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Article(id=1208106715300602394, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208106710208717234, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.04.0326, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1615824000000, receivedDateStr=2021-03-16, revisedDate=null, revisedDateStr=null, acceptedDate=1626192000000, acceptedDateStr=2021-07-14, onlineDate=1765964686465, onlineDateStr=2025-12-17, pubDate=1651075200000, pubDateStr=2022-04-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765964686465, onlineIssueDateStr=2025-12-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765964686465, creator=13701087609, updateTime=1765964686465, updator=13701087609, issue=Issue{id=1208106710208717234, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='4', pageStart='321', pageEnd='426', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1765964685250, creator=13701087609, updateTime=1765964685250, updator=13701087609, preIssue=null, nextIssue=null, ext=null, issueFiles=null}, startPage=326, endPage=333, ext={EN=ArticleExt(id=1208106715711644208, articleId=1208106715300602394, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Effect of Rickettsia heilongjiangensis infection on the transcription of immune-related genes in the spleen of mice, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To screen key targets modulating the progression of Rickettsia heilongjiang infection using a mouse infection model by profiling the transcription expression dynamics of immune-related genes. Methods A total of 20 female C3H/HeN mice were randomized into 4 groups (5 mice/group): 0 hpi (hours post-infection), 3 hpi, 3 dpi (days post-infection), and 6 dpi. Animals were infected with 5×106 CFU Rickettsia heilongjiangensis intravenously. We harvested and extracted total RNA from spleens of animals at the indicated time points. After sequencing the total RNA, we further analyzed the sequencing results by GO annotation, R language enrichment, and KEGG visualization function analysis. Results A total of 19 930 mRNAs were specifically transcribed in the spleen post-infection. Using GO annotation and enrichment, we identified three types of immune-related genes with significant changes: first, 35 innate immune-related genes, among which the transcription of irg1 and gbp10 genes involved in the IFN-γ signaling pathway rises most significantly (P<0.05); second, 31 acquired immune-related genes, among which the transcription of gzmb gene involved in the apoptosis pathway rises most significantly (P<0.05); third, 41 inflammatory responses related genes, among which the transcription of ccl4 gene involved in cytokine and cytokine receptor signaling pathway rises most significantly (P<0.05). Conclusions The irg1 and gbp10 genes involved in the IFN-γ signaling pathway, the gzmb gene involved in the apoptosis pathway, and the ccl4 gene involved in the cytokine and cytokine receptor signaling pathway affect the pathogenesis of Rickettsia heilongjiangensis infection.

, correspAuthors=Xuan Ouyang, Xiao-Lu Xiong, authorNote=null, correspAuthorsNote=
* Xiong Xiao-Lu, E-mail: ;
Ouyang Xuan, E-mail:
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目的 分析黑龙江立克次体感染小鼠脾脏免疫相关基因的转录变化，筛选影响黑龙江立克次体感染致病进程的关键靶标。方法 取20只雌性C3H/HeN小鼠，随机分为未感染组(0 hpi)、感染3 h组(3 hpi)、感染3 d组(3 dpi)及感染6 d组(6 dpi)，每组5只，采用尾静脉注射法感染黑龙江立克次体，在4个时相点解剖小鼠取脾，提取总RNA进行测序，筛选出特异性转录基因并进行GO注释、R语言富集及KEGG可视化功能分析。结果 小鼠感染黑龙江立克次体后，脾脏有219 930个mRNA发生了特异性转录，通过GO注释及富集筛选出显著性变化的3类基因：(1)35个天然免疫相关基因，其中参与γ干扰素(IFN-γ)信号通路的irg1、gbp10基因转录上调最明显(P<0.05)；(2)31个获得性免疫相关基因，其中参与细胞凋亡通路的gzmb基因转录上调最明显(P<0.05)；(3)41个炎症反应相关基因，其中参与细胞因子与细胞因子受体信号通路的ccl4基因转录上调最明显(P<0.05)。结论 宿主IFN-γ信号通路中的irg1、gbp10基因，细胞凋亡通路中的gzmb基因，细胞因子及细胞因子受体信号通路中的ccl4基因影响黑龙江立克次体感染的致病进程。

