Crimean-Congo haemorrhagic fever virus (CCHFV) causes human disease ranging from subclinical to a fatal haemorrhagic syndrome. Determinants of CCHF pathogenesis are largely unknown and animal models that recapitulate human disease are limited. A recently described mouse model uses a monoclonal antibody (mAb 5A3) targeting the interferon (IFN) alpha/beta receptor to suppress type I IFN responses, making animals transiently susceptible to infection. To advance utility of this model, we investigated effects of challenge route, timing of 5A3 delivery, mouse sex and age, and virus strain on clinical course and outcome. C57BL/6J mice received mAb 5A3 -1, 0, or -1/+1 days post-infection (dpi). Subsets were challenged with CCHFV strain Turkey04 or IbAr10200 subcutaneously or intraperitoneally, and serially euthanized 3- and 7-dpi, when meeting euthanasia criteria or at study completion (14 dpi). CCHFV-IbAr10200-infected mice almost uniformly succumbed to infection, whereas CCHFV-Turkey04-infected mice transiently lost weight but survived. These results were consistent regardless of mAb timing or route of challenge. Viral replication and dissemination were comparable between the two strains at 3 dpi. However, in the plasma and livers of non-survivors, expression of proinflammatory cytokines/chemokines that correspond with macrophage activation and recruitment were significantly elevated. Lethal disease was also associated with elevated levels of macrophage activation marker CD163 in plasma. Further, mouse macrophages were more permissive to IbAr1200 infection in vitro, suggesting tropism for these cells may influence pathogenesis. Our data suggest that early inflammation may be a critical determinant of CCHF outcome and therapeutics to control inflammation may be worthwhile targets for future investigation.

中文翻译：

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与单核细胞/巨噬细胞活化和募集相关的炎症与克里米亚-刚果出血热小鼠模型中的致死结果相对应1。


克里米亚-刚果出血热病毒 （CCHFV） 可引起从亚临床到致命性出血综合征的人类疾病。CCHF 发病机制的决定因素在很大程度上是未知的，概括人类疾病的动物模型是有限的。最近描述的一种小鼠模型使用靶向干扰素 （IFN） α/β 受体的单克隆抗体 （mAb 5A3） 来抑制 I 型 IFN 反应，使动物暂时易受感染。为了提高该模型的实用性，我们调查了激发途径、 5A3 递送时间、小鼠性别和年龄以及病毒株对临床病程和结果的影响。C57BL/6J 小鼠在感染后 （dpi） 接受 mAb 5A3 -1、0 或 -1/+1 天。当满足安乐死标准或研究完成时 （14 dpi），用 CCHFV 菌株 Turkey04 或 IbAr10200 皮下或腹膜内攻击亚群，并连续安乐死 3 和 7 dpi。CCHFV-IbAr10200 感染的小鼠几乎一致地死于感染，而 CCHFV-Turkey04 感染的小鼠体重短暂减轻但存活下来。无论 mAb 时间或攻击途径如何，这些结果都是一致的。两种菌株之间的病毒复制和传播在 3 dpi 时相当。然而，在非幸存者的血浆和肝脏中，与巨噬细胞活化和募集相对应的促炎细胞因子/趋化因子的表达显著升高。致死性疾病也与血浆中巨噬细胞活化标志物 CD163 水平升高有关。此外，小鼠巨噬细胞在体外对 IbAr1200 感染更宽容，表明这些细胞的趋向性可能影响发病机制。 我们的数据表明，早期炎症可能是 CCHF 结果的关键决定因素，控制炎症的疗法可能是未来研究的有价值的目标。