Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes acute, subacute, and chronic human arthritogenic diseases and, in rare instances, can lead to neurological complications and death. Here, we combined epidemiological, virological, histopathological, cytokine, molecular dynamics, metabolomic, proteomic, and genomic analyses to investigate viral and host factors that contribute to chikungunya-associated (CHIK) death. Our results indicate that CHIK deaths are associated with multi-organ infection, central nervous system damage, and elevated serum levels of pro-inflammatory cytokines and chemokines compared with survivors. The histopathologic, metabolite, and proteomic signatures of CHIK deaths reveal hemodynamic disorders and dysregulated immune responses. The CHIKV East-Central-South-African lineage infecting our study population causes both fatal and survival cases. Additionally, CHIKV infection impairs the integrity of the blood-brain barrier, as evidenced by an increase in permeability and altered tight junction protein expression. Overall, our findings improve the understanding of CHIK pathophysiology and the causes of fatal infections.

基孔肯雅病毒 (CHIKV) 是一种蚊媒甲病毒，可引起急性、亚急性和慢性人类关节炎疾病，在极少数情况下，可导致神经并发症和死亡。在这里，我们结合流行病学、病毒学、组织病理学、细胞因子、分子动力学、代谢组学、蛋白质组学和基因组分析来研究导致基孔肯雅热相关（CHIK）死亡的病毒和宿主因素。我们的结果表明，与幸存者相比，CHIK 死亡与多器官感染、中枢神经系统损伤以及促炎细胞因子和趋化因子血清水平升高有关。 CHIK 死亡的组织病理学、代谢物和蛋白质组学特征揭示了血流动力学紊乱和免疫反应失调。感染我们研究人群的东非中南部 CHIKV 谱系导致死亡和存活病例。此外，CHIKV 感染会损害血脑屏障的完整性，通透性增加和紧密连接蛋白表达改变就证明了这一点。总体而言，我们的研究结果提高了对 CHIK 病理生理学和致命感染原因的理解。