Congenital cytomegalovirus infection: identification of factors determining vertical transmission and clinical outcome of infected neonates

新生儿先天性巨细胞病毒(CMV)感染是导致永久性残疾的最常见的感染原因。目前，尚无既定的治疗方法可用于预防新生儿巨细胞病毒病。尽管被认为是一个全球性的临床问题，但决定病毒从母亲向胎儿垂直传播的产前因素仍然未知。此外，目前尚不清楚为什么大多数感染的新生儿仍然没有症状，而一些新生儿表现出中度或严重的疾病症状。在此，我们旨在调查可能增加产前CMV感染风险和新生儿CMV疾病严重程度的因素。利用从王子队列(服务项目S1)获得的人类样本，结合先天性CMV感染的小鼠模型，我们将确定产前挑战、母子抗CMV T细胞反应和病毒致病因素的作用。使用已建立的CMV小鼠模型，我们将阐明母亲的压力和怀孕期间的药物摄入--这些挑战可能是可以避免的--是否会使后代更容易发展成严重的早期CMV感染过程。对母体和新生儿抗原特异性T细胞的深入研究将确定它们在生命早期控制巨细胞病毒感染中的作用。最后，在宿主免疫反应的同时，我们将调查病原体本身，以确定决定其致病性和垂直传播可能性的病毒遗传因素。总之，我们打算在生殖、儿科、免疫学和病毒学的交界处回答CMV感染生物学的悬而未决的问题，这些问题可能为新的诊断或治疗方法奠定基础。

Congenital infection with cytomegalovirus (CMV) in newborns is the most frequent infectious cause of permanent disabilities. Currently, there is no established therapy available to prevent neonatal CMV disease. Although recognized as a global clinical problem, prenatal factors determining vertical virus transmission from mother to foetus are still unknown. Moreover, it remains poorly understood why most infected neonates remain asymptomatic whereas some show moderate or severe disease symptoms.Here, we aim to investigate factors that could increase the risk of prenatal CMV-infection and severity of neonatal CMV disease. Utilizing human samples obtained from the PRINCE cohort (Service Project S1) in combination with a mouse model for congenital CMV infection we will determine the role of prenatal challenges, the anti-CMV T cell response of mother and child, and viral pathogenicity factors. Using an established CMV mouse model, we will clarify if maternal stress and medication intake during pregnancy - challenges which are potentially avoidable – render the offspring more prone to develop a severe course of early life CMV infection. In depth characterisation of maternal and neonatal antigen-specific T cells will define their role in control of CMV infection during the early life phase. Finally, in parallel to the host immune response we will investigate the pathogen itself to identify viral genetic factors that determine its pathogenicity and likelihood of vertical transmission. In summary, we intend to answer pending questions of CMV infection biology at the interface of reproduction, paediatrics, immunology, and virology that could lay the basis for new diagnostic or therapeutic approaches.