单细胞转录组分析COVID-19重症患者肺泡巨噬细胞亚型
文章信息
文章题目:Single-cell transcriptome identifies FCGR3B upregulated subtype of alveolar macrophages in patients with critical COVID-19 日期:2021-09-24 期刊:iScience DOI:https://doi.org/10.1016/j.isci.2021.103030
一句话概括
数据分析文章:scRNA分析重症COVID-19患者多个样本,得到一种单核细胞衍生的肺泡巨噬细胞 (MoAMs) 亚型,并且FCGR3B基因在其中特异性表达,提供了一个新的biomarker。
使用的数据
- 对照1:10例健康气管样本( Deprez et al., 2020)
- 对照2:4例健康肺样本(Madissoon et al., 2019)
- BALF单细胞数据(支气管肺泡灌洗液, broncho-alveolar lavage fluid):总共14个样本,包括对照、轻度和重症患者样本 (Liao et al., 2020)
BALF单细胞群初步注释
利用Liao文章的marker基因,大致分成macrophages, myeloid dendritic cells, and T-cells,但发现很多cluster的细胞类型不好确定【A) Control. B) Moderate. C) Severe BALF clusters using Liao et al markers】
于是自己又细分亚群,分别得到19, 17, and 18个cluster, 21939, 7316 and 37197 cells
然后又找了一些marker自行细胞注释:https://www.cell.com/cms/10.1016/j.isci.2021.103030/attachment/24e25182-6d40-41fa-a4f5-fc33e365f86f/mmc2
重症样本注释
包括了:
- basal cells,
- vascular cells,
- dendritic cells,
- ionocytes,
- monocyte-derived alveolar macrophages,
- plasma cells,
- alveolar epithelial cells
重症样本的cluster11与COVID-19并发症基因之间的关联
并发症包括了:encoding cytokines and cytokine receptors, or associated with rare infectious diseases, rare syndromes, chronic obstructive pulmonary disease, cardiovascular disease, hypertension, obesity, and diabetes
基因列表:https://www.cell.com/cms/10.1016/j.isci.2021.103030/attachment/0b421468-3a53-48b6-8c28-3eee4d7e06f7/mmc4
发现重症的17个cluster中,cluster11表现非常突出,9个基因列表中表达了8个,并且表达量还主要是上调
因此,这个cluster11就被标记为monocyte-derived alveolar macrophages (MoAMs),它的marker 基因就是CCl3L1 ,而且这个MoAMs亚型在 moderate or control样本中都没发现
之后也看了一下富集分析,主要集中在:
- host immune response signaling networks related to TNFα
- cytokine and interferon gamma responses
- response to type1 interferon and biotic stimulus
- innate immune and inflammatory responses
MoAM亚型top20基因分析
既然感兴趣的cluster找到,那么接下来就看其中的top基因(这里选择前20)
做了一个气泡图【 A) Control. B) Moderate and C) Severe BALF】,不过感觉没啥必要,既然选择cluster11的前20,那么肯定这些基因(横坐标)就主导啊
然后就定位到了其中一个差异最大的基因:FCGR3B
然后开始研究这个基因了:
- regulate both adaptive and innate immune responses which are crucial for the defense against infection and prevention of chronic inflammation or autoimmune diseases
- FcRs mediate important immune responses such as release of cytokines or phagocytosis (Ben Mkaddem et al., 2019)
并且图C中cluster11表达的FCGR3B,比其他FcR族基因更多
FCGR3B的数据集验证
在bulk PBMC data进行验证 (Arunachalam et al., 2020) ,并且发现在non-classical monocytes中表达更多
在 bulk data set from nasopharyngeal swabs数据集验证(左图),另外之前看cluster11特异性表达CCL3L1,那么同样在重症的CCL3L1高表达细胞中,FCGR3B表达同样高
不过,不同于FCGR3B,CCL3L1和TNFAIP6 (indicator of COVID-19 severity) 在其他数据集中并非一直是重症表达量高于对照组。所以最后的目光又集中于FCGR3B 这一个基因了
FCGR3B的实验验证
qPCR positive COVID-19 patients (n = 31) and qPCR negative controls (n = 11),发现:
- 左图(单纯covid):50% had greater than 1.5-fold change of FCGR3B compared with 28.1% in controls
- 右图(covid+并发症):57.1% of patients with severe COVID-19 with comorbidity had greater than 1.5-fold change of FCGR3B compared with 28.1% in controls
当然,最后还拓展了一下,做了个体外并发症(肥胖)关联实验,发现:FCGR3B as a potential modulator of COVID-19 severity in patients with obesity
文中链接
[1]
Deprez et al., 2020: https://www.cell.com/iscience/fulltext/S2589-0042(21)00998-6?rss=yes&utm_source=dlvr.it&utm_medium=twitter#bib14
[2]
Madissoon et al., 2019: https://www.cell.com/iscience/fulltext/S2589-0042(21)00998-6?rss=yes&utm_source=dlvr.it&utm_medium=twitter#bib30
[3]
Liao et al., 2020: https://www.cell.com/iscience/fulltext/S2589-0042(21)00998-6?rss=yes&utm_source=dlvr.it&utm_medium=twitter#bib29
[4]
Ben Mkaddem et al., 2019: https://www.cell.com/iscience/fulltext/S2589-0042(21)00998-6?rss=yes&utm_source=dlvr.it&utm_medium=twitter#bib5
[5]
Arunachalam et al., 2020: https://www.cell.com/iscience/fulltext/S2589-0042(21)00998-6?rss=yes&utm_source=dlvr.it&utm_medium=twitter#bib2
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