, correspAuthors=欧阳譞, 熊小路, authorNote=null, correspAuthorsNote=
熊小路，E-mail：;
欧阳譞，E-mail：
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于永慧，硕士研究生，主要从事立克次体与胞内寄生菌致病机制方面的研究

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于永慧，硕士研究生，主要从事立克次体与胞内寄生菌致病机制方面的研究

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于永慧，硕士研究生，主要从事立克次体与胞内寄生菌致病机制方面的研究

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A. reads碱基分布；B. 碱基测序质量分布

, figureFileSmall=2kHQB+eyHvoZ4CUon9oV7Q==, figureFileBig=tDj6zkcWVojEIOhDyaVWMw==, tableContent=null), ArticleFig(id=1208435601007816709, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=EN, label=Fig. 2, caption=GO enrichment analysis of phase transcription difference gene, figureFileSmall=Q7nWXBUy77vVPshL8fRm2g==, figureFileBig=Pq+P4/1hyHGWQTg774PvpA==, tableContent=null), ArticleFig(id=1208435601070731271, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=CN, label=图2, caption=时相转录差异基因GO富集分析

A－D. 黑龙江立克次体感染小鼠0 h(0 hpi)、3 h(3 hpi)、3 d(3 dpi)、6 d(6 dpi)

, figureFileSmall=Q7nWXBUy77vVPshL8fRm2g==, figureFileBig=Pq+P4/1hyHGWQTg774PvpA==, tableContent=null), ArticleFig(id=1208435601129451529, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=EN, label=Fig. 3, caption=Immune-related specific transcription genes in 3 phases after mice infection of Reckettsia helongjinggensis, figureFileSmall=fsPKJof7eNPxWwYH6jEdKQ==, figureFileBig=h9m6H2TmEXyEfBm9ZbxW9A==, tableContent=null), ArticleFig(id=1208435601209143306, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=CN, label=图3, caption=小鼠感染黑龙江立克次体后3个时相免疫相关特异性转录基因分析

A. 天然免疫相关基因；B. 获得性免疫相关基因；C. 炎症反应相关基因；D. 维恩图

, figureFileSmall=fsPKJof7eNPxWwYH6jEdKQ==, figureFileBig=h9m6H2TmEXyEfBm9ZbxW9A==, tableContent=null), ArticleFig(id=1208435601280446476, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=EN, label=Fig. 4, caption=R language enrichment analysis of immune-related transcriptional differential genes, figureFileSmall=4lZJD5Z8w4XF3VYigkQDnw==, figureFileBig=rblTAOYzibaXpj5NkIqeeQ==, tableContent=null), ArticleFig(id=1208435601347555342, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=CN, label=图4, caption=免疫相关转录差异基因的R语言富集分析, figureFileSmall=4lZJD5Z8w4XF3VYigkQDnw==, figureFileBig=rblTAOYzibaXpj5NkIqeeQ==, tableContent=null), ArticleFig(id=1208435602551320592, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=EN, label=Fig. 5, caption=KEGG visual function analysis of cytokine-cytokine receptor interaction signaling pathway红色星号代表差异表达基因, figureFileSmall=JkyxIa7anB4UjaRpby2JtQ==, figureFileBig=Vn6/kJznG2jkaOWA0ZNEcA==, tableContent=null), ArticleFig(id=1208435602626818066, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=CN, label=图5, caption=细胞因子-细胞因子受体相互作用信号通路的KEGG可视化功能分析, figureFileSmall=JkyxIa7anB4UjaRpby2JtQ==, figureFileBig=Vn6/kJznG2jkaOWA0ZNEcA==, tableContent=null), ArticleFig(id=1208435602693926932, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=EN, label=Tab. 1, caption=

The number of transcripts and multi-exon after clearing redundant reads

, figureFileSmall=null, figureFileBig=null, tableContent=
样本连接点转录本多外显子多外显子/转录本
0 hpi150 23497 94428 2780.288 716
3 hpi167 634112 67528 3400.251 520
3 dpi171 88684 77327 2580.321 541
6 dpi170 67679 93127 0110.337 929
合并–219 93069 0350.313 900
), ArticleFig(id=1208435602807173142, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106715300602394, language=CN, label=表1, caption=

