Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo.

IF 5.8 2区 医学 Q1 Medicine
Aaqib Sohail, Fakhar H Waqas, Peter Braubach, Laurien Czichon, Mohamed Samir, Azeem Iqbal, Leonardo de Araujo, Stephan Pleschka, Michael Steinert, Robert Geffers, Frank Pessler
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引用次数: 0

Abstract

Background: The first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa.

Results: Pseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77-82%; lncRNA 15-17%; pseudogenes 4-5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection.

Conclusions: Human lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level.

人肺组织外植体在病毒和细菌感染早期的宿主转录组反应差异。
背景:感染的头 24 小时是病原体与宿主组织相互作用的关键时间窗口。然而,由于临床上无法获得感染早期的组织,因此无法研究人体肺部自然感染的早期事件。因此,我们对肺气肿患者的体外培养人肺组织外植体(HLTE)进行了RNA测序,以研究在感染甲型流感病毒(IAV)、牛分枝杆菌卡介苗(BCG)和铜绿假单胞菌的最初24小时内,小非编码RNA、mRNA和长非编码RNA(lncRNA、lincRNA)种群的整体变化:结果:铜绿假单胞菌引起的表达变化最强,是唯一明显影响微RNA和PIWI相关RNA表达的病原体。在感染三种病原体后出现差异表达的RNA中,主要长RNA类别(> 100 nt)的代表性相似(mRNA 77-82%;lncRNA 15-17%;假基因 4-5%),但lnc-DDX60-1、RP11-202G18.1和lnc-THOC3-2是与IAV感染特别相关的RNA特征的一部分(此外还包括SNX10和SLC8A1)。IAV 感染诱导了快速的干扰素反应,CCL8 是上调最强烈的 mRNA。单细胞 RNA 测序确定气道上皮细胞和巨噬细胞是主要的 IAV 宿主细胞,但在表达很少或没有 IAV 转录本的细胞类型中也检测到了炎症反应。对大量和单细胞 RNAseq 数据的综合分析确定了一组 6 个 mRNA(IFI6、IFI44L、IRF7、ISG15、MX1、MX2)是对 IAV 感染的核心转录组反应。两种细菌病原体诱导的 mRNA 表达和预测的信号通路发生了非常相似的定性变化,但铜绿假单胞菌感染的变化幅度更大。GJB2、VNN1、DUSP4、SerpinB7和IL10的上调以及PKMYT1、S100A4、GGTA1P和SLC22A31的下调与细菌感染的关系最为密切:结论:人类肺组织对 IAV 感染的转录组反应与对卡介苗和铜绿假单胞菌感染的反应大不相同,而对这两种不同细菌病原体的反应却惊人地相似。在感染的早期阶段,这种 HLTE 模型应能在组织和单细胞水平上用于 RNA 引导的发病机制研究和组织生物标记物的发现。
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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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