新冠病毒感染转录组学数据及比较医学分析

doi:10.12300/j.issn.1674-5817.2023.079

实验动物与比较医学 ›› 2024, Vol. 44 ›› Issue (1): 62-73.DOI: 10.12300/j.issn.1674-5817.2023.079

新冠病毒感染转录组学数据及比较医学分析

冯婷婷, 李依桐, 吴玥, 王珏, 孔琪()()

中国医学科学院医学实验动物研究所, 北京协和医学院比较医学中心, 国家人类疾病动物模型资源库, 国家卫生健康委员会人类疾病比较医学重点实验室, 新发再发传染病动物模型研究北京市重点实验室, 北京市人类重大疾病实验动物模型工程技术研究中心, 北京 100021

收稿日期:2023-06-16 修回日期:2023-10-13 出版日期:2024-02-25 发布日期:2024-03-07
通讯作者: 孔琪（1978—），男，博士，研究员，研究方向：比较医学。E-mail： kongqi@ cnilas.org。ORCID： 0000-0003-2867-7382
作者简介:冯婷婷（1999—），女，硕士研究生，研究方向：比较医学。E-mail： fengtingting@ cnilas.org
基金资助:
北京市自然科学基金资助项目“基于大数据的新型冠状病毒肺炎动物模型数据库建立”(M21027)

Transcriptome Data and Comparative Medical Analysis of COVID-19 Virus Infection

Tingting FENG, Yitong LI, Yue WU, Jue WANG, Qi KONG()()

Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing 100021, China

Received:2023-06-16 Revised:2023-10-13 Published:2024-02-25 Online:2024-03-07
Contact: KONG Qi (ORCID: 0000-0003-2867-7382), E-mail: kongqi@ cnilas.org

摘要/Abstract

摘要：

目的通过系统梳理与分析新冠病毒感染相关的转录组数据，为研究新冠病毒感染过程中的生物学变化和致病机制提供更多的比较医学基础信息。方法按照检索策略，以COVID-19和SARS-CoV-2为检索词，从GEO、ArrayExpress、GEN三大转录组数据库收集获得2020年1月—2023年5月的新冠病毒感染转录组数据集，分析得到新冠病毒感染转录组的数据资源组成、分布和研究应用情况，并对数据分布进行可视化展示及关联分析。从临床医学和比较医学两个方面，围绕临床相关分子机制、生物标志物及相关免疫反应、治疗干预策略等方面，分析现有新冠病毒感染转录组数据的研究应用和局限性，阐述其研究价值和应用前景。结果共纳入新冠病毒感染转录组数据975组，在3个数据库中样本来源于人的数据集最多，分别占71.9%、77.9%和90.0%。除人以外，小鼠等是数据主要来源物种，呼吸系统和神经系统是数据分布排名在前的两个系统。在临床意义方面关联27个数据集。分析显示，基于转录组数据挖掘得到呼吸道损伤等相关分子机制，cfDNA等生物标志物可作为治疗靶点，以M1型巨噬细胞为代表的细胞变化和失调与新冠病毒感染严重程度相关。比较医学分析表明小鼠、仓鼠等均为新冠病毒易感动物，其中恒河猴和食蟹猴与人类的感染特征高度相似，仓鼠除了呼吸道症状还存在消化系统症状。新冠病毒能在各种易感动物呼吸系统器官、雪貂的肠道及水貂的耳部进行复制，产生肺炎、弥漫性肺损伤等不同程度的病理变化；基于免疫应答差异，可使用仓鼠进行中和抗体反应研究。结论目前新冠病毒感染转录组数据较多，但缺少比较转录组研究，可将转录组学与比较医学进一步结合，从而对新冠病毒感染的比较医学差异进行更深入的挖掘。

关键词: 新冠病毒, 转录组, 大数据, 分子机制, 数据分析

Abstract:

Objective To provide more basic information of comparative medicine for the study of biological changes and pathogenesis of COVID-19 by systematical sorting and analyzing the transcriptome data. Methods Following a retrieval strategy, using COVID-19 and SARS-CoV-2 as key words, transcriptome datasets related to COVID-19 from January 2020 to May 2023 were collected from GEO, ArrayExpress and GEN Transcriptome databases. The composition, distribution, and research application of COVID-19 transcriptome data resources were analyzed. Data distribution was visually displayed and correlation analysis was performed. The research applications and limitations of existing COVID-19 transcriptome data were analyzed from the perspectives of clinical medicine and comparative medicine, focusing on clinical-related molecular mechanisms, biomarkers and related immune responses, treatment intervention strategies, etc. The research value and application prospects were discussed. Results A total of 975 sets of COVID-19 transcriptome data were included. Among three databases, datasets from humans accounted for the highest proportion, namely 71.9%, 77.9%, and 90%, respectively. Species other than humans, such as mice, were the main sources of data, with the respiratory and nervous systems having the highest distribution of data. Twenty-seven datasets were associated with clinical significance. Analysis revealed that respiratory tract injury and other related molecular mechanisms were obtained through transcriptome data mining. Biomarkers such as cfDNA could be used as therapeutic targets. The severity of COVID-19 infection was associated with cell changes and disorders represented by M1 macrophages. Comparative medical analysis showed that mice, hamsters, and other animals were susceptible to SARS-CoV-2. Rhesus monkeys and cynomolgus monkeys exhibited infection characteristics highly similar to human. Apart from respiratory symptoms, hamsters also exhibited digestive system symptoms. SARS-CoV-2 can replicate in the respiratory organs of various susceptible animals, the intestines of ferrets and the ears of minks, resulting in interstitial pneumonia, diffuse lung injury and other pathological changes of varying degrees. Based on the differences in immune responses, hamsters can be used for neutralizing antibody reaction research. Conclusion Currently there is a wealth of COVID-19 transcriptome data, but there is a lack of comparative transcriptome research. Transcriptomics can be combined with comparative medicine to further explore the differences in comparative medicine of COVID-19.

Key words: COVID-19, Transcriptome, Big data, Molecular mechanisms, Data analysis

中图分类号:

R-332

冯婷婷, 李依桐, 吴玥, 王珏, 孔琪. 新冠病毒感染转录组学数据及比较医学分析[J]. 实验动物与比较医学, 2024, 44(1): 62-73.

Tingting FENG, Yitong LI, Yue WU, Jue WANG, Qi KONG. Transcriptome Data and Comparative Medical Analysis of COVID-19 Virus Infection[J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 62-73.

图/表 8

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样本来源 Sample origins	组织/细胞 Tissues/cells	发现 Finding	数据集编号 Datasets' number
人；雪貂 Human; ferrets	NHBE、A549、Calu3细胞，肺组织（人）；鼻腔冲洗液（雪貂）	新冠病毒感染肺损伤相关机制	GSE147507
人；雪貂 Human; ferrets	NHBE、A549、Calu3细胞（人）；鼻腔冲洗液（雪貂）	应对新冠病毒感染时NHBE细胞上调MALAT1和NEAT1表达	GSE147507
人；C57BL/6小鼠 Human; C57BL/6 mice	PBMC、肺泡灌洗液（人）；淋巴结（小鼠）	髓细胞、上皮细胞和T细胞之间的相互作用驱动组织损伤	GSE149689； GSE155673; GSE145926; GSE149443
金黄仓鼠 Golden hamsters	心脏	新冠病毒感染对心脏的损伤机制	PRJNA884511
人Human	肺、肝脏	新冠病毒感染肝损伤相关机制	GSE150316
人Human	肺泡灌洗液	严重新冠病毒感染患者的支气管肺泡灌洗液中富含促炎单核细胞衍生的巨噬细胞	GSE145926
人Human	肺泡灌洗液	M1型巨噬细胞和重度新冠病毒感染患者之间的关系最高	GSE145926
人Human	肺泡灌洗液	在重症监护室的新冠病毒感染患者中，中性粒细胞高度激活	EGAS00001004571 (EGA)
人Human	皮肤	新冠病毒感染引起皮疹机制	GSE161225
人Human	血液、鼻上皮、唾液	CCL3等基因为严重新冠病毒感染鼻腔、口腔和血液中的生物标志物	GSE183071
人Human	上呼吸道、鼻咽、全血	发现与新冠病毒感染每种分子亚型相关的特定基因	GSE156063; GSE163151
人Human	外周血、全血、血浆和白细胞	ARG1等7个基因生物标志物可区分SARS-CoV-2相关的ARI和其他类型的ARI	GSE161731; GSE171110 GSE152641; GSE157103 GSE172114; GSE161777
人Human	PBMC、全血、血浆和白细胞	生物标志物TGFBI、TTYH2和CD4参与免疫反应和炎症	GSE152418; GSE166424; GSE157103
人Human	全血	新冠病毒感染严重程度的转折点与S100A9等8个中性粒细胞特征基因有关	E-MTAB-11240 (EMBL-EBI)
人Human	外周血	神经损伤相关的UCHL1表达增加与严重症状有关	GSE152418
人Human	外周血	miR-146-146a-5p等3个非编码RNA是新冠病毒感染的潜在治疗靶点	HRA000238 (NGDC)
人Human	外周血	鉴定了6个具有不同分子特征的新冠肺炎亚型	GSE143507
人Human	血沉棕黄层细胞、A549细胞	cfDNA能够作为查看疾病严重程度的非侵入性生物标志物	GSE147507; GSE154998
人Human	PBMC	无症状患者中PBMC的免疫反应较弱，复阳患者的PBMC具有高炎症免疫反应	GSE179627
人Human	PBMC	循环单核淋巴细胞的变化可预测新冠病毒感染的严重程度	GSE180594
人Human	额叶皮质、脉络丛	新冠病毒感染患者脑和脉络丛细胞的功能失调	GSE159812