清除冗余reads后的转录本及多外显子数目

, figureFileSmall=null, figureFileBig=null, tableContent=
样本连接点转录本多外显子多外显子/转录本
0 hpi150 23497 94428 2780.288 716
3 hpi167 634112 67528 3400.251 520
3 dpi171 88684 77327 2580.321 541
6 dpi170 67679 93127 0110.337 929
合并–219 93069 0350.313 900
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黑龙江立克次体感染对小鼠脾脏免疫相关基因转录的影响
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于永慧 , 段长松 , 焦俊 , 赵月峨 , 周冬生 , 温博海 , 欧阳譞 * , 熊小路 *
解放军医学杂志 | 基础研究 2022,47(4): 326-333
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解放军医学杂志 | 基础研究 2022, 47(4): 326-333
黑龙江立克次体感染对小鼠脾脏免疫相关基因转录的影响
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于永慧, 段长松, 焦俊, 赵月峨, 周冬生, 温博海, 欧阳譞* , 熊小路*
作者信息
  • 军事医学研究院微生物流行病研究所病原微生物生物安全国家重点实验室，北京 100071

    • 于永慧，硕士研究生，主要从事立克次体与胞内寄生菌致病机制方面的研究

通讯作者:

熊小路，E-mail：;
欧阳譞，E-mail：
Effect of Rickettsia heilongjiangensis infection on the transcription of immune-related genes in the spleen of mice
Yong-Hui Yu, Chang-Song Duan, Jun Jiao, Yue-E Zhao, Dong-Sheng Zhou, Bo-Hai Wen, Xuan Ouyang* , Xiao-Lu Xiong*
Affiliations
  • State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
出版时间: 2022-04-28 doi: 10.11855/j.issn.0577-7402.2022.04.0326
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摘要
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目的 分析黑龙江立克次体感染小鼠脾脏免疫相关基因的转录变化，筛选影响黑龙江立克次体感染致病进程的关键靶标。方法 取20只雌性C3H/HeN小鼠，随机分为未感染组(0 hpi)、感染3 h组(3 hpi)、感染3 d组(3 dpi)及感染6 d组(6 dpi)，每组5只，采用尾静脉注射法感染黑龙江立克次体，在4个时相点解剖小鼠取脾，提取总RNA进行测序，筛选出特异性转录基因并进行GO注释、R语言富集及KEGG可视化功能分析。结果 小鼠感染黑龙江立克次体后，脾脏有219 930个mRNA发生了特异性转录，通过GO注释及富集筛选出显著性变化的3类基因：(1)35个天然免疫相关基因，其中参与γ干扰素(IFN-γ)信号通路的irg1、gbp10基因转录上调最明显(P<0.05)；(2)31个获得性免疫相关基因，其中参与细胞凋亡通路的gzmb基因转录上调最明显(P<0.05)；(3)41个炎症反应相关基因，其中参与细胞因子与细胞因子受体信号通路的ccl4基因转录上调最明显(P<0.05)。结论 宿主IFN-γ信号通路中的irg1、gbp10基因，细胞凋亡通路中的gzmb基因，细胞因子及细胞因子受体信号通路中的ccl4基因影响黑龙江立克次体感染的致病进程。

