The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events
The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events
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DOI：
10.1371/journal.ppat.1005286
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发表时间：
2015-12-01
期刊：
影响因子：
6.7
通讯作者：
Hogquist, Kristin A.
中科院分区：
文献类型：
--
作者：
Dunmire, Samantha K.;Grimm, Jennifer M.;Hogquist, Kristin A.
EB病毒（EBV）是一种人类疱疹病毒，可引起急性传染性单核细胞增多症，并与癌症和自身免疫性疾病有关。虽然已经进行了许多研究，检查成人原发感染后的急性疾病，但由于从该感染阶段收集样品的挑战，对EBV漫长的6周潜伏期期间的病毒学和免疫学事件知之甚少。我们在大学生中进行了一项前瞻性研究，特别强调在潜伏期内频繁筛查以捕获血液和口腔清洗样本。在这里，我们描述了在急性传染性单核细胞增多症症状发作前6周内的病毒传播和免疫反应。虽然推测病毒从传播时起就存在于口腔中，但我们直到症状发作前一周才在口腔洗液中检测到病毒基因组，此时病毒基因组以高拷贝数存在，表明初始病毒复制控制丧失。相比之下，使用灵敏的巢式PCR方法，我们在症状发生前约3周在血液中检测到低水平的病毒基因组。然而，血液中高水平的EBV仅在接近症状发作时观察到，与口腔中病毒检测增加同时发生或刚好发生。这些数据意味着B细胞是传染性单核细胞增多症之前口腔中病毒的主要储存库。血液中病毒基因组的早期存在，即使是低水平，也与症状发作前循环浆细胞样树突状细胞数量的显著减少相关，在整个恢复期都保持抑制状态。另一方面，自然杀伤细胞仅在症状发作后才扩增。同样，CD4+ Foxp3+调节性T细胞减少了两倍，但仅在症状发作后。我们在孵育期间没有观察到大量的病毒特异性CD8 T细胞扩增，尽管多克隆CD8活化与血液和口腔中的病毒基因组增加一致，可能是由于全身I型干扰素应答。这项研究首次描述了人类自然EBV感染潜伏期的事件，并提供了明确的数据，以制定病毒控制和疾病发病机制的理论。
Epstein-Barr virus (EBV) is a human herpesvirus that causes acute infectious mononucleosis and is associated with cancer and autoimmune disease. While many studies have been performed examining acute disease in adults following primary infection, little is known about the virological and immunological events during EBV's lengthy 6 week incubation period owing to the challenge of collecting samples from this stage of infection. We conducted a prospective study in college students with special emphasis on frequent screening to capture blood and oral wash samples during the incubation period. Here we describe the viral dissemination and immune response in the 6 weeks prior to onset of acute infectious mononucleosis symptoms. While virus is presumed to be present in the oral cavity from time of transmission, we did not detect viral genomes in the oral wash until one week before symptom onset, at which time viral genomes were present in high copy numbers, suggesting loss of initial viral replication control. In contrast, using a sensitive nested PCR method, we detected viral genomes at low levels in blood about 3 weeks before symptoms. However, high levels of EBV in the blood were only observed close to symptom onset-coincident with or just after increased viral detection in the oral cavity. These data imply that B cells are the major reservoir of virus in the oral cavity prior to infectious mononucleosis. The early presence of viral genomes in the blood, even at low levels, correlated with a striking decrease in the number of circulating plasmacytoid dendritic cells well before symptom onset, which remained depressed throughout convalescence. On the other hand, natural killer cells expanded only after symptom onset. Likewise, CD4+ Foxp3+ regulatory T cells decreased two fold, but only after symptom onset. We observed no substantial virus specific CD8 T cell expansion during the incubation period, although polyclonal CD8 activation was detected in concert with viral genomes increasing in the blood and oral cavity, possibly due to a systemic type I interferon response. This study provides the first description of events during the incubation period of natural EBV infection in humans and definitive data upon which to formulate theories of viral control and disease pathogenesis.