Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model.
Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model.
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转录分析证实了登革热疾病模型中肥大细胞稳定的治疗作用。
DOI：
10.1128/jvi.00617-17
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发表时间：
2017-09-15
影响因子：
5.4
通讯作者：
St John AL
中科院分区：
文献类型：
--
作者：
Morrison J;Rathore APS;Mantri CK;Aman SAB;Nishida A;St John AL
尽管登革热病毒（DENV）及其蚊媒在全球流行，但目前还没有批准的治疗登革热病的疗法。由于 DENV 能够感染多种免疫和非免疫细胞群，因此 DENV 感染可导致血管并发症、出血和休克。越来越多的研究表明宿主反应是严重疾病的主要原因。各种细胞类型的炎症产物，包括反应性 T 细胞、肥大细胞 (MC) 和受感染的单核细胞，都可能导致免疫病理学。在这项研究中，我们发现免疫活性小鼠对 DENV 感染的宿主反应重现了人类研究中描述的转录变化。我们发现 DENV 感染强烈诱导代谢失调、补体信号传导和炎症。 DENV 还影响脾脏和肝脏的免疫细胞含量，增强 NK、NKT 和 CD8+ T 细胞的激活。 MC 稳定药物酮替芬逆转了许多此类反应，而不抑制记忆 T 细胞的形成，并诱导脾脏转录组和免疫细胞组成的额外变化，这与炎症的减少相一致。这项研究提供了免疫活性宿主的 DENV 靶器官中免疫激活的全局转录图谱，并支持进一步开发治疗 DENV 疾病的靶向免疫调节策略。重要性 登革热病毒 (DENV) 会导致发热性疾病，通过蚊媒在世界热带和亚热带地区传播。 DENV 感染的症状包括血管损伤，在极少数情况下，还会出现出血和休克。目前，还没有治疗登革热病毒感染的靶向疗法，但人们认为，针对宿主免疫反应的药物可能可以有效限制过度炎症引起的症状。在这项研究中，我们使用小鼠疾病模型测量了宿主对多个 DENV 靶器官感染的转录反应。我们发现 DENV 感染会引起代谢失调和炎症反应，并影响脾脏和肝脏的免疫细胞含量。肥大细胞稳定药物酮替芬的使用逆转了许多这些反应，并引起转录组和免疫细胞库的额外变化，从而有助于减少登革热疾病。
There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. DENV infections can lead to vascular complications, hemorrhage, and shock due to the ability of DENV to infect a variety of immune and nonimmune cell populations. Increasingly, studies have implicated the host response as a major contributor to severe disease. Inflammatory products of various cell types, including responding T cells, mast cells (MCs), and infected monocytes, can contribute to immune pathology. In this study, we show that the host response to DENV infection in immunocompetent mice recapitulates transcriptional changes that have been described in human studies. We found that DENV infection strongly induced metabolic dysregulation, complement signaling, and inflammation. DENV also affected the immune cell content of the spleen and liver, enhancing NK, NKT, and CD8+ T cell activation. The MC-stabilizing drug ketotifen reversed many of these responses without suppressing memory T cell formation and induced additional changes in the transcriptome and immune cell composition of the spleen, consistent with reduced inflammation. This study provides a global transcriptional map of immune activation in DENV target organs of an immunocompetent host and supports the further development of targeted immunomodulatory strategies to treat DENV disease. IMPORTANCE Dengue virus (DENV), which causes febrile illness, is transmitted by mosquito vectors throughout tropical and subtropical regions of the world. Symptoms of DENV infection involve damage to blood vessels and, in rare cases, hemorrhage and shock. Currently, there are no targeted therapies to treat DENV infection, but it is thought that drugs that target the host immune response may be effective in limiting symptoms that result from excessive inflammation. In this study, we measured the host transcriptional response to infection in multiple DENV target organs using a mouse model of disease. We found that DENV infection induced metabolic dysregulation and inflammatory responses and affected the immune cell content of the spleen and liver. The use of the mast cell stabilization drug ketotifen reversed many of these responses and induced additional changes in the transcriptome and immune cell repertoire that contribute to decreased dengue disease.