立克次体感染  /  转录，遗传  /  黑龙江立克次体  /  天然免疫  /  获得性免疫  /  炎症反应

Objective To screen key targets modulating the progression of Rickettsia heilongjiang infection using a mouse infection model by profiling the transcription expression dynamics of immune-related genes. Methods A total of 20 female C3H/HeN mice were randomized into 4 groups (5 mice/group): 0 hpi (hours post-infection), 3 hpi, 3 dpi (days post-infection), and 6 dpi. Animals were infected with 5×106 CFU Rickettsia heilongjiangensis intravenously. We harvested and extracted total RNA from spleens of animals at the indicated time points. After sequencing the total RNA, we further analyzed the sequencing results by GO annotation, R language enrichment, and KEGG visualization function analysis. Results A total of 19 930 mRNAs were specifically transcribed in the spleen post-infection. Using GO annotation and enrichment, we identified three types of immune-related genes with significant changes: first, 35 innate immune-related genes, among which the transcription of irg1 and gbp10 genes involved in the IFN-γ signaling pathway rises most significantly (P<0.05); second, 31 acquired immune-related genes, among which the transcription of gzmb gene involved in the apoptosis pathway rises most significantly (P<0.05); third, 41 inflammatory responses related genes, among which the transcription of ccl4 gene involved in cytokine and cytokine receptor signaling pathway rises most significantly (P<0.05). Conclusions The irg1 and gbp10 genes involved in the IFN-γ signaling pathway, the gzmb gene involved in the apoptosis pathway, and the ccl4 gene involved in the cytokine and cytokine receptor signaling pathway affect the pathogenesis of Rickettsia heilongjiangensis infection.

