Department of Microbiology and Immunology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205.
Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205.
J Parasitol. 2023 May 1;109(3):200-210. doi: 10.1645/22-94.
Cutaneous leishmaniasis is caused by infection with the protozoan parasite Leishmania, which resides intracellularly in dermal macrophages (Mø), producing lesions. The skin lesions are characterized by proinflammatory cytokines and growth factors as well as inflammatory hypoxia, creating a stressful microenvironment for Mø. Of importance, not all Mø in lesions harbor parasites. To distinguish the influence of the parasite from the inflammatory microenvironment after Leishmania major (LM) infection on the Mø, we performed single-cell RNA sequencing and compared Mø associated with LM transcripts (or 'infected' Mø) with Mø not associated with LM transcripts (or 'bystander' Mø) within the lesions. Our findings show coordinated lysosomal expression and regulation signaling with increased cathepsin and H+-ATPase transcripts are upregulated in infected compared with bystander Mø. Additionally, eukaryotic initiation factor 2 (EIF2) signaling is downregulated in infected compared with bystander Mø, which includes many small and large ribosomal subunit (Rps and Rpl) transcripts being decreased in Mø harboring parasites. Furthermore, we also find EIF2 signaling including EIF, Rps, and Rpl transcripts being downregulated in bystander Mø compared with Mø from naïve skin. These data suggest that both the parasite and the inflammatory host microenvironment affect the transcription of ribosomal machinery in lesional Mø, thereby potentially affecting the ability of these cells to perform translation, protein synthesis, and thus function. Altogether, these results suggest that both the parasite and host inflammatory microenvironment independently drive transcriptional remodeling in Mø during LM infection in vivo.
皮肤利什曼病是由原生动物寄生虫利什曼原虫感染引起的，该寄生虫存在于皮肤巨噬细胞（Mø）内，导致病变。皮肤病变的特征是促炎细胞因子和生长因子以及炎症缺氧，为 Mø 创造了一个应激微环境。重要的是，并非病变中的所有 Mø 都携带寄生虫。为了区分寄生虫和炎症微环境在感染大丽轮枝菌（LM）后对 Mø 的影响，我们进行了单细胞 RNA 测序，并比较了与 LM 转录本相关的 Mø（或“感染”Mø）与未与 LM 转录本相关的 Mø（或“旁观者”Mø）。我们的研究结果表明，在感染的 Mø 中，溶酶体表达和调节信号协调上调，与旁观者 Mø 相比，溶酶体中组织蛋白酶和 H+-ATPase 转录本上调。此外，与旁观者 Mø 相比，感染的 Mø 中真核起始因子 2（EIF2）信号下调，包括许多小和大亚基（Rps 和 Rpl）转录物在携带寄生虫的 Mø 中减少。此外，我们还发现与旁观者 Mø 相比，感染的 Mø 中包括 EIF、Rps 和 Rpl 转录物在内的 EIF2 信号下调，而来自未感染皮肤的 Mø 中这些转录物的表达水平则较高。这些数据表明，寄生虫和炎症宿主微环境都会影响病变 Mø 中核糖体机制的转录，从而可能影响这些细胞进行翻译、蛋白质合成以及功能的能力。总而言之，这些结果表明，寄生虫和宿主炎症微环境在体内 LM 感染期间独立地驱动 Mø 中的转录重塑。
