4.5 Article

Arenaviral infection causes bleeding in mice due to reduced serotonin release from platelets

期刊

SCIENCE SIGNALING
卷 15, 期 722, 页码 -

出版社

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.abb0384

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资金

  1. NIH, USA [HL42846, HL117722, HL135294, AI40696]
  2. European Research Council [250219, 281648, 725038]
  3. Italian Ministry of Health [GR-2008-1135776, GR-2008-1138756, RF-201102346754, GR-2011-02347925, RF-2013-02355209]
  4. Italian Association for Cancer Research [18468, 22737, 22820, 15350, 19891, 9965]
  5. Lombardy Foundation for Biomedical Research [2015-0010]
  6. European Molecular Biology Organization Young Investigator Program
  7. Giovanni Armenise-Harvard Foundation
  8. MERU Foundation, Italy, at the MERU-Roon Research Center for Vascular Biology of the Scripps Research Institute
  9. European Research Council (ERC) [250219, 725038] Funding Source: European Research Council (ERC)

向作者/读者索取更多资源

In viral hemorrhagic fevers, the increase in IFN-I reduces the expression of certain genes involved in lipid biosynthesis and platelet formation, leading to reduced platelet count and defects in the arachidonic acid synthetic pathway. This results in decreased serotonin release from platelets and can cause bleeding when the serotonin level falls below a critical threshold. Transfusion of normal platelets can help control hemorrhage by increasing serotonin release.
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 (cyclooxygenase 1 and thromboxane A synthase 1) and a thrombopoietic transcription factor (Nf-e2). 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 6-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.

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