Rickettsia infections  /  transcription, genetic  /  Rickettsia heilongjiangensis  /  innate immunity  /  acquired immunity  /  inflammatory response
于永慧, 段长松, 焦俊, 赵月峨, 周冬生, 温博海, 欧阳譞, 熊小路. 黑龙江立克次体感染对小鼠脾脏免疫相关基因转录的影响. 解放军医学杂志, 2022 , 47 (4) : 326 -333 . DOI: 10.11855/j.issn.0577-7402.2022.04.0326
Yong-Hui Yu, Chang-Song Duan, Jun Jiao, Yue-E Zhao, Dong-Sheng Zhou, Bo-Hai Wen, Xuan Ouyang, Xiao-Lu Xiong. Effect of Rickettsia heilongjiangensis infection on the transcription of immune-related genes in the spleen of mice[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (4) : 326 -333 . DOI: 10.11855/j.issn.0577-7402.2022.04.0326
正文
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黑龙江立克次体(Rickettsia heilongjiangensis)是远东斑点热(far eastern spotted fever，FESF)的病原体，属于斑点热群立克次体(spotted fever group rickettsiae，SFGR)，1983年由我国科学家分离并鉴定，是我国主要的斑点热流行株[1]。黑龙江立克次体为革兰阴性专性胞内寄生菌，在自然界中通过蜱叮咬感染人。人感染后，普遍出现多器官病灶炎性损伤、炎性浸润及脾大等。脾脏作为立克次体感染的主要靶器官，是人体最大的外周免疫器官及成熟淋巴细胞聚集区，也是发生免疫应答的重要器官。机体感染病原体后产生的免疫应答分为即刻天然免疫应答(0~4 h)、早期诱导天然免疫应答(4~96 h)及获得性免疫应答(>96 h)3个阶段。有研究对恙虫病立克次体感染内皮细胞的转录情况进行分析发现，感染早期(1~3 h)有40个转录因子发生明显变化，其中在感染3 h后白细胞介素(interleukin，IL)-6、趋化因子CCL2(C-C motif chemokine ligand 2，CCL2)、IL-10等因子的表达明显上调[2]。在康氏立克次体(Rickettsia conorii)感染小鼠3 d的肺部转录组研究中，有206个长链非编码RNA(long noncoding RNA，lncRNA)明显上调、277个明显下调。细胞毒性T淋巴细胞(cytotoxic T-lymphocyte，CTL)能够通过识别被感染细胞表面的主要组织相容性复合体Ⅰ类(major histocompatibility complex class I，MHC-Ⅰ)分子，分泌γ干扰素(IFN-γ)，以增强宿主抵抗澳大利亚立克次体(Rickettsia australis)感染的能力[3]。本研究分析了黑龙江立克次体感染后小鼠免疫相关基因的转录变化，旨在明确机体抵抗黑龙江立克次体感染的免疫调控过程。
1 材料与方法
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1.1 材料
1.1.1 菌株与细胞株
黑龙江立克次体054株(Rickettsia heilongjiangensis str. 054，ATCC VR-1524)为本实验室保存。非洲绿猴肾细胞E6株(Vero-E6)购自中国科学院上海生科院细胞资源中心。
1.1.2 实验动物
5周龄SPF级雌性C3H/HeN小鼠20只，体重14~15 g，购自北京维通利华实验动物有限公司。小鼠在军事医学研究院丰台动物中心饲养，饲养及实验操作均符合军事医学研究院实验动物伦理委员会的要求。
1.1.3 主要试剂及仪器
Trizol(15596-062)购自美国Invitrogen公司；DMEM培养基(SH3022.01B)、胎牛血清(SH30070.03)、胰蛋白酶(SH30042.02)、磷酸盐缓冲液(PBS，SH30256.01B)购自美国Hyclone公司；复方泛影葡胺注射液(国药准字H31021607)购自上海旭东海普药业有限公司；异丙醇(80109218)、无水乙醇(10009218)购自国药集团化学试剂有限公司；DEPC处理水(R1600)、去离子水(F0025)购自北京索莱宝科技有限公司。细胞培养箱、超低温冰箱购自日本Sanyo公司；光学显微镜购自日本Olympus公司；生物安全柜Ⅱ购自美国Nuaire公司；高速冷冻离心机购自美国Beckman公司；微量分光光度计购自美国Thermo Fisher公司。
