由克里米亚-刚果出血热病毒（CCHFV）引起的克里米亚-刚果出血热（CCHF）是世界卫生组织优先进行紧急研究的流行病紧急公共卫生事件之一。克里米亚-刚果出血热病毒感染后宿主反应的轨迹是多方面的，尚不清楚。在此，我们利用全基因组血液转录组学分析、先进的系统生物学分析、时间相关的免疫病理变化以及特定背景下的逐渐进展和感染后基因组规模代谢模型（GSMM），报告了CCHFV感染后病理发展的时间谱。维甲酸诱导基因I样/核苷酸结合寡聚化领域样受体和肿瘤坏死因子信号传导之间的相互作用主导了抗病毒免疫反应的轨迹。在急性CCHFV感染期间，胞内代谢通量重组向氨基酸代谢转变和向氧化磷酸化和脂肪酸氧化的代谢偏移决定了致病性。与未感染的健康对照组和疾病严重程度组之间相比，CCHFV感染期间三羧酸循环的上调表明能量需求和细胞应激增加。糖酵解和丙酮酸代谢的上调通过与感染的严重程度相关的替代途径加速能量生成。在恢复期的代谢过程下调，通过血液细胞转录组学和单细胞类型蛋白质组学对五种免疫细胞（CD4+和CD8+ T细胞、CD14+单核细胞、B细胞和NK细胞）的研究，潜在地导致了由于急性期间的高活性引发的代谢重塑，从而出现了病毒后疲劳综合征。

Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection. The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.