Department of Molecular Medicine, MERU-Roon Research Center for Vascular Biology, Scripps Research, La Jolla, CA 92037, USA.
Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Sci Signal. 2022 Feb 22;15(722):eabb0384. doi: 10.1126/scisignal.abb0384.
Bleeding correlates with disease severity in viral hemorrhagic fevers. We found that the increase in type I interferon (IFN-I) in mice caused by infection with the Armstrong strain of lymphocytic choriomeningitis virus (LCMV; an arenavirus) reduced the megakaryocytic expression of genes encoding enzymes involved in lipid biosynthesis ( and ) and a thrombopoietic transcription factor (). The decreased expression of these genes was associated with reduced numbers of circulating platelets and defects in the arachidonic acid synthetic pathway, thereby suppressing serotonin release from δ-granules in platelets. Bleeding resulted when severe thrombocytopenia and altered platelet function reduced the amount of platelet-derived serotonin below a critical threshold. Bleeding was facilitated by the absence of the activity of the kinase Lyn or the administration of aspirin, an inhibitor of arachidonic acid synthesis. Mouse platelets were not directly affected by IFN-I because they lack the receptor for the cytokine (IFNAR1), suggesting that transfusion of normal platelets into LCMV-infected mice could increase the amount of platelet-released serotonin and help to control hemorrhage.
出血与病毒性出血热的疾病严重程度相关。我们发现，感染淋巴细胞性脉络丛脑膜炎病毒（LCMV；沙粒病毒）的 Armstrong 株会导致小鼠体内 I 型干扰素（IFN-I）增加，从而减少编码参与脂质生物合成的酶（和）和一个促血小板生成转录因子（）的巨核细胞表达。这些基因表达的减少与循环血小板数量减少和花生四烯酸合成途径缺陷有关，从而抑制血小板δ-颗粒中 5-羟色胺的释放。当严重的血小板减少症和血小板功能改变使血小板衍生的 5-羟色胺释放量低于临界阈值时，就会导致出血。在缺乏激酶 Lyn 活性或给予阿司匹林（一种花生四烯酸合成抑制剂）的情况下，出血会得到促进。由于缺乏细胞因子（IFNAR1）的受体，因此小鼠血小板不受 IFN-I 的直接影响，这表明将正常血小板输注到 LCMV 感染的小鼠中可以增加血小板释放的 5-羟色胺的量，并有助于控制出血。