1.2 方法
1.2.1 黑龙江立克次体培养及纯化
复苏Vero-E6细胞，加入含10%胎牛血清的DMEM培养基，接种于T175细胞培养瓶(每瓶约2×107个)，置于37 ℃、5%CO2孵箱内培养至细胞单层。按感染复数(multiplicity of infection，MOI)=20将立克次体悬液加到预先培养好的Vero-E6细胞单层上，33 ℃吸附4 h。补充含5%胎牛血清的DMEM培养基，置于33 ℃、5%CO2孵箱内培养。当感染黑龙江立克次体的Vero-E6细胞出现严重的空斑样脱落时富集细胞。富集的细胞经玻璃珠破碎后，以400×g离心20 min，收集上清，采用泛影葡胺密度梯度离心法纯化黑龙江立克次体[4]，菌体沉淀用PBS重悬，保存于–80 ℃备用。
1.2.2 黑龙江立克次体感染小鼠
采用随机抽样法将20只小鼠分为未感染组(0 hpi)、感染3 h组(3 hpi)、感染3 d组(3 dpi)和感染6 d组(6 dpi)，每组5只。在Ⅲ级生物安全实验室内，将5×106个菌落形成单位(CFU)的黑龙江立克次体自尾静脉注射感染小鼠。在4个时相点解剖该组5只小鼠取脾，每个脾剪碎后称取100 mg，立即置入装有1 ml Trizol溶液的EP管中。使用手动研磨器将脾脏研磨均匀，室温静置15 min后置于–20 ℃冰箱冻存，2 h后转移至–80 ℃冰箱保存，待所有样品收集完后提取总RNA。
1.2.3 总RNA提取及测序
每组取出冻存的样品1 ml，在室温解冻后采用Trizol法提取总RNA。使用Agilent 2100 Bioanalyzer检测总RNA浓度、RIN值、28S/18S及片段大小。利用Oligo-dT磁珠纯化mRNA，经片段化处理后，进行cDNA合成及磁珠纯化，纯化后的cDNA经A碱基及Adapter连接并行磁珠纯化，利用PCR反应及磁珠纯化获得文库检测样本。采用Agilent 2100 Bioanalyzer进行文库检测，测序由Illumina Solexa HiSeq 2000平台完成，采用100 bp双端测序，文库使用插入片段330 bp的链特异性文库，每个样品设计测序数据产出为40 M reads，数据产出量为每个样品8 GB。
1.2.4 测序数据处理与分析
采用Cut adapt(v1.15)对测序所得的原始数据(raw reads)进行过滤，得到纯净序列(clean reads)用于后续分析。采用TopHat2 v2.0.4软件[5]将clean reads回贴至小鼠基因组(mm9)。采用软件Cufflinks 2.0分析4个测序样本回贴至基因组后的比对结果，重新构建转录本。单个样本构建的转录本集合并不完全，或者可能并未构建出全长，因此用软件Cuffcompare 2.0将4个样本中鉴定到的所有转录本进行差补、均一化合并成统一的转录本矩阵(同一转录本出现多次采用最高的读数作为该转录本的定量信息)[6]。采用软件Cuffdiff 2.0计算4个测序样本的JS散度(Jensen Shannon score，JS score)。
1.2.5 免疫相关特异性转录基因筛选
对小鼠基因进行功能注释分析，按照GO功能分类的天然免疫(GO:0045087)、获得性免疫(GO:0002250)及炎症反应(GO:0006954)，将特异性转录基因中免疫相关基因提取出来。采用软件Cuffdiff 2.0定量分析免疫相关基因的表达，筛选免疫相关显著的特异性转录基因。筛选条件为：与感染前(0 hpi)相比，感染后3个时相免疫相关基因转录差异倍数|log2(Fold change)|>1。
1.2.6 功能富集分析
利用R包ClusterProfiler对黑龙江立克次体感染小鼠后转录差异基因进行功能富集分析。基于人工判读文献及基因注释，选取天然免疫相关基因、获得性免疫相关基因、炎症反应相关基因并进行分析。KEGG信号通路富集分析发现这3类基因显著富集于参与感染相关过程的通路。
1.3 统计学处理
转录差异基因通过JS score分析，用于度量两个概率分布的相似度，其取值为0~1间的连续变量，随基因表达特异性增强而增大[7]，根据经验值以JS score>0.9作为各时相特异性转录基因的筛选条件。GO与KEGG以转录组差异基因变化倍数|log2(倍数)|>1为具有显著性差异；免疫功能转录差异基因R语言功能富集以–log10(q value) >1.3为具有显著性差异。P<0.05为显著性富集。
2 结果
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2.1 黑龙江立克次体感染小鼠脾脏组织转录组测序结果
本实验样品所有reads (读长)的4种碱基分布均匀(图1A)，且测序质量>20(图1B)，得到219 930个转录本(表1)，0 hpi、3 hpi、3 dpi、6 dpi 4个时相分别筛选出特异性转录基因164、152、90、122个。
2.2 时相转录差异基因GO富集分析
在显著上调的前30个GO富集通路中，0 hpi时，小鼠脾脏MAPK信号通路、葡萄糖转运、肌纤维组装等基础生理功能明显上调(P<0.05)(图2A)；3 hpi时，脾脏细胞中趋化因子受体结合、趋化因子活性、巨噬细胞等天然免疫反应通路明显上调(P<0.05)(图2B)；3 dpi时，鸟苷酸激酶/L型钙通道区域、蛋白酪氨酸激酶、蛋白酪氨酸激酶活性等明显上调(P<0.05)(图2C)；6 dpi时，抗生素、2Fe-2S铁氧还蛋白、铁硫蛋白结合位点、黄嘌呤脱氢酶等明显上调(P<0.05)(图2D)。
2.3 免疫功能转录差异基因分析
GO注释分析结果显示，分别有35个天然免疫相关基因(图3A)、31个获得性免疫相关基因(图3B)及41个炎症反应相关基因(图3C)转录发生显著性变化(P<0.05)。维恩分析显示，免疫相关特异性转录基因具有时相差异性及共同性，其中感染后3个时相(3 hpi、3 dpi、6 dpi)分别有7、6、6个基因特异性转录，有37个共同基因特异性转录(图3D)。在天然免疫相关基因中，显著特异性转录基因有irg1、ccl2、il12b、cd14、ubd、gbp10；在获得性免疫相关基因中，显著特异性转录基因有gzmb、batf、irf7、fcgr1、il18bp、cr2、c4b；在炎症反应相关基因中，显著特异性转录基因有il27、nos2、cxcl11、cxcl10、cxcl9、il10。
2.4 免疫功能转录差异基因R语言功能富集分析结果
早期激活信号受体通路、中期激活胞内信号传导通路、晚期激活细胞凋亡通路及细胞因子-细胞因子受体相互作用信号通路贯穿黑龙江立克次体感染全过程，且在早期感染阶段炎症反应相关基因显著性富集(P<0.05) (图4)。
2.5 免疫功能转录差异基因KEGG可视化功能分析结果
在黑龙江立克次体感染早期，细胞因子-细胞因子受体相互作用信号通路中有21个基因显著性富集，主要包含16个趋化因子家族基因，其中CC子集包含ccl3、ccl4、ccl8、ccl11、ccl12、ccr7、ccr3、ccr5共8个基因，CXC子集包含cxcl1、cxcl2、cxcl5、cxcl9、cxcl10、cxcl13、cxcl11、cxcr3共8个基因(图5)。
3 讨论
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在自然界，立克次体通过节肢动物的叮咬进入宿主血液，沿血行扩散到身体其他部位。有研究发现，Balb/c小鼠感染黑龙江立克次体后，出现类似人感染立克次体的特征，包括血源散布性、多器官病灶炎性损伤及炎性浸润、脾大等[4]。本研究选用对斑点热立克次体敏感的C3H/HeN小鼠作为模型鼠，采用尾静脉注射的方法模拟节肢动物叮咬，使黑龙江立克次体直接进入小鼠血液循环系统引起感染。
在天然免疫进程中，IFN-γ可诱导巨噬细胞活化，使其对胞内病原菌的杀伤作用显著增强[8]，并具有诱导T细胞向Th1(T-helper 1，Th1)亚群分化、促进CTL分化并增强其杀伤功能等多种免疫活性，是哺乳动物对抗胞内寄生菌入侵发挥重要作用的细胞因子[9]。本研究发现，小鼠感染黑龙江立克次体3 h后，与IFN-γ相关的gbp10、irg1、ccl2、ubd基因转录水平显著升高；感染3 d后其表达量逐渐下降，但仍维持较高的水平，提示小鼠感染黑龙江立克次体后脾脏细胞对IFN-γ的应答活跃。IL-12b是IL-12的一个亚基，IL-12由活化的巨噬细胞分泌，主要作用于T细胞及自然杀伤(natural killer，NK)细胞，促进其分泌IFN-γ、肿瘤坏死因子(TNF)-α等细胞因子[10]。本研究结果显示，小鼠感染黑龙江立克次体3 h后，IL-12b转录水平显著升高，提示NK细胞数量增加，IFN-γ大量产生，机体启动了抗立克次体天然免疫。CD14是革兰阴性菌脂多糖(LPS)及LPS结合蛋白复合物的高亲和力受体，能介导LPS对细胞的刺激作用，通过激活核转录因子(NF)-κB及丝裂原活化蛋白激酶(MAPK)两条通路促进IL-1、IL-6、TNF-α等细胞因子的释放[11]。本研究发现，小鼠感染黑龙江立克次体3 h后，CD14基因转录水平升高约30倍，随后逐渐下降，但仍维持在较高水平，提示黑龙江立克次体的LPS具有刺激CD14+免疫细胞增殖的作用。
获得性免疫相关基因中，gzmb基因编码一种丝氨酸蛋白酶(granzyme B，GZMB)，其主要来自CTL及NK细胞释放的细胞质颗粒。CTL在识别被感染细胞的膜表面异己成分后，通过释放GZMB至被感染细胞内，诱导被感染细胞凋亡，因此GZMB在诱导细胞凋亡中起关键作用[12]。本研究结果显示，gzmb是转录上调最显著的获得性免疫相关基因，提示感染6 d后，CTL通过细胞凋亡途径高效、特异地杀伤感染立克次体的细胞。抗体Fc受体fcgr1基因在感染3 d、6 d后均转录上调，提示宿主产生抗体依赖的细胞毒作用，杀伤被立克次体感染的细胞。C4B补体活化相关基因在感染3 d后表达水平上调，提示补体系统参与了抗立克次体的免疫应答。在宿主抗胞内病原体感染过程中，Th1型免疫反应发挥了重要作用。Th1型细胞可通过释放IFN-γ、IL-12等细胞因子而活化巨噬细胞及淋巴细胞，诱导细胞免疫反应，也可通过直接接触诱导CTL分化[13]。根据基因功能注释，il18bp基因与Th1型免疫反应相关，其转录水平升高提示黑龙江立克次体感染激活了Th1型免疫反应。batf基因编码一种B细胞转录激活因子，控制免疫细胞特别是Th17细胞的分化。batf基因在感染后转录上调并持续处于3倍以上的升高水平，提示Th17亦参与了抗立克次体感染的细胞免疫应答。
对炎症反应相关基因进行分析发现，感染后多种基因转录水平呈先升高后降低的趋势，包括趋化因子CCL、CXCL及其相应受体基因和白细胞介素基因等。小鼠感染黑龙江立克次体3 h后，CCL、CXCL等趋化因子转录水平升高，提示炎症反应启动，多种效应细胞(如单核/巨噬细胞、中性粒细胞、CD8+ T细胞等)被募集活化参与抗感染免疫。其中转录上调明显的ccl2可趋化单核/巨噬细胞到炎症部位，cxcl10可趋化T淋巴细胞及单核细胞，介导Th1型炎性反应。活化的巨噬细胞对胞内病原菌具有强大的杀伤破坏作用。一氧化氮合酶(NOS)2是NOS家族3种亚型中的第2类，为诱导型NOS(iNOS)。NOS2能与L-精氨酸及氧发生作用，产生NO及L-瓜氨酸，其中NO具有杀灭病原体的作用。其转录水平在感染3 d后升高99倍，感染6 d后下降至30倍，提示感染3 d后免疫活性细胞产生的NO较多，杀伤立克次体的活性较强。il27是转录上调最明显的基因，其编码的IL-27由激活的抗原提呈细胞分泌，具有促进或抑制IFN-γ分泌的双重作用，能双向调节Th1型免疫反应。IL-10是一种免疫抑制因子，可抑制Th1型反应。本研究中il10基因转录上调，可能是IL-10通过抑制宿主抗立克次体免疫应答，起到免疫调节、维持宿主免疫平衡的作用[14]。
综上所述，C3H/HeN小鼠感染黑龙江立克次体后，在抗感染免疫的不同阶段，脾脏中多种基因的转录水平发生变化，包括35个天然免疫相关基因、31个获得性免疫相关基因及41个炎症反应相关基因。在感染早期，参与IFN-γ信号通路的irg1、gbp10基因及促炎因子转录上调，炎症反应启动；细胞因子及细胞因子受体信号通路中ccl4基因转录上调，多种免疫效应细胞被募集活化。在获得性免疫阶段，参与细胞凋亡通路的gzmb基因转录上调，Th1及CTL细胞介导的细胞免疫在抗立克次体感染中发挥了重要作用。本研究初步揭示了小鼠在抗黑龙江立克次体感染中的免疫调控过程，为了解远东斑点热的致病过程及宿主免疫防御机制提供了依据。但本研究只是基于RNA转录组学分析，挑选出来的实际靶点如irg1、gbp10、gzmb、ccl2等关键宿主因子，仍需通过体外相互作用生化实验、体内敲低/敲除/过表达细胞系或小鼠实验进行验证。
基金
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  • 国家自然科学基金(31970178)
  • 北京市自然科学基金(5204039)
文献
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2022年第47卷第4期
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doi: 10.11855/j.issn.0577-7402.2022.04.0326
  • 接收时间：2021-03-16
  • 首发时间：2025-12-17
  • 出版时间：2022-04-28
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  • 收稿日期：2021-03-16
  • 录用日期：2021-07-14
基金
National Natural Science Foundation of China(31970178)
国家自然科学基金(31970178)
Beijing Natural Science Foundation(5204039)
北京市自然科学基金(5204039)
作者信息
    军事医学研究院微生物流行病研究所病原微生物生物安全国家重点实验室，北京 100071

通讯作者:

熊小路，E-mail：;
欧阳譞，E-mail：
参考文献
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https://castjournals.cast.org.cn/joweb/jfjyxzz/CN/10.11855/j.issn.0577-7402.2022.04.0326
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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