|
Supervised by: Francesco Colucci (fc287@cam.ac.uk) & Norman Shreeve (ns665@cam.ac.uk) |
|
|
Project Title |
How does maternal tissue immunity regulate placentation and offspring health? |
|
Project description A woman dies of pregnancy complications every two minutes and one tenth of all diseases are due to something gone wrong around childbirth. This means that what happens in this critical time has far reaching ramifications on the health of both women and children. For example, birth weight is a predictor of cardiovascular and metabolic disease in adult life [1]. Foetuses exposed to maternal immune activation are predisposed to autism spectrum disorders [2]. Prenatal maternal infections shape offspring immunity [3]. Tissue lymphocytes are integral to health and disease and maternal immunity most likely also underlies the disorder of pregnancy pre-eclampsia, which often associates with poor foetal growth [4]. Tissue lymphocytes in the womb orchestrate key vascular adaptations in the uterