Trypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein complex that contains APOL1, the lytic component. Human TLF confers sterile immunity to many animal-infective extracellular Trypanosoma Ssp, which have been extensively investigated. Here, we have dissected the underappreciated role of TLF and neutrophils against intracellular Leishmania in intradermal infection. Our data show that mice producing human or baboon TLF have reduced parasite burdens when infected intradermally with metacyclic promastigotes of L. major . This TLF-mediated reduction in parasite burden was lost in neutrophil-depleted TLF mice, suggesting that early recruitment of neutrophils is required for TLF-mediated killing of L. major . Neutrophils and macrophages are the predominant phagocytes recruited to the site of infection. Our data show that acidification of the macrophage phagosome is essential for TLF-mediated lysis of metacyclic promastigotes. In vitro we find that only metacyclic promastigotes co-incubated with TLF in an acidic milieu were lysed. However, amastigotes were not killed by TLF at any pH. These findings correlated with binding experiments, revealing that labeled TLF binds specifically to the surface of metacyclic promastigotes, but not to amastigotes. During differentiation to the amastigote stage, the parasites shed their surface glycoconjugates. Metacyclic promastigotes of L. major deficient in the synthesis of surface glycoconjugates ( lpg1 - and lpg5A - /lpg5B - ) were partially resistant to TLF lysis. We propose that TLF binds to the outer surface glycoconjugates of metacyclic promastigotes, whereupon APOL1 forms a pH-gated ion channel in the plasma membrane, resulting in osmotic lysis. We hypothesize that resistance to TLF requires shedding of the surface glycoconjugates, which occurs upon phagocytosis by immune cells.

中文翻译：

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锥虫溶细胞因子与先天免疫细胞在皮肤利什曼原虫感染消退中的相互作用

锥虫溶细胞因子（TLF）是灵长类特定的高密度脂蛋白复合物，其中含有溶胞成分APOL1。人类TLF对许多动物感染的细胞外锥虫Ssp赋予了无菌免疫，对此已经进行了广泛研究。在这里，我们已经剖析了TLF和嗜中性粒细胞在皮内感染中对细胞内利什曼原虫的作用不足。我们的数据表明，当用大劳氏菌的前环前鞭毛皮内感染时，产生人或狒狒TLF的小鼠寄生虫负担降低。在贫中性白细胞的TLF小鼠中失去了TLF介导的寄生虫负担的减轻，这表明TLF介导的大麦芽孢杆菌的杀死需要早期募集嗜中性白细胞。中性粒细胞和巨噬细胞是募集到感染部位的主要吞噬细胞。我们的数据表明，巨噬细胞吞噬体的酸化对于TLF介导的前环前鞭毛体的裂解至关重要。在体外，我们发现只有与TLF在酸性环境中共同孵育的元环前鞭毛体才被裂解。但是，在任何pH下，氨苄糖类都不会被TLF杀死。这些发现与结合实验相关，揭示了标记的TLF特异地结合到亚环前鞭毛体的表面，而不结合到变形虫。在分化到鞭毛体阶段期间，寄生虫脱落了其表面糖缀合物。缺乏表面糖缀合物（lpg1-和lpg5A-/ lpg5B-）合成的L. major的亚环前鞭毛体对TLF裂解有部分抗性。我们建议TLF结合到环前鞭毛体的外表面糖缀合物上，因此，APOL1在质膜上形成pH门控离子通道，导致渗透裂解。我们假设对TLF的抗性需要脱落表面糖缀合物，这在免疫细胞吞噬时发生。