样本来源 Sample origins	组织/细胞 Tissues/cells	发现 Finding	数据集编号 Datasets' number
人；雪貂 Human; ferrets	NHBE、A549、Calu3细胞，肺组织（人）；鼻腔冲洗液（雪貂）	新冠病毒感染肺损伤相关机制	GSE147507
人；雪貂 Human; ferrets	NHBE、A549、Calu3细胞（人）；鼻腔冲洗液（雪貂）	应对新冠病毒感染时NHBE细胞上调MALAT1和NEAT1表达	GSE147507
人；C57BL/6小鼠 Human; C57BL/6 mice	PBMC、肺泡灌洗液（人）；淋巴结（小鼠）	髓细胞、上皮细胞和T细胞之间的相互作用驱动组织损伤	GSE149689； GSE155673; GSE145926; GSE149443
金黄仓鼠 Golden hamsters	心脏	新冠病毒感染对心脏的损伤机制	PRJNA884511
人Human	肺、肝脏	新冠病毒感染肝损伤相关机制	GSE150316
人Human	肺泡灌洗液	严重新冠病毒感染患者的支气管肺泡灌洗液中富含促炎单核细胞衍生的巨噬细胞	GSE145926
人Human	肺泡灌洗液	M1型巨噬细胞和重度新冠病毒感染患者之间的关系最高	GSE145926
人Human	肺泡灌洗液	在重症监护室的新冠病毒感染患者中，中性粒细胞高度激活	EGAS00001004571 (EGA)
人Human	皮肤	新冠病毒感染引起皮疹机制	GSE161225
人Human	血液、鼻上皮、唾液	CCL3等基因为严重新冠病毒感染鼻腔、口腔和血液中的生物标志物	GSE183071
人Human	上呼吸道、鼻咽、全血	发现与新冠病毒感染每种分子亚型相关的特定基因	GSE156063; GSE163151
人Human	外周血、全血、血浆和白细胞	ARG1等7个基因生物标志物可区分SARS-CoV-2相关的ARI和其他类型的ARI	GSE161731; GSE171110 GSE152641; GSE157103 GSE172114; GSE161777
人Human	PBMC、全血、血浆和白细胞	生物标志物TGFBI、TTYH2和CD4参与免疫反应和炎症	GSE152418; GSE166424; GSE157103
人Human	全血	新冠病毒感染严重程度的转折点与S100A9等8个中性粒细胞特征基因有关	E-MTAB-11240 (EMBL-EBI)
人Human	外周血	神经损伤相关的UCHL1表达增加与严重症状有关	GSE152418
人Human	外周血	miR-146-146a-5p等3个非编码RNA是新冠病毒感染的潜在治疗靶点	HRA000238 (NGDC)
人Human	外周血	鉴定了6个具有不同分子特征的新冠肺炎亚型	GSE143507
人Human	血沉棕黄层细胞、A549细胞	cfDNA能够作为查看疾病严重程度的非侵入性生物标志物	GSE147507; GSE154998
人Human	PBMC	无症状患者中PBMC的免疫反应较弱，复阳患者的PBMC具有高炎症免疫反应	GSE179627
人Human	PBMC	循环单核淋巴细胞的变化可预测新冠病毒感染的严重程度	GSE180594
人Human	额叶皮质、脉络丛	新冠病毒感染患者脑和脉络丛细胞的功能失调	GSE159812

物种 Species	常用品种/品系 Breeds/ strains in common use	感染滴度或剂量 Infection titer or dose	感染途径 Routes of infection	用途 Applications	优点 Advantages	缺点 Disadvantages	GEO数据集数量 Number of GEO datasets
小鼠 Mice	hACE2转基因小鼠	1×10⁵ TCID₅₀	滴鼻	致病机制研究，疫苗和药物评估	方便，便宜	耗时	21
小鼠 Mice	K18-hACE2小鼠	1×10² TCID₅₀	滴鼻	致病机制研究，疫苗和药物评估	方便，便宜	非致死模型	9
小鼠 Mice	hACE2-KI人源化小鼠	4×10⁵ PFU	滴鼻	病毒感染抗体评价，疫苗评价	方便，便宜	非致死模型	-
仓鼠 Hamsters	金黄地鼠	8×10⁴ TCID₅₀	滴鼻	致病机制研究，疫苗和药物评估	便宜，有消化系统症状	操作不如小鼠方便，病毒7 d清除，不致死	41
雪貂 Ferrets	-	1×10⁵ PFU	滴鼻	致病机制研究，疫苗和药物评估	能通过直接接触和气溶胶感染	检测不如小鼠经济	5
猴 Monkeys	恒河猴	1×10⁶ TCID₅₀	经气管感染	致病机制研究，疫苗和药物评估	与人类高度相似	价格昂贵	25
猴 Monkeys	食蟹猴	1×10⁶ PFU	气管、鼻腔、黏膜联合感染	评价新冠药物与疫苗	与人类高度相似	价格昂贵	8
水貂 Minks	-	1×10⁶ TCID₅₀	经气管感染	临床病理机制阐述，药物和疫苗评价，生物标志物筛选	与人类症状较为相似	应用少，相关试剂较少	-
树鼩 Tree shrews	-	1×10⁷ TCID₅₀	口、气管、眼联合感染	药物筛选和疫苗评估	便宜，与灵长类相似	没有纯遗传背景的品系，个体差异较大	-

