PDF(Pubmed)
Abstract：
Fungal sepsis remains a major health threat with high mortality, where the adrenal gland stress response has been rarely reported. Candida albicans (C.albicans) is the most common opportunistic fungal pathogen of life-threatening disseminated candidiasis and fungal sepsis. In the present study, we performed single-cell RNA sequencing (scRNA-Seq) using the 10x Genomics platform to analyze the changes in murine adrenal transcriptome following systemic C.albicans infection. A total of 16 021 cells were categorized into 18 transcriptionally distinct clusters, representing adrenocortical cells, endothelial cells, various immune cells, mesenchymal cells, smooth muscle cells, adrenal capsule, chromaffin cells, neurons and glials. As the main cell component in the adrenal gland responsible for steroidogenesis, the adrenocortical cells dramatically diminished and were further grouped into 10 subclusters, which differently distributed in the infected and uninfected samples. Pseudo-time analysis revealed transitions of the adrenocortical cells from the initial normal states to active or dysfunctional states following systemic C.albicans infection via two trajectory paths. Endothelial cells in the highly vascularized organ of adrenal gland further proliferated following infection, with the upregulation of genes positively regulating angiogenesis and downregulation of protective genes of endothelial cells. Immune cells were also excessively infiltrated in adrenal glands of C.albicans-infected mice. Macrophages dominated the immune microenvironments in murine adrenal glands both before and after C.albicans infection, mediating the crosstalk among the steroid-producing cells, endothelial cells and immune cells within the adrenal gland. NLR family, pyrin domain containing 3 (NLRP3, encoded by Nlrp3) and complement receptor 3 (CR3, encoded by Itgam) were found to be significantly upregulated on the adrenal macrophages upon systemic C.albicans infection and might play critical roles in mediating the myeloid response. Meanwhile, the number and strength of the interactions between the infiltrating immune cells and adrenal resident cells were unveiled by cell-cell communication analysis to be dramatically increased after systemic C.albicans infection, indicating that the immune-adrenal crosstalk might contribute to the compromised functions of adrenal cells. Overall, our comprehensive picture of the murine adrenal gland microenvironment in systemic C.albicans infection provides deeper insights into the immune-adrenal cell communications during fungal sepsis.
摘要：
真菌败血症仍然是一个主要的健康威胁，死亡率高，肾上腺应激反应的报道很少。白色念珠菌(C.白色念珠菌）是威胁生命的播散性念珠菌病和真菌败血症的最常见机会性真菌病原体。在本研究中,我们使用10x基因组学平台进行了单细胞RNA测序(scRNA-Seq),以分析系统性白色念珠菌感染后小鼠肾上腺转录组的变化.共有16021个细胞被分为18个转录上不同的簇，代表肾上腺皮质细胞，内皮细胞，各种免疫细胞，间充质细胞，平滑肌细胞，肾上腺囊,嗜铬细胞,神经元和神经胶质.作为肾上腺中负责类固醇生成的主要细胞成分，肾上腺皮质细胞急剧减少，并进一步分为10个亚簇，在受感染和未感染的样本中分布不同。伪时间分析显示，系统性白色念珠菌感染后，肾上腺皮质细胞通过两条轨迹路径从初始正常状态转变为活跃或功能失调状态。肾上腺高度血管化器官的内皮细胞在感染后进一步增殖，基因的上调正调控血管生成和内皮细胞保护性基因的下调。免疫细胞在感染白色念珠菌的小鼠的肾上腺中也过度浸润。在白色念珠菌感染之前和之后，巨噬细胞主导了小鼠肾上腺的免疫微环境。介导类固醇产生细胞之间的串扰，肾上腺内的内皮细胞和免疫细胞。NLR家族,在系统性白色念珠菌感染后，发现含3（NLRP3，由Nlrp3编码）和补体受体3（CR3，由Itgam编码）的pyrin结构域在肾上腺巨噬细胞上被显着上调，并且可能在介导髓样反应中起关键作用。同时,细胞间通讯分析揭示了浸润性免疫细胞和肾上腺驻留细胞之间相互作用的数量和强度，在系统性白色念珠菌感染后急剧增加，表明免疫-肾上腺串扰可能导致肾上腺细胞功能受损。总的来说,我们对系统性白色念珠菌感染中小鼠肾上腺微环境的全面了解为真菌性败血症期间的免疫-肾上腺细胞通讯提供了更深入的见解.
