Genetic diversity in the collaborative cross model recapitulates human West Nile virus disease outcomes.
Genetic diversity in the collaborative cross model recapitulates human West Nile virus disease outcomes.
复制标题
DOI：
10.1128/mbio.00493-15
复制
发表时间：
2015-05-05
期刊：
影响因子：
6.4
通讯作者：
Lund JM
中科院分区：
文献类型：
--
作者：
Graham JB;Thomas S;Swarts J;McMillan AA;Ferris MT;Suthar MS;Treuting PM;Ireton R;Gale M Jr;Lund JM
西尼罗河病毒（WNV）是一种新兴的神经侵入性黄病毒，目前在全球范围内引起显著的发病率和死亡率。对WNV感染的先天和适应性免疫反应已在C57 BL/6 J近交系小鼠中得到了充分研究，但该模型缺乏在人类中观察到的对WNV感染的易感性、免疫力和结果的变化，从而限制了其了解WNV感染机制的有用性和免疫动力学。为了建立捕获人类感染结果的WNV感染模型，我们使用了协作交叉（CC）小鼠模型。我们表明，这个模型，概括了人类群体的遗传多样性，表现出多样性的易感性和结果观察到的西尼罗河病毒感染的人类。使用CC小鼠的多个F1杂交，我们确定了广泛的感染易感性，如通过外周组织和中枢神经系统中的存活率、临床疾病评分、病毒滴度以及先天性和适应性免疫应答的差异所证明的。此外，我们检查了CC小鼠中的Oas 1b等位基因，并证实了先前的发现，即Oas 1b在对WNV的易感性中起作用;然而，即使在给定的Oas 1b等位基因状态下，我们也确定了广泛的菌株特异性WNV相关表型。这些结果证实了CC模型对于鉴定参与WNV抗性和易感性的宿主基因库是有效的。CC有效地模拟了广泛的WNV临床，病毒学和免疫表型，从而克服了传统C57 BL/6 J模型的局限性，允许在不同易感人群中进行WNV感染和免疫的遗传和机制研究。西尼罗河病毒感染的小鼠模型揭示了关于对这种新出现的病毒感染的先天性和适应性免疫应答的重要细节。然而，传统的小鼠模型缺乏人类群体中存在的遗传多样性，因此限制了我们研究西尼罗河病毒感染后各种疾病结果和免疫机制的能力。在这项研究中，我们使用协作交叉小鼠模型，更有效地模拟了广泛的临床，病毒学和免疫表型后，西尼罗河病毒感染的人。
West Nile virus (WNV) is an emerging neuroinvasive flavivirus that now causes significant morbidity and mortality worldwide. The innate and adaptive immune responses to WNV infection have been well studied in C57BL/6J inbred mice, but this model lacks the variations in susceptibility, immunity, and outcome to WNV infection that are observed in humans, thus limiting its usefulness to understand the mechanisms of WNV infection and immunity dynamics. To build a model of WNV infection that captures human infection outcomes, we have used the Collaborative Cross (CC) mouse model. We show that this model, which recapitulates the genetic diversity of the human population, demonstrates diversity in susceptibility and outcomes of WNV infection observed in humans. Using multiple F1 crosses of CC mice, we identified a wide range of susceptibilities to infection, as demonstrated through differences in survival, clinical disease score, viral titer, and innate and adaptive immune responses in both peripheral tissues and the central nervous system. Additionally, we examined the Oas1b alleles in the CC mice and confirmed the previous finding that Oas1b plays a role in susceptibility to WNV; however, even within a given Oas1b allele status, we identified a wide range of strain-specific WNV-associated phenotypes. These results confirmed that the CC model is effective for identifying a repertoire of host genes involved in WNV resistance and susceptibility. The CC effectively models a wide range of WNV clinical, virologic, and immune phenotypes, thus overcoming the limitations of the traditional C57BL/6J model, allowing genetic and mechanistic studies of WNV infection and immunity in differently susceptible populations. Mouse models of West Nile virus infection have revealed important details regarding the innate and adaptive immune responses to this emerging viral infection. However, traditional mouse models lack the genetic diversity present in human populations and therefore limit our ability to study various disease outcomes and immunologic mechanisms subsequent to West Nile virus infection. In this study, we used the Collaborative Cross mouse model to more effectively model the wide range of clinical, virologic, and immune phenotypes present upon West Nile virus infection in humans.