PDF(Pubmed)
Abstract：
Berardinelli-Seip congenital lipodystrophy (CGL), a rare autosomal recessive disorder, is characterized by a lack of adipose tissue. Infections are one of the major causes of CGL individuals\' premature death. The mechanisms that predispose to infections are poorly understood. We used Leishmania infantum as an in vitro model of intracellular infection to explore mechanisms underlying the CGL infection processes, and to understand the impact of host mutations on Leishmania survival, since this pathogen enters macrophages through specialized membrane lipid domains. The transcriptomic profiles of both uninfected and infected monocyte-derived macrophages (MDMs) from CGL (types 1 and 2) and controls were studied. MDMs infected with L. infantum showed significantly downregulated expression of genes associated with infection-response pathways (MHC-I, TCR-CD3, and granzymes). There was a transcriptomic signature in CGL cells associated with impaired membrane trafficking and signaling in response to infection, with concomitant changes in the expression of membrane-associated genes in parasites (e.g. δ-amastins). We identified pathways suggesting the lipid storage dysfunction led to changes in phospholipids expression and impaired responses to infection, including immune synapse (antigen presentation, IFN-γ signaling, JAK/STAT); endocytosis; NF-kappaB signaling; and phosphatidylinositol biosynthesis. In summary, lipid metabolism of the host plays an important role in determining antigen presentation pathways.
摘要：
Berardinelli-Seip先天性脂肪营养不良（CGL），一种罕见的常染色体隐性疾病,其特点是缺乏脂肪组织。感染是CGL个体过早死亡的主要原因之一。易感感染的机制知之甚少。我们使用婴儿利什曼原虫作为细胞内感染的体外模型来探索CGL感染过程的潜在机制。并了解宿主突变对利什曼原虫存活的影响，因为这种病原体通过专门的膜脂结构域进入巨噬细胞。研究了来自CGL（1型和2型）和对照的未感染和感染的单核细胞衍生巨噬细胞（MDMs）的转录组学谱。感染婴儿乳球菌的MDMs显示与感染反应途径相关的基因表达显着下调（MHC-I，TCR-CD3和颗粒酶)。在CGL细胞中存在与受损的膜运输和响应于感染的信号相关的转录组特征,伴随着寄生虫中膜相关基因表达的变化（例如δ-amastins）。我们确定了提示脂质储存功能障碍导致磷脂表达变化和感染反应受损的通路。包括免疫突触（抗原呈递，IFN-γ信号，JAK/STAT）；内吞作用；NF-κB信号传导；和磷脂酰肌醇生物合成。总之,宿主的脂质代谢在决定抗原呈递途径中起着重要作用。
