MPEG1/Perforin-2 Haploinsufficiency Associated Polymicrobial Skin Infections and Considerations for Interferon-γ Therapy.
MPEG1/Perforin-2 Haploinsufficiency Associated Polymicrobial Skin Infections and Considerations for Interferon-γ Therapy.
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MPEG1/穿孔素 - 2单倍体不足相关的多种微生物皮肤感染以及干扰素 - γ治疗的思考
DOI：
10.3389/fimmu.2020.601584
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发表时间：
2020
影响因子：
7.3
通讯作者：
Butte MJ
中科院分区：
文献类型：
--
作者：
Merselis LC;Jiang SY;Nelson SF;Lee H;Prabaker KK;Baker JL;Munson GP;Butte MJ
巨噬细胞表达基因1（MPEG 1）在巨噬细胞和其它吞噬细胞中高度表达。该基因编码一种杀菌性成孔蛋白，称为穿孔蛋白-2。基于结构、动物和细胞的研究已经确定，穿孔素-2在酸性吞噬体内激活后促进吞噬微生物的破坏。相对于野生型对照，Mpeg 1基因敲除小鼠遭受显着更高的死亡率时，革兰氏阴性或阳性病原体的挑战。只有四种变体的MPEG 1已被功能上的特点，每一个与肺部感染。在这里，我们报告了一个新的MPEG 1无义变异的患者与一个新描述的协会与持续性多微生物感染的皮肤和软组织。一名年轻的成年女性患者进行了评估，复发性乳腺炎和蜂窝织炎的乳房，并证明了杂合子，罕见变异的MPEG 1 p.Tyr430*。多个疗程的广谱抗菌药物和手术切开引流未能解决感染。功能研究显示，截短变体导致患者吞噬细胞杀死细胞内细菌的能力显著降低。患者源性巨噬细胞通过显著增加MPEG 1的表达对干扰素γ（IFN-γ）作出反应。IFN-γ治疗支持穿孔素-2依赖性杀菌活性和伤口愈合。该病例扩大了MPEG 1缺陷的表型，包括严重的皮肤和软组织感染。我们发现穿孔素-2的单倍不足降低了人吞噬细胞的杀菌能力。干扰素-γ治疗增加穿孔素-2的表达，这可以补偿这种变体。因此，用IFN-γ治疗可以帮助预防感染。
Macrophage expressed gene 1 (MPEG1) is highly expressed in macrophages and other phagocytes. The gene encodes a bactericidal pore-forming protein, dubbed Perforin-2. Structural-, animal-, and cell-based studies have established that perforin-2 facilitates the destruction of phagocytosed microbes upon its activation within acidic phagosomes. Relative to wild-type controls, Mpeg1 knockout mice suffer significantly higher mortality rates when challenged with gram-negative or -positive pathogens. Only four variants of MPEG1 have been functionally characterized, each in association with pulmonary infections. Here we report a new MPEG1 non-sense variant in a patient with the a newly described association with persistent polymicrobial infections of the skin and soft tissue. A young adult female patient was evaluated for recurrent abscesses and cellulitis of the breast and demonstrated a heterozygous, rare variant in MPEG1 p.Tyr430*. Multiple courses of broad-spectrum antimicrobials and surgical incision and drainage failed to resolve the infection. Functional studies revealed that the truncation variant resulted in significantly reduced capacity of the patient’s phagocytes to kill intracellular bacteria. Patient-derived macrophages responded to interferon gamma (IFN-γ) by significantly increasing the expression of MPEG1. IFN-γ treatment supported perforin-2 dependent bactericidal activity and wound healing. This case expands the phenotype of MPEG1 deficiency to include severe skin and soft tissue infection. We showed that haploinsufficiency of perforin-2 reduced the bactericidal capacity of human phagocytes. Interferon-gamma therapy increases expression of perforin-2, which may compensate for such variants. Thus, treatment with IFN-γ could help prevent infections.
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影响因子：
7.7
作者：
McCormack, Ryan M.;de Armas, Lesley R.;Podack, Eckhard R.
通讯作者：
Podack, Eckhard R.
影响因子：
3.1
作者：
McCormack, Ryan;Bahnan, Wael;Schesser, Kurt
通讯作者：
Schesser, Kurt
DOI：
10.1016/j.bjps.2017.05.023
发表时间：
2017-10-01
影响因子：
2.7
作者：
Sherif, Rami D.;Ingargiola, Michael;Harmaty, Marco A.
通讯作者：
Harmaty, Marco A.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
抑制成纤维细胞中细胞内细菌复制的抑制取决于巨噬细胞表达的基因1所编码的穿孔蛋白样蛋白（Perforin-2）。
影响因子：
5.3
作者：
McCormack R;de Armas LR;Shiratsuchi M;Ramos JE;Podack ER
通讯作者：
Podack ER