Cell Type Specificity and Host Genetic Polymorphisms Influence Antibody-Dependent Enhancement of Dengue Virus Infection
Cell Type Specificity and Host Genetic Polymorphisms Influence Antibody-Dependent Enhancement of Dengue Virus Infection
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DOI：
10.1128/jvi.00220-10
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发表时间：
2011-02-01
影响因子：
5.4
通讯作者：
Marovich, Mary A.
中科院分区：
文献类型：
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作者：
Boonnak, Kobporn;Dambach, Kaitlyn M.;Marovich, Mary A.
抗体依赖性增强（ADE）与严重的，通常是继发性的登革热病毒（DV）感染有关。先前存在的异型抗体，通过其Fc- γ受体（Fc γ R）相互作用，可能通过增强靶细胞感染来增加疾病的严重程度。大量的受感染靶细胞可能导致较高的病毒血症和过量的细胞因子水平，通常在严重疾病中观察到。单核细胞、巨噬细胞以及未成熟和成熟的树突状细胞（DC）被认为是DV的主要细胞靶点。多个供体的单采可以分离自体原代髓系靶细胞类型，以便在直接感染（无抗体）或ADE条件下（有抗体）对感染率、病毒输出量和细胞因子产生进行正面比较。除未成熟DC外，所有被研究的细胞类型都支持ADE。所有经历ADE的细胞都以增强滴度分泌促炎细胞因子（白细胞介素-6 [IL-6]和肿瘤坏死因子α [tnf - α]），但其他相关蛋白（α / β干扰素[ifn - α / β]和IL-10）的细胞类型特异性模式不同。巨噬细胞产生由ADE调节的I型干扰素（ifn - α / β）。成熟DC主要分泌ifn - β。有趣的是，只有单核细胞分泌IL-10，并且仅在抗体增强感染时。尽管供体之间单核细胞的ADE感染率非常一致（10 - 15%），但IL-10蛋白水平根据先前描述的IL-10启动子区域的调节性单核苷酸多态性（snp）而变化。纯合子的GCC单倍型与高水平的IL-10分泌相关，而ACC和ATA单倍型分别产生中低水平的IL-10。我们的数据表明，ADE效应是细胞类型特异性的，受宿主遗传的影响，并且取决于相对感染率，可能进一步导致DV发病机制的复杂性。
Antibody-dependent enhancement (ADE) is implicated in severe, usually secondary, dengue virus (DV) infections. Preexisting heterotypic antibodies, via their Fc-gamma receptor (Fc gamma R) interactions, may increase disease severity through enhanced target cell infection. Greater numbers of infected target cells may contribute to higher viremia and excess cytokine levels often observed in severe disease. Monocytes, macrophages, and immature and mature dendritic cells (DC) are considered major cellular targets of DV. Apheresis of multiple donors allowed isolation of autologous primary myeloid target cell types for head-to-head comparison of infection rates, viral output, and cytokine production under direct infection (without antibody) or ADE conditions (with antibody). All studied cell types except immature DC supported ADE. All cells undergoing ADE secreted proinflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF-alpha]) at enhancement titers, but distinct cell-type-specific patterns were observed for other relevant proteins (alpha/beta interferon [IFN-alpha/beta] and IL-10). Macrophages produced type I interferons (IFN-alpha/beta) that were modulated by ADE. Mature DC mainly secreted IFN-beta. Interestingly, only monocytes secreted IL-10, and only upon antibody-enhanced infection. While ADE infection rates were remarkably consistent in monocytes (10 to 15%) across donors, IL-10 protein levels varied according to previously described regulatory single nucleotide polymorphisms (SNPs) in the IL-10 promoter region. The homozygous GCC haplotype was associated with high-level IL-10 secretion, while the ACC and ATA haplotypes produced intermediate and low levels of IL-10, respectively. Our data suggest that ADE effects are cell type specific, are influenced by host genetics, and, depending on relative infection rates, may further contribute to the complexity of DV pathogenesis.