Wilson Jane A C, Prow Natalie A, Schroder Wayne A, Ellis Jonathan J, Cumming Helen E, Gearing Linden J, Poo Yee Suan, Taylor Adam, Hertzog Paul J, Di Giallonardo Francesca, Hueston Linda, Le Grand Roger, Tang Bing, Le Thuy T, Gardner Joy, Mahalingam Suresh, Roques Pierre, Bird Phillip I, Suhrbier Andreas
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Australian Infectious Disease Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
PLoS Pathog. 2017 Feb 16;13(2):e1006155. doi: 10.1371/journal.ppat.1006155. eCollection 2017 Feb.
Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme A-/- and to a lesser extent granzyme K-/-, but not granzyme B-/-, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme A-/- mice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy.
ClinicalTrials.gov NCT00281294.
基孔肯雅病毒（CHIKV）是一种致关节炎的甲病毒，可引发急性和慢性关节炎疾病的流行。在此，我们描述了在CHIKV成年野生型小鼠模型中，在病毒血症高峰期（感染后第2天）、急性关节炎期（第7天）和慢性疾病期（第30天）对足部和淋巴结进行的全面RNA测序分析。先前在CHIKV患者中显示上调的基因在小鼠模型中也上调。还获得了CHIKV序列信息，高达约8%的读数映射到病毒基因组；然而，未发现明显的适应性病毒基因组变化。尽管第2天、第7天和第30天代表感染和疾病的不同阶段，但上调的宿主基因和通路存在明显重叠。即使在第7天和第30天I型干扰素诱导缺失后，I型干扰素反应基因（IRGs）仍占上调基因的约50%。生物信息学分析表明，一些干扰素反应因子主要负责维持I型IRG诱导。一组在RNA测序分析中突出且迄今在病毒性关节病中未被探索的基因是颗粒酶A、B和K。颗粒酶A基因敲除小鼠以及程度较轻的颗粒酶K基因敲除小鼠，但不是颗粒酶B基因敲除小鼠，足部肿胀和关节炎明显减轻，对颗粒酶A基因敲除小鼠的分析显示病毒载量没有降低，但CHIKV感染后NK和T细胞浸润减少。用颗粒酶A抑制剂Serpinb6b治疗也可减轻野生型小鼠的关节炎炎症。在非人类灵长类动物中，CHIKV感染后循环颗粒酶A水平升高，且升高与病毒载量相关。在一小群人类CHIKV患者中也观察到颗粒酶A水平升高。综合这些结果表明，颗粒酶A是关节炎炎症的重要驱动因素，也是潜在的治疗靶点。
ClinicalTrials.gov NCT00281294。
Zotero 插件
