Jiang Na, Wu Jing, He Yating, Zhang Rui, Ji Mengmeng, Zhu Linjing, Cui Shengwei, You Qiao, Cai Yurong, Liu Bingxin, Lyu Ruining, Chen Yuxin, Zhu Jin, Wu Zhiwei
Center for Public Health Research, Medical School, Nanjing University, Nanjing, China.
Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
EMBO Rep. 2025 Aug 11. doi: 10.1038/s44319-025-00541-2.
Hemorrhage is a major pathological manifestation of certain viral infections, such as severe fever with thrombocytopenia syndrome (SFTS), Ebola, Crimean-Congo hemorrhagic fever and Dengue. SFTS is an emerging viral hemorrhagic fever caused by the SFTS virus (SFTSV). Hemorrhage and angiogenesis dysfunction are key manifestations of SFTSV infection but the underlying mechanisms remain unclear. Here, we demonstrate that SFTSV infection increases soluble vascular endothelial growth factor-receptor 1 (sVEGFR1) secretion from monocytes/macrophages. Increased sVEGFR1 in the serum of SFTS patients is positively correlated with disease severity. Moreover, we show that SFTSV induces sVEGFR1 upregulation via early growth response gene 1 (EGR1), of which VEGFR1 is a downstream target. Serum from SFTS patients containing high levels of sVEGFR1 inhibit angiogenesis, which can be reversed by removal of sVEGFR1. Treatment of SFTSV-infected animals with sVEGFR1 neutralizing antibodies improves angiogenesis and prevents blood vessel leaks in vivo. In conclusion, we show that SFTSV infection induces sVEGFR1 secretion through EGR1 upregulation, thereby contributing to hemorrhage.
出血是某些病毒感染的主要病理表现，如严重发热伴血小板减少综合征（SFTS）、埃博拉病毒、克里米亚-刚果出血热和登革热。SFTS是一种由SFTS病毒（SFTSV）引起的新型病毒性出血热。出血和血管生成功能障碍是SFTSV感染的关键表现，但其潜在机制尚不清楚。在此，我们证明SFTSV感染会增加单核细胞/巨噬细胞可溶性血管内皮生长因子受体1（sVEGFR1）的分泌。SFTS患者血清中sVEGFR1的增加与疾病严重程度呈正相关。此外，我们表明SFTSV通过早期生长反应基因1（EGR1）诱导sVEGFR1上调，其中VEGFR1是其下游靶点。含有高水平sVEGFR1的SFTS患者血清会抑制血管生成，去除sVEGFR1后这种抑制作用可被逆转。用sVEGFR1中和抗体治疗SFTSV感染的动物可改善血管生成并防止体内血管渗漏。总之，我们表明SFTSV感染通过上调EGR1诱导sVEGFR1分泌，从而导致出血。
