Probing Dermal Immunity to Mycobacteria through a Controlled Human Infection Model.

Q3 Medicine
E Chandler Church, Emma Bishop, Andrew Fiore-Gartland, Krystle K Q Yu, Ming Chang, Richard M Jones, Justin K Brache, Lamar Ballweber Fleming, Jolie M Phan, Mohau S Makatsa, Jack Heptinstall, Kelvin Chiong, One Dintwe, Anneta Naidoo, Valentin Voillet, Koshlan Mayer-Blackwell, Gift Nwanne, Erica Andersen-Nissen, Jay C Vary, Georgia D Tomaras, M Juliana McElrath, David R Sherman, Sean C Murphy, James G Kublin, Chetan Seshadri
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Abstract

Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections.

通过受控人体感染模型探究皮肤对分枝杆菌的免疫力
皮肤分枝杆菌感染会导致大量发病,而且诊断和治疗都很困难。进一步了解皮肤对分枝杆菌的免疫反应可能会激发新的治疗方法。我们进行了一项人体感染对照研究,10 名参与者皮内接受了 2 × 106 CFU 的牛分枝杆菌卡介苗-桂林杆菌(Tice 株),并被随机分配接受异烟肼治疗或不接受治疗。在多个时间点采集外周血,进行流式细胞术、大量 RNA 测序(RNA-seq)和血清 Ab 评估。在这群对牛海绵状芽孢杆菌(M. bovis bacillus Calmette-Guérin)无免疫反应的人群中,早在挑战后 8 d 就检测到了全身免疫反应。注射部位皮肤活检是在药敏试验后第 3 天和第 15 天进行的,使用质谱细胞计数法和单细胞 RNA-seq 进行了免疫分析,并对细菌存活率和负担进行了定量评估。分子存活率检测和标准培养结果相关性良好,但治疗组之间未观察到差异。单细胞 RNA 截图显示了皮肤中的各种免疫和非免疫细胞类型,并通过配体受体基因表达推断出它们之间的交流。第 3 天,单核细胞主要通过迁移抑制因子途径和 HLA-E-KLRK1 相互作用与角质形成细胞、肌肉、上皮细胞和内皮细胞进行交流。在第 15 天,细胞类型之间的交流更加平衡。这些数据揭示了非免疫细胞在皮肤对分枝杆菌的免疫反应中的潜在作用,以及人体挑战研究在增强我们对分枝杆菌感染的了解方面的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.70
自引率
0.00%
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0
审稿时长
4 weeks
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