RNA Viruses Section, Laboratory of Infectious Diseases (LID), NIAID, NIH, Bethesda, Maryland, USA
Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
J Virol. 2019 Oct 29;93(22). doi: 10.1128/JVI.01216-19. Print 2019 Nov 15.
Respiratory syncytial virus (RSV) infects and causes disease in infants and reinfects with reduced disease throughout life without significant antigenic change. In contrast, reinfection by influenza A virus (IAV) largely requires antigenic change. The adaptive immune response depends on antigen presentation by dendritic cells (DC), which may be too immature in young infants to induce a fully protective immune response against RSV reinfections. We therefore compared the ability of RSV and IAV to activate primary human cord blood (CB) and adult blood (AB) myeloid DC (mDC). While RSV and IAV infected with similar efficiencies, RSV poorly induced maturation and cytokine production in CB and AB mDC. This difference between RSV and IAV was more profound in CB mDC. While IAV activated CB mDC to some extent, RSV did not induce CB mDC to increase the maturation markers CD38 and CD86 or CCR7, which directs DC migration to lymphatic tissue. Low CCR7 surface expression was associated with high expression of CCR5, which keeps DC in inflamed peripheral tissues. To evaluate a possible inhibition by RSV, we subjected RSV-inoculated AB mDC to secondary IAV inoculation. While RSV-inoculated AB mDC responded to secondary IAV inoculation by efficiently upregulating activation markers and cytokine production, IAV-induced CCR5 downregulation was slightly inhibited in cells exhibiting robust RSV infection. Thus, suboptimal stimulation and weak and mostly reversible inhibition seem to be responsible for inefficient mDC activation by RSV. The inefficient mDC stimulation and immunological immaturity in young infants may contribute to reduced immune responses and incomplete protection against RSV reinfection. Respiratory syncytial virus (RSV) causes disease early in life and can reinfect symptomatically throughout life without undergoing significant antigenic change. In contrast, reinfection by influenza A virus (IAV) requires antigenic change. The adaptive immune response depends on antigen presentation by dendritic cells (DC). We used myeloid DC (mDC) from cord blood and adult blood donors to evaluate whether immunological immaturity contributes to the inability to mount a fully protective immune response to RSV. While IAV induced some activation and chemokine receptor switching in cord blood mDC, RSV did not. This appeared to be due to a lack of activation and a weak and mostly reversible inhibition of DC functions. Both viruses induced a stronger activation of mDC from adults than mDC from cord blood. Thus, inefficient stimulation of mDC by RSV and immunological immaturity may contribute to reduced immune responses and increased susceptibility to RSV disease and reinfection in young infants.
呼吸道合胞病毒（RSV）感染并导致婴儿患病，并在一生中再次感染，疾病减轻，而无需发生重大抗原变化。相比之下，甲型流感病毒（IAV）的再感染在很大程度上需要抗原变化。适应性免疫反应取决于树突状细胞（DC）的抗原呈递，而年轻婴儿的 DC 可能过于不成熟，无法对 RSV 再感染产生完全保护性的免疫反应。因此，我们比较了 RSV 和 IAV 激活原代人脐带血（CB）和成人血（AB）髓样 DC（mDC）的能力。虽然 RSV 和 IAV 的感染效率相似，但 RSV 对 CB 和 AB mDC 的成熟和细胞因子产生诱导作用较差。这种 RSV 和 IAV 之间的差异在 CB mDC 中更为明显。虽然 IAV 在某种程度上激活了 CB mDC，但 RSV 并未诱导 CB mDC增加成熟标志物 CD38 和 CD86 或 CCR7，而 CCR7 指导 DC 向淋巴组织迁移。低 CCR7 表面表达与高 CCR5 表达相关，CCR5 将 DC 保留在发炎的外周组织中。为了评估 RSV 可能的抑制作用，我们将 RSV 接种的 AB mDC 进行二次 IAV 接种。虽然 RSV 接种的 AB mDC 对二次 IAV 接种的反应是通过有效地上调激活标志物和细胞因子产生，但在表现出强烈 RSV 感染的细胞中，IAV 诱导的 CCR5 下调受到轻微抑制。因此，低效率的刺激和弱且大多可逆的抑制似乎是 RSV 引起 mDC 激活效率低下的原因。婴儿期 mDC 刺激不足和免疫不成熟可能导致针对 RSV 再感染的免疫反应减弱和不完全保护。呼吸道合胞病毒（RSV）在生命早期引起疾病，并可在无症状情况下终生再次感染，而无需发生重大抗原变化。相比之下，甲型流感病毒（IAV）的再感染需要抗原变化。适应性免疫反应取决于树突状细胞（DC）的抗原呈递。我们使用来自脐带血和成人血液供体的髓样 DC（mDC）来评估免疫不成熟是否导致无法对 RSV 产生完全保护性的免疫反应。虽然 IAV 诱导了脐带血 mDC 的一些激活和趋化因子受体转换，但 RSV 没有。这似乎是由于缺乏激活以及 DC 功能的弱且大多可逆的抑制。两种病毒都比来自脐带血的 mDC 诱导了更强的成人 mDC 激活。因此，RSV 对 mDC 的低效刺激和免疫不成熟可能导致婴儿期对 RSV 疾病和再感染的免疫反应减弱和易感性增加。
