Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Drive, Baton Rouge, LA 70803, USA.
Virol J. 2013 Apr 23;10:127. doi: 10.1186/1743-422X-10-127.
Dengue virus (DENV) research has historically been hampered by the lack of a susceptible vertebrate transmission model. Recently, there has been progress towards such models using several varieties of knockout mice, particularly those deficient in type I and II interferon receptors. Based on the critical nature of the type I interferon response in limiting DENV infection establishment, we assessed the permissiveness of a mouse strain with a blunted type I interferon response via gene deficiencies in interferon regulatory factors 3 and 7 (IRF3/7 -/- -/-) with regards to DENV transmission success. We investigated the possibility of transmission to the mouse by needle and infectious mosquito, and subsequent transmission back to mosquito from an infected animal during its viremic period.
Mice were inoculated subcutaneously with non-mouse adapted DENV-2 strain 1232 and serum was tested for viral load and cytokine production each day. Additionally, mosquitoes were orally challenged with the same DENV-2 strain via artificial membrane feeder, and then allowed to forage or naïve mice. Subsequently, we determined acquisition potential by allowing naïve mosquitoes on forage on exposed mice during their viremic period.
Both needle inoculation and infectious mosquito bite(s) resulted in 100% infection. Significant differences between these groups in viremia on the two days leading to peak viremia were observed, though no significant difference in cytokine production was seen. Through our determination of transmission and acquisition potentials, the transmission cycle (mouse-to mosquito-to mouse) was completed. We confirmed that the IRF3/7 -/- -/- mouse supports DENV replication and is competent for transmission experiments, with the ability to use a non-mouse adapted DENV-2 strain. A significant finding of this study was that this IRF3/7 -/- -/- mouse strain was able to be infected by and transmit virus to mosquitoes, thus providing means to replicate the natural transmission cycle of DENV.
As there is currently no approved vaccine for DENV, public health monitoring and a greater understanding of transmission dynamics leading to outbreak events are critical. The further characterization of DENV using this model will expand knowledge of key entomological, virological and immunological components of infection establishment and transmission events.
登革热病毒（DENV）的研究一直受到缺乏易感脊椎动物传播模型的阻碍。最近，使用多种基因敲除小鼠品系，特别是缺乏 I 型和 II 型干扰素受体的小鼠品系，在建立这种模型方面取得了进展。基于 I 型干扰素反应在限制 DENV 感染建立中的关键性质，我们评估了一种通过干扰素调节因子 3 和 7（IRF3/7-/-/-）基因缺陷导致 I 型干扰素反应迟钝的小鼠品系在 DENV 传播成功方面的易感性。我们研究了通过针和感染性蚊子向小鼠传播的可能性，以及在感染动物的病毒血症期间从受感染动物向蚊子传播的可能性。
将小鼠皮下接种非鼠适应的 DENV-2 株 1232，并每天检测血清中的病毒载量和细胞因子产生情况。此外，通过人工膜饲养器用相同的 DENV-2 株对蚊子进行经口挑战，然后让它们觅食或感染未感染的小鼠。随后，我们通过允许未感染的蚊子在感染动物的病毒血症期间在暴露的动物上觅食来确定获得能力。
针接种和感染性蚊子叮咬均导致 100%感染。在导致峰值病毒血症的前两天，两组之间的病毒血症存在显著差异，但细胞因子产生无显著差异。通过我们对传播和获得潜力的确定，完成了传播周期（鼠-蚊-鼠）。我们证实，IRF3/7-/-/- 小鼠支持 DENV 复制，并且能够进行传播实验，能够使用非鼠适应的 DENV-2 株。本研究的一个重要发现是，这种 IRF3/7-/-/- 小鼠品系能够被感染并将病毒传播给蚊子，从而提供了复制 DENV 自然传播周期的手段。
由于目前尚无批准的 DENV 疫苗，因此公共卫生监测和更好地了解导致暴发事件的传播动态至关重要。使用这种模型对 DENV 的进一步表征将扩展对感染建立和传播事件中关键昆虫学、病毒学和免疫学成分的认识。
