Milligan Gregg N, Sarathy Vanessa V, White Mellodee M, Greenberg M Banks, Campbell Gerald A, Pyles Richard B, Barrett Alan D T, Bourne Nigel
Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555, USA.
J Gen Virol. 2017 Oct;98(10):2507-2519. doi: 10.1099/jgv.0.000923. Epub 2017 Sep 27.
The mosquito-borne disease dengue is caused by four serologically and genetically related flaviviruses termed DENV-1 to DENV-4. Dengue is a global public health concern, with both the geographical range and burden of disease increasing rapidly. Clinically, dengue ranges from a relatively mild self-limiting illness to a severe life-threatening and sometimes fatal disease. Infection with one DENV serotype produces life-long homotypic immunity, but incomplete and short-term heterotypic protection. The development of small-animal models that recapitulate the characteristics of the disseminated disease seen clinically has been difficult, slowing the development of vaccines and therapeutics. The AG129 mouse (deficient in interferon alpha/beta and gamma receptor signalling) has proven to be valuable for this purpose, with the development of models of disseminated DENV-2,-3 and -4 disease. Recently, a DENV-1 AG129 model was described, but it requires antibody-dependent enhancement (ADE) to produce lethality. Here we describe a new AG129 model utilizing a non-mouse-adapted DENV-1 strain, West Pacific 74, that does not require ADE to induce lethal disease. Following high-titre intraperitoneal challenge, animals experience a virus infection with dissemination to multiple visceral tissues, including the liver, spleen and intestine. The animals also become thrombocytopenic, but vascular leakage is less prominent than in AG129 models with other DENV serotypes. Taken together, our studies demonstrate that this model is an important addition to dengue research, particularly for understanding the pathological basis of the disease between DENV serotypes and allowing the full spectrum of activity to test comparisons for putative vaccines and antivirals.
由蚊子传播的登革热是由四种血清学和遗传学相关的黄病毒引起的，分别称为登革病毒1型至4型（DENV-1至DENV-4）。登革热是一个全球公共卫生问题，其疾病的地理范围和负担都在迅速增加。临床上，登革热的症状从相对轻微的自限性疾病到严重的危及生命甚至有时致命的疾病不等。感染一种登革病毒血清型可产生终身同型免疫，但异型保护不完整且持续时间短。建立能够重现临床所见播散性疾病特征的小动物模型一直很困难，这减缓了疫苗和治疗方法的研发进程。AG129小鼠（缺乏α/β干扰素和γ受体信号传导）已被证明在此方面具有重要价值，已建立了播散性DENV-2、-3和-4疾病模型。最近，有人描述了一种DENV-1 AG129模型，但它需要抗体依赖性增强（ADE）才能产生致死性。在此，我们描述了一种新的AG129模型，该模型利用一种非小鼠适应性的DENV-1毒株——西太平洋74株，该毒株无需ADE即可诱导致死性疾病。经高滴度腹腔注射攻击后，动物会感染病毒，并扩散至多个内脏组织，包括肝脏、脾脏和肠道。这些动物还会出现血小板减少，但血管渗漏不如其他登革病毒血清型的AG129模型明显。综上所述，我们的研究表明，该模型是登革热研究的重要补充，特别是对于理解不同登革病毒血清型之间疾病的病理基础，以及全面测试假定疫苗和抗病毒药物的活性比较而言。
