Dual Transcriptome Profiling of Leishmania-Infected Human Macrophages Reveals Distinct Reprogramming Signatures.
Dual Transcriptome Profiling of Leishmania-Infected Human Macrophages Reveals Distinct Reprogramming Signatures.
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DOI：
10.1128/mbio.00027-16
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发表时间：
2016-05-10
期刊：
影响因子：
6.4
通讯作者：
El-Sayed NM
中科院分区：
文献类型：
--
作者：
Fernandes MC;Dillon LA;Belew AT;Bravo HC;Mosser DM;El-Sayed NM
巨噬细胞是单核吞噬细胞，构成了抵御病原体的第一道防线。虽然它们对许多微生物是致命的，但它们是利什曼原虫的主要宿主细胞。寄生虫，导致利什曼病的专性细胞内病原体。我们通过使用高通量RNA测序对两种利什曼原虫和人类巨噬细胞在细胞内感染过程中的转录图谱进行了分析，以表征病原体与其宿主之间相互作用所依据的全球基因表达变化和重新编程事件。系统地排除大颗粒吞噬作用的一般影响，揭示了感染早期人类巨噬细胞的强烈、寄生虫特异性反应，这种反应在后来的时间点上大大减弱。在寄生虫身上观察到了类似的时间表达模式，这表明当寄生虫转变为细胞内形式时，大部分重新编程通常在进入后不久就稳定下来。此后，寄生虫在巨噬细胞内建立了一个细胞内的生态位，在感染后的过程中，寄生虫和宿主细胞之间的交流最少。不同寄生虫种类之间的转录差异不显著，也没有观察到每种寄生虫感染的巨噬细胞的转录反应有显著差异。我们对利什曼原虫感染小鼠和人类巨噬细胞时发生的基因表达变化进行了比较分析。指向利什曼原虫-巨噬细胞感染组的一般特征。对含有细胞内病原体的哺乳动物细胞内发生的转录变化知之甚少。本研究对利什曼原虫的基因表达特征进行了研究。寄生虫和被感染的人类巨噬细胞在病原体进入并持续存在时的协调反应。在考虑了大颗粒吞噬的一般效应后，我们观察到人类巨噬细胞感染早期的寄生虫特异性反应，在以后的时间点减少。在寄生虫中也观察到了类似的表达模式。我们的分析为人类巨噬细胞和利什曼原虫之间的相互作用提供了具体的见解，并为研究病原体如何逃避宿主防御并调节细胞功能以在细胞内生存提供了重要的一般资源。
Macrophages are mononuclear phagocytes that constitute a first line of defense against pathogens. While lethal to many microbes, they are the primary host cells of Leishmania spp. parasites, the obligate intracellular pathogens that cause leishmaniasis. We conducted transcriptomic profiling of two Leishmania species and the human macrophage over the course of intracellular infection by using high-throughput RNA sequencing to characterize the global gene expression changes and reprogramming events that underlie the interactions between the pathogen and its host. A systematic exclusion of the generic effects of large-particle phagocytosis revealed a vigorous, parasite-specific response of the human macrophage early in the infection that was greatly tempered at later time points. An analogous temporal expression pattern was observed with the parasite, suggesting that much of the reprogramming that occurs as parasites transform into intracellular forms generally stabilizes shortly after entry. Following that, the parasite establishes an intracellular niche within macrophages, with minimal communication between the parasite and the host cell later during the infection. No significant difference was observed between parasite species transcriptomes or in the transcriptional response of macrophages infected with each species. Our comparative analysis of gene expression changes that occur as mouse and human macrophages are infected by Leishmania spp. points toward a general signature of the Leishmania-macrophage infectome. Little is known about the transcriptional changes that occur within mammalian cells harboring intracellular pathogens. This study characterizes the gene expression signatures of Leishmania spp. parasites and the coordinated response of infected human macrophages as the pathogen enters and persists within them. After accounting for the generic effects of large-particle phagocytosis, we observed a parasite-specific response of the human macrophages early in infection that was reduced at later time points. A similar expression pattern was observed in the parasites. Our analyses provide specific insights into the interplay between human macrophages and Leishmania parasites and constitute an important general resource for the study of how pathogens evade host defenses and modulate the functions of the cell to survive intracellularly.