Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites.
Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites.
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DOI：
10.1038/nm.4023
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发表时间：
2016-02
期刊：
影响因子：
82.9
通讯作者：
Lieberman J
中科院分区：
文献类型：
--
作者：
Dotiwala F;Mulik S;Polidoro RB;Ansara JA;Burleigh BA;Walch M;Gazzinelli RT;Lieberman J
原生动物感染是一个严重的全球健康问题。自然杀伤 (NK) 细胞和溶细胞 T 淋巴细胞 (CTL) 通过将溶细胞颗粒内容物（颗粒酶 (Gzm) 蛋白酶和成孔穿孔素 (PFN)）释放到受感染的细胞中来消灭病原体感染的细胞。然而，这些细胞毒性分子不会杀死细胞内的寄生虫。 CD8+ CTL 主要通过分泌干扰素 (IFN)-γ 来防止小鼠体内的寄生虫感染。然而，人类而非啮齿动物的细胞毒性颗粒含有抗菌肽颗粒溶素 (GNLY)，它可以选择性地破坏缺乏胆固醇的微生物膜，并且 GNLY、PFN 和 Gzms 可以快速杀死细胞内细菌。在这里，我们展示了 GNLY 将 Gzms 传递到三种原生动物寄生虫（克氏锥虫、弓形虫和大利什曼原虫）中，其中 Gzms 产生超氧化物并灭活氧化防御酶以杀死寄生虫。 PFN 将 GNLY 和 Gzms 传递到受感染的细胞中，然后 GNLY 将 Gzms 传递到细胞内寄生虫。杀伤细胞介导的寄生虫死亡，我们称之为“微生物程序性细胞死亡”或“微小下垂”，与半胱天冬酶无关，但类似于哺乳动物细胞凋亡，导致线粒体肿胀、跨膜电位耗散、膜起泡、磷脂酰丝氨酸暴露、DNA损伤和染色质浓缩。 GNLY 转基因小鼠可以免受克氏弓形虫和刚地弓形虫的感染，并能在对野生型小鼠致命的感染中存活下来。因此，GNLY、PFN 和 Gzm 介导的细胞内原生动物寄生虫消除是一种未被重视的免疫防御机制。
Protozoan infections are a serious global health problem. Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) eliminate pathogen-infected cells by releasing cytolytic granule contents—granzyme (Gzm) proteases and the pore-forming perforin (PFN)—into the infected cell. However, these cytotoxic molecules do not kill intracellular parasites. CD8+ CTLs protect against parasite infections in mice primarily by secreting interferon (IFN)-γ. However, human, but not rodent, cytotoxic granules contain the antimicrobial peptide granulysin (GNLY), which selectively destroys cholesterol-poor microbial membranes, and GNLY, PFN and Gzms rapidly kill intracellular bacteria. Here we show that GNLY delivers Gzms into three protozoan parasites (Trypanosoma cruzi, Toxoplasma gondii and Leishmania major), in which the Gzms generate superoxide and inactivate oxidative defense enzymes to kill the parasite. PFN delivers GNLY and Gzms into infected cells, and GNLY then delivers Gzms to the intracellular parasites. Killer cell–mediated parasite death, which we term ‘microbe-programmed cell death’ or ‘microptosis’, is caspase independent but resembles mammalian apoptosis, causing mitochondrial swelling, transmembrane potential dissipation, membrane blebbing, phosphatidylserine exposure, DNA damage and chromatin condensation. GNLY-transgenic mice are protected against infection by T. cruzi and T. gondii, and survive infections that are lethal to wild-type mice. Thus, GNLY-, PFN- and Gzm-mediated elimination of intracellular protozoan parasites is an unappreciated immune defense mechanism.
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影响因子：
3.8
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Hotez PJ;Alvarado M;Basáñez MG;Bolliger I;Bourne R;Boussinesq M;Brooker SJ;Brown AS;Buckle G;Budke CM;Carabin H;Coffeng LE;Fèvre EM;Fürst T;Halasa YA;Jasrasaria R;Johns NE;Keiser J;King CH;Lozano R;Murdoch ME;O'Hanlon S;Pion SD;Pullan RL;Ramaiah KD;Roberts T;Shepard DS;Smith JL;Stolk WA;Undurraga EA;Utzinger J;Wang M;Murray CJ;Naghavi M
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Radi, Rafael
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