Milligan Gregg N, Sarathy Vanessa V, Infante Ernesto, Li Li, Campbell Gerald A, Beatty P Robert, Harris Eva, Barrett Alan D T, Bourne Nigel
Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America; Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
PLoS One. 2015 May 4;10(5):e0125476. doi: 10.1371/journal.pone.0125476. eCollection 2015.
Dengue is a mosquito-borne disease of global public health significance that is caused by four serologically and genetically related viruses (DENV-1 to DENV-4). Most human DENV infections are asymptomatic, but clinical cases can range in severity from a relatively mild self-limiting illness to a severe life-threatening disease. Infection with one serotype of DENV results in life-long homotypic immunity but only short term heterotypic protection. There are no licensed vaccines or antivirals for dengue due in part to difficulty in developing small animal models that mimic the systemic disease seen in humans. Consequently, an important advance was the description of models of DENV-2 infection in AG129 mice (deficient in interferon alpha/beta and gamma receptor signaling) that resemble human disease. However, the need for well characterized models of disease due to DENV-1, -3, and -4 still remains. Here we describe a new AG129 mouse model utilizing a non-mouse-adapted Thai human DENV-4 strain 703-4. Following intraperitoneal challenge, animals experience a rapidly progressive lethal infection without developing neurologic clinical signs of disease. High virus titers are seen in multiple visceral tissues including the liver, spleen and large intestine, and the infected animals develop vascular leakage and thrombocytopenia, hallmarks of human dengue. Taken together, our studies demonstrate that this model is an important addition to the field of dengue research particularly in understanding similarities and differences in the pathologic basis of the disease caused by different DENV serotypes and in determining comparative efficacy of putative vaccines and antivirals.
登革热是一种具有全球公共卫生意义的蚊媒疾病，由四种血清学和遗传学相关的病毒（登革病毒1型至4型）引起。大多数人类登革病毒感染是无症状的，但临床病例的严重程度范围较广，从相对轻微的自限性疾病到严重的危及生命的疾病。感染一种血清型的登革病毒可产生终身同型免疫，但仅有短期异型保护作用。目前尚无登革热的许可疫苗或抗病毒药物，部分原因是难以开发出能模拟人类系统性疾病的小动物模型。因此，一个重要进展是描述了AG129小鼠（缺乏干扰素α/β和γ受体信号传导）中的登革病毒2型感染模型，该模型类似于人类疾病。然而，对于由登革病毒1型、3型和4型引起的疾病的特征明确的模型仍有需求。在此，我们描述了一种新的AG129小鼠模型，该模型利用了一种未适应小鼠的泰国人登革病毒4型毒株703-4。经腹腔接种后，动物会经历快速进展的致死性感染，且不会出现神经系统疾病临床症状。在包括肝脏、脾脏和大肠在内的多个内脏组织中可检测到高病毒滴度，并且感染的动物会出现血管渗漏和血小板减少，这是人类登革热的特征。综上所述，我们的研究表明，该模型是登革热研究领域的一项重要补充，特别是在理解由不同登革病毒血清型引起的疾病的病理基础的异同，以及确定推定疫苗和抗病毒药物的比较疗效方面。
