Role of dendritic cells in antibody-dependent enhancement of dengue virus infection
Role of dendritic cells in antibody-dependent enhancement of dengue virus infection
复制标题
DOI：
10.1128/jvi.02484-07
复制
发表时间：
2008-04-01
影响因子：
5.4
通讯作者：
Marovich, Mary A.
中科院分区：
文献类型：
--
作者：
Boonnak, Kobporn;Slike, Bonnie M.;Marovich, Mary A.
登革病毒（DV）由四种不同的血清型（DV1至DV4）组成，每年导致5000万至1亿例感染。感染后会产生持久的同型免疫，但可能会使后续的异型感染更为严重，这种风险部分是由免疫反应本身造成的。抗体依赖增强作用（ADE）是一种在体外得到充分描述的过程，在流行病学上与复杂的登革病毒感染有关，尤其是在东南亚。在此，我们首次报道了在原代人树突状细胞（DC，登革病毒感染的早期靶细胞）以及具有Fc受体的人细胞系中存在ADE现象。我们发现ADE与DC - SIGN（DC特异性细胞间黏附分子 - 3 - 结合非整合素）的表面表达呈负相关，并且需要Fcγ受体IIa（FcγRIIa）。成熟的DC表现出ADE，而未成熟的DC虽然表达更高水平的DC - SIGN且FcγRIIa水平相近，但未出现ADE。ADE导致成熟DC内新的登革病毒蛋白质合成增加、病毒RNA产生和释放增加以及上清液的传染性增强。有趣的是，在登革热患者血清存在的情况下，会释放肿瘤坏死因子α和白细胞介素 - 6（IL - 6），但一般仅在增强滴度时释放，这表明ADE存在一个信号传导成分。用单克隆抗体抑制FcγRIIa可消除ADE及其相关的下游效应。登革病毒在成熟DC中进入途径（FcγRIIa或DC - SIGN）的多样性拓宽了靶标选择，并提示了DC对严重登革病毒感染发病机制产生影响的其他方式。研究登革病毒感染的细胞靶标及其对ADE的易感性将有助于我们理解复杂的疾病，并对疫苗开发领域有所贡献。
Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million infections annually. Durable homotypic immunity follows infection but may predispose to severe subsequent heterotypic infections, a risk conferred in part by the immune response itself. Antibody-dependent enhancement (ADE), a process best described in vitro, is epidemiologically linked to complicated DV infections, especially in Southeast Asia. Here we report for the first time the ADE phenomenon in primary human dendritic cells (DC), early targets of DV infection, and human cell lines bearing Fc receptors. We show that ADE is inversely correlated with surface expression of DC-SIGN (DC-specific intercellular adhesion molecule-3-grabbing nonintegrin) and requires Fc gamma receptor IIa (Fc gamma RIIa). Mature DC exhibited ADE, whereas immature DC, expressing higher levels of DC-SIGN and similar Fc gamma RIIa levels, did not undergo ADE. ADE results in increased intracellular de novo DV protein synthesis, increased viral RNA production and release, and increased infectivity of the supernatants in mature DC. Interestingly, tumor necrosis factor alpha and interleukin-6 (IL-6), but not IL-10 and gamma interferon, were released in the presence of dengue patient sera but generally only at enhancement titers, suggesting a signaling component of ADE. Fc gamma RIIa inhibition with monoclonal antibodies abrogated ADE and associated downstream consequences. DV versatility in entry routes (Fc gamma RIIa or DC-SIGN) in mature DC broadens target options and suggests additional ways for DC to contribute to the pathogenesis of severe DV infection. Studying the cellular targets of DV infection and their susceptibility to ADE will aid our understanding of complex disease and contribute to the field of vaccine development.