物种 Species	常用品种/品系 Breeds/ strains in common use	感染滴度或剂量 Infection titer or dose	感染途径 Routes of infection	用途 Applications	优点 Advantages	缺点 Disadvantages	GEO数据集数量 Number of GEO datasets
小鼠 Mice	hACE2转基因小鼠	1×10⁵ TCID₅₀	滴鼻	致病机制研究，疫苗和药物评估	方便，便宜	耗时	21
小鼠 Mice	K18-hACE2小鼠	1×10² TCID₅₀	滴鼻	致病机制研究，疫苗和药物评估	方便，便宜	非致死模型	9
小鼠 Mice	hACE2-KI人源化小鼠	4×10⁵ PFU	滴鼻	病毒感染抗体评价，疫苗评价	方便，便宜	非致死模型	-
仓鼠 Hamsters	金黄地鼠	8×10⁴ TCID₅₀	滴鼻	致病机制研究，疫苗和药物评估	便宜，有消化系统症状	操作不如小鼠方便，病毒7 d清除，不致死	41
雪貂 Ferrets	-	1×10⁵ PFU	滴鼻	致病机制研究，疫苗和药物评估	能通过直接接触和气溶胶感染	检测不如小鼠经济	5
猴 Monkeys	恒河猴	1×10⁶ TCID₅₀	经气管感染	致病机制研究，疫苗和药物评估	与人类高度相似	价格昂贵	25
猴 Monkeys	食蟹猴	1×10⁶ PFU	气管、鼻腔、黏膜联合感染	评价新冠药物与疫苗	与人类高度相似	价格昂贵	8
水貂 Minks	-	1×10⁶ TCID₅₀	经气管感染	临床病理机制阐述，药物和疫苗评价，生物标志物筛选	与人类症状较为相似	应用少，相关试剂较少	-
树鼩 Tree shrews	-	1×10⁷ TCID₅₀	口、气管、眼联合感染	药物筛选和疫苗评估	便宜，与灵长类相似	没有纯遗传背景的品系，个体差异较大	-

物种 Species	病毒复制部位 Virus replication site	病理变化 Pathological change	免疫应答 Immune response	参考文献 References
人类 Human	主要在呼吸道和肠道	肺炎，急性呼吸窘迫综合征	产生针对S和N蛋白以及RBD的IgG抗体	[32]
小鼠（hACE2转基因小鼠） Mice( hACE2 transgenic mice )	肺	间质性肺炎	产生抗S蛋白的特异性抗体	[33]
仓鼠 Hamsters	肺、鼻甲、气管、肠道	肺炎，弥漫性肺泡损伤	中和抗体反应，IFN-R、IL-4、IL-6、TNF-a、 IL-12p40上调中和抗体反应	[34]
雪貂 Ferrets	鼻甲、气管、肺、肠道	毛细支气管炎	-	[35]
水貂 Minks	鼻腔、直肠、耳	间质性肺炎，血管周炎，细支气管周炎，鼻黏膜损伤	-	[36]
恒河猴 Rhesus monkey	肺、气管、支气管	间质性肺炎	白细胞和中性粒细胞减少，淋巴细胞增加	[37]

新冠病毒感染转录组学数据及比较医学分析

Transcriptome Data and Comparative Medical Analysis of COVID-19 Virus Infection

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类别 Category	内容 Content	数量 Number
物种 Species	人、雪貂	2
病毒亚型 Virus subtypes	野生型、USA-WA1型	2
细胞/组织类型 Tissue/ cell types	肺、气管、鼻腔，肺癌Calu3、A549、A549_oeACE2、H1299细胞，结直肠癌Caco2细胞，正常人类支气管上皮细胞	9
时间点 Time point	4 h、8 h、12 h、24 h、36 h、72 h、7 d、14 d	8
感染剂量 Infection dose	0 MOI、0.2 MOI、0.3 MOI、2 MOI、5×10⁴ PFU	5
数据集编号 Dataset number	GSE147507，GSE148729	2

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