0.03), had higher MASP-1 and lower MASP-3 levels (P≤0.009). Those with GC_CCG, presented increasing susceptibility (OR = 1.7, Pcorr = 0.006) and higher MAp44 levels (P = 0.015). MASP-3 expression decreased in patients, compared with controls carrying rs1109452_rs850314*CA or CG (P≤0.02), which may rely on exon 12 CpG methylation and/or miR-2861/miR-3181 mRNA binding.
CONCLUSION
Polymorphisms regulating MASP-3/MAp44 availability in serum modulate leprosy susceptibility, underlining the importance of lectin pathway regulation against pathogens that exploit phagocytosis to parasitize host macrophages.
背景
分枝杆菌上补体因子的沉积可能增强吞噬作用。这种沉积可能通过补体的凝集素途径发生。凝集素途径的三种蛋白由 MASP1 基因产生：甘露聚糖结合凝集素相关丝氨酸蛋白酶 1（MASP-1）和 MASP-3 和甘露聚糖结合凝集素相关蛋白 44 kDa（MAp44）。尽管它们非常重要，但这些蛋白在麻风病中的作用从未被研究过。
方法
我们通过多重序列特异性 PCR 对五个 MASP1 多态性进行了单体型分析（内含子 rs7609662G>A 和 rs13064994C>T、外显子 12 3'-非翻译 rs72549262C>G、rs1109452C>T 和 rs850314*G>A），并测量了 196 例麻风病患者（60%，瘤型）和 193 例对照者的 MASP-1、MASP-3 和 MAp44 血清水平。
主要发现
与对照组相比，患者的 MASP-3 和 MAp44 水平较低（P=0.0002 和 P<0.0001），与非瘤型患者相比，瘤型患者的 MASP-3 和 MAp44 水平较低（P=0.008 和 P=0.002）。携带与麻风病抗性相关的变异体/单体型的对照组中，MASP-3 水平较高（rs13064994T、rs1109452_rs850314CG 内 GT_CCG 和 rs850314A：OR=0.5-0.6，Pcorr=0.01-0.04）。包含在易感性单体型中的 rs1109452T （GT_GTG/GT_CTG：OR=2.0，Pcorr=0.03）的对照组中，MASP-1 和 MASP-3 水平较高（P≤0.009）。GC_CCG 患者的易感性增加（OR=1.7，Pcorr=0.006），MAp44 水平升高（P=0.015）。与携带 rs1109452_rs850314*CA 或 CG 的对照组相比，患者的 MASP-3 表达降低（P≤0.02），这可能依赖于外显子 12 CpG 甲基化和/或 miR-2861/miR-3181 mRNA 结合。
结论
调节血清中 MASP-3/MAp44 可用性的多态性调节麻风病的易感性，突出了针对利用吞噬作用寄生宿主巨噬细胞的病原体调节凝集素途径的重要性。
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