Morrison Juliet, Rathore Abhay P S, Mantri Chinmay K, Aman Siti A B, Nishida Andrew, St John Ashley L
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA
Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore.
J Virol. 2017 Aug 24;91(18). doi: 10.1128/JVI.00617-17. Print 2017 Sep 15.
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. 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.
尽管登革病毒（DENV）及其蚊媒在全球广泛存在，但目前尚无经批准用于治疗登革热疾病的疗法。由于DENV能够感染多种免疫细胞和非免疫细胞群体，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促成因素。包括反应性T细胞、肥大细胞（MCs）和受感染单核细胞在内的各种细胞类型的炎症产物，都可能导致免疫病理。在本研究中，我们表明免疫功能正常的小鼠对DENV感染的宿主反应概括了人类研究中所描述的转录变化。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，增强自然杀伤细胞（NK）、自然杀伤T细胞（NKT）和CD8 T细胞的活化。MC稳定药物酮替芬逆转了许多这些反应，同时不抑制记忆T细胞的形成，并在脾脏的转录组和免疫细胞组成中诱导了额外的变化，这与炎症减轻一致。本研究提供了免疫功能正常宿主的DENV靶器官中免疫激活的全局转录图谱，并支持进一步开发针对性免疫调节策略来治疗登革热疾病。登革病毒（DENV）可引起发热性疾病，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，在罕见情况下会出现出血和休克。目前，尚无治疗DENV感染的靶向疗法，但人们认为靶向宿主免疫反应的药物可能有效限制过度炎症导致的症状。在本研究中，我们使用疾病小鼠模型测量了多个DENV靶器官中宿主对感染的转录反应。我们发现DENV感染诱导代谢失调和炎症反应，并影响脾脏和肝脏的免疫细胞含量。使用肥大细胞稳定药物酮替芬逆转了许多这些反应，并在转录组和免疫细胞库中诱导了额外的变化，有助于减轻登革热疾病。
