Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
Center for International Health Research, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
PLoS Negl Trop Dis. 2018 Dec 17;12(12):e0006975. doi: 10.1371/journal.pntd.0006975. eCollection 2018 Dec.
Hyperendemic circulation of all four types of dengue virus (DENV-1-4) has expanded globally, fueling concern for increased incidence of severe dengue. While the majority of DENV infections are subclinical, epidemiologic studies suggest that type-cross-reactive immunity can influence disease outcome in subsequent infections. The mechanisms controlling these differential clinical outcomes remain poorly defined.
METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were collected from a cohort of school-aged Thai children who subsequently experienced a subclinical DENV infection or developed dengue illness. PBMC collected prior to infection were stimulated in vitro with DENV and the secretion of 30 cytokines was measured using a multiplexed, bead-based array. Significant differences were found in cytokine production based on both the type of DENV used for stimulation and the occurrence of clinical illness. Secretion of IL-15 and MCP-1 was significantly higher by PBMC of subjects who later developed symptomatic DENV infection. In addition, IL-6 was produced by PBMC from all subjects who subsequently developed symptomatic infection, versus 59% of subjects who had subclinical infection. Secretion of IL-12, IL-2R, MIP-1α, RANTES, GM-CSF, and TNFα was significantly lower by PBMC from subjects with symptomatic infection.
CONCLUSIONS/SIGNIFICANCE: These data demonstrate significant differences in pre-existing immune responses to DENV associated with the clinical outcome of subsequent infection. The finding of higher levels of some cytokines in subjects with symptomatic infection and higher levels of other cytokines in subjects with subclinical infection supports the existence of both protective and pathologic immune profiles. Clinical-immunological correlations identified in the context of natural DENV infection may be useful for evaluating immune responses to dengue vaccines.
所有四种登革热病毒（DENV-1-4）的高度流行循环在全球范围内扩大，引发了对严重登革热发病率增加的担忧。虽然大多数登革热感染是无症状的，但流行病学研究表明，型交叉反应性免疫可以影响随后感染的疾病结局。控制这些不同临床结果的机制仍未得到很好的定义。
方法/主要发现：从一组随后经历无症状登革热感染或出现登革热疾病的泰国学龄儿童队列中采集血样。在感染前采集的 PBMC 用 DENV 进行体外刺激，并使用基于多重微珠的阵列测量 30 种细胞因子的分泌。基于用于刺激的 DENV 的类型和临床疾病的发生，发现细胞因子产生存在显著差异。随后发展为有症状登革热感染的受试者的 PBMC 分泌的 IL-15 和 MCP-1 明显更高。此外，所有随后发展为有症状感染的受试者的 PBMC 均产生了 IL-6，而仅有 59%的无症状感染受试者产生了 IL-6。来自有症状感染受试者的 PBMC 分泌的 IL-12、IL-2R、MIP-1α、RANTES、GM-CSF 和 TNFα 明显较低。
结论/意义：这些数据表明，与随后感染的临床结局相关，预先存在的针对 DENV 的免疫反应存在显著差异。在有症状感染受试者中某些细胞因子水平较高，而在无症状感染受试者中其他细胞因子水平较高的发现支持存在保护性和病理性免疫特征。在自然登革热感染背景下确定的临床免疫学相关性可能有助于评估登革热疫苗的免疫反应。
