Hypoxia enhances antibody-dependent dengue virus infection.
Hypoxia enhances antibody-dependent dengue virus infection.
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DOI：
10.15252/embj.201695642
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发表时间：
2017-05-15
期刊：
影响因子：
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通讯作者：
Ooi EE
中科院分区：
文献类型：
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作者：
Gan ES;Cheong WF;Chan KR;Ong EZ;Chai X;Tan HC;Ghosh S;Wenk MR;Ooi EE
在尸检分析中发现登革病毒（DENV）在淋巴结、脾脏和肝脏等淋巴器官中复制。已知这些器官由于血管解剖结构而具有低氧水平（~0.5- 4.5%O2）。然而，生理上低水平的氧气如何通过缺氧诱导的免疫反应变化影响DENV感染仍然是未知的。在这里，我们发现适应3%O2的单核细胞对DENV感染的抗体依赖性增强表现出更大的易感性。低氧水平诱导片段可结晶γ受体IIA（FcγRIIA）的HIF 1 α依赖性上调以及膜醚脂质浓度的HIF 1 α非依赖性改变。增加的FcγRIIA表达与改变的膜组成协同作用，可能通过增加膜流动性来增加DENV免疫复合物的摄取以增强感染。因此，我们的研究结果表明，与继发性DENV感染相关的病毒负荷增加是抗体依赖性的，但缺氧诱导的，并表明靶向缺氧诱导因子用于抗登革热治疗的作用。
Dengue virus (DENV) has been found to replicate in lymphoid organs such as the lymph nodes, spleen, and liver in post‐mortem analysis. These organs are known to have low oxygen levels (~0.5–4.5% O2) due to the vascular anatomy. However, how physiologically low levels of oxygen affect DENV infection via hypoxia‐induced changes in the immune response remains unknown. Here, we show that monocytes adapted to 3% O2 show greater susceptibility to antibody‐dependent enhancement of DENV infection. Low oxygen level induces HIF1α‐dependent upregulation of fragment crystallizable gamma receptor IIA (FcγRIIA) as well as HIF1α‐independent alterations in membrane ether lipid concentrations. The increased FcγRIIA expression operates synergistically with altered membrane composition, possibly through increase membrane fluidity, to increase uptake of DENV immune complexes for enhanced infection. Our findings thus indicate that the increased viral burden associated with secondary DENV infection is antibody‐dependent but hypoxia‐induced and suggest a role for targeting hypoxia‐induced factors for anti‐dengue therapy.