Dantoft Widad, Martínez-Vicente Pablo, Jafali James, Pérez-Martínez Lara, Martin Kim, Kotzamanis Konstantinos, Craigon Marie, Auer Manfred, Young Neil T, Walsh Paul, Marchant Arnaud, Angulo Ana, Forster Thorsten, Ghazal Peter
Division of Infection and Pathway Medicine, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Immunology Unit, Department of Biomedical Sciences, Medical School, University of Barcelona, Barcelona, Spain.
Front Immunol. 2017 Sep 25;8:1146. doi: 10.3389/fimmu.2017.01146. eCollection 2017.
Neonates and especially premature infants are highly susceptible to infection but still can have a remarkable resilience that is poorly understood. The view that neonates have an incomplete or deficient immune system is changing. Human neonatal studies are challenging, and elucidating host protective responses and underlying cognate pathway biology, in the context of viral infection in early life, remains to be fully explored. In both resource rich and poor settings, human cytomegalovirus (HCMV) is the most common cause of congenital infection. By using unbiased systems analyses of transcriptomic resources for HCMV neonatal infection, we find the systemic response of a preterm congenital HCMV infection, involves a focused IFN regulatory response associated with dendritic cells. Further analysis of transcriptional-programming of neonatal dendritic cells in response to HCMV infection in culture revealed an early dominant IFN-chemokine regulatory subnetworks, and at later times the plasticity of pathways implicated in cell-cycle control and lipid metabolism. Further, we identify previously unknown suppressed networks associated with infection, including a select group of GPCRs. Functional siRNA viral growth screen targeting 516-GPCRs and subsequent validation identified novel GPCR-dependent antiviral (ADORA1) and proviral (GPR146, RGS16, PTAFR, SCTR, GPR84, GPR85, NMUR2, FZ10, RDS, CCL17, and SORT1) roles. By contrast a gene family cluster of protocadherins is significantly differentially induced in neonatal cells, suggestive of possible immunomodulatory roles. Unexpectedly, programming responses of adult and neonatal dendritic cells, upon HCMV infection, demonstrated comparable quantitative and qualitative responses showing that functionally, neonatal dendritic cell are not overly compromised. However, a delay in responses of neonatal cells for IFN subnetworks in comparison with adult-derived cells are notable, suggestive of subtle plasticity differences. These findings support a set-point control mechanism rather than immaturity for explaining not only neonatal susceptibility but also resilience to infection. In summary, our findings show that neonatal HCMV infection leads to a highly plastic and functional robust programming of dendritic cells and . In comparison with adults, a minimal number of subtle quantitative and temporal differences may contribute to variability in host susceptibility and resilience, in a context dependent manner.
新生儿尤其是早产儿极易受到感染，但他们仍具有很强的恢复力，而这种恢复力目前还 poorly understood 。认为新生儿免疫系统不完整或有缺陷的观点正在改变。人类新生儿研究具有挑战性，在生命早期病毒感染的背景下，阐明宿主的保护反应及相关同源通路生物学仍有待充分探索。在资源丰富和匮乏的环境中，人巨细胞病毒（HCMV）都是先天性感染最常见的原因。通过对HCMV新生儿感染的转录组资源进行无偏系统分析，我们发现早产先天性HCMV感染的全身反应涉及与树突状细胞相关的集中的IFN调节反应。对培养中HCMV感染的新生儿树突状细胞转录编程的进一步分析揭示了早期占主导地位的IFN-趋化因子调节子网，以及后期与细胞周期控制和脂质代谢相关通路的可塑性。此外，我们鉴定出了与感染相关的先前未知的受抑制网络，包括一组特定的GPCR。针对516种GPCR的功能性siRNA病毒生长筛选及后续验证确定了新型GPCR依赖性抗病毒（ADORA1）和促病毒（GPR146、RGS16、PTAFR、SCTR、GPR84、GPR85、NMUR2、FZ10、RDS、CCL17和SORT1）作用。相比之下，原钙黏蛋白基因家族簇在新生儿细胞中显著差异诱导，提示可能具有免疫调节作用。出乎意料的是，HCMV感染后成人和新生儿树突状细胞的编程反应显示出相当的定量和定性反应，表明在功能上，新生儿树突状细胞并未过度受损。然而，与成人来源的细胞相比，新生儿细胞对IFN子网的反应存在延迟，这表明存在细微的可塑性差异。这些发现支持一种设定点控制机制，而非不成熟，来解释新生儿不仅对感染易感，而且具有恢复力。总之，我们的研究结果表明，新生儿HCMV感染导致树突状细胞高度可塑性且功能强大的编程，与成人相比，少量细微的定量和时间差异可能以上下文依赖的方式导致宿主易感性和恢复力的变化。
