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Guanylate Binding Proteins Restrict Leishmania donovani Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting

机译:吉瓜酸酯结合蛋白质限制<命名含量含量型=“属型”> Leishmania Donovani 非血小杂细胞的生长无关,无论是寄生的真空靶向

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Interferon (IFN)-inducible guanylate binding proteins (GBPs) play important roles in host defense against many intracellular pathogens that reside within pathogen-containing vacuoles (PVs). For instance, members of the GBP family translocate to PVs occupied by the protozoan pathogen Toxoplasma and facilitate PV disruption and lytic parasite killing. While the GBP defense program targeting Toxoplasma has been studied in some detail, the role of GBPs in host defense to other protozoan pathogens is poorly characterized. Here, we report a critical role for both mouse and human GBPs in the cell-autonomous immune response against the vector-borne parasite Leishmania donovani . Although L. donovani can infect both phagocytic and nonphagocytic cells, it predominantly replicates inside professional phagocytes. The underlying basis for this cell type tropism is unclear. Here, we demonstrate that GBPs restrict growth of L. donovani in both mouse and human nonphagocytic cells. GBP-mediated restriction of L. donovani replication occurs via a noncanonical pathway that operates independent of detectable translocation of GBPs to L. donovan -containing vacuoles (LCVs). Instead of promoting the lytic destruction of PVs, as reported for GBP-mediated killing of Toxoplasma in phagocytic cells, GBPs facilitate the delivery of L. donovani into autolysosomal-marker-positive compartments in mouse embryonic fibroblasts as well as the human epithelial cell line A549. Together our results show that GBPs control a novel cell-autonomous host defense program, which renders nonphagocytic cells nonpermissible for efficient Leishmania replication.
机译:干扰素(IFN) - 剩余的胍基酯结合蛋白(Gbps)在宿主防毒中起重要作用,这些病原体在含病原体含有真空(PVS)中的许多细胞内病原体中。例如,GBP系列的成员易于由原生动物病原体弓形虫弓形虫占据的PV,并促进PV中断和裂解寄生虫杀伤。虽然已经详细研究了靶向弓形虫的GBP防御程序,但Gbps在宿主对其他原生动物病原体的作用表现得很差。在这里,我们在细胞 - 自主免疫应答中向载体传染寄生虫Leishmania Donovani报告了对小鼠和人类Gbps的关键作用。虽然L. Dovovani可以感染吞噬细胞和非吞噬细胞,但它主要是在专业吞噬细胞内复制。这种细胞类型的潜在依据尚不清楚。在这里,我们证明Gbps在小鼠和人类非核细胞中限制L. Dovovani的生长。 GBP介导的L. Dovovani复制的限制通过非碳途径发生,其独立于Gbps可检测到的Gbps易位转移到L. Donovan - 甲型核(LCV)。据报道,对于GBP介导的吞噬细胞弓形虫杀伤弓形虫杀伤,Gbps促进了在小鼠胚胎成纤维细胞以及人上皮细胞系A549中,Gbps促进了L. Donovani的递送至自糖蛋白标记阳性隔室的GBP介导的裂解PVS的裂解破坏。 。我们的结果表明,GBPS控制了一种新型细胞自主宿主防御程序,使壬代杀细胞不可受理,以高效的利什曼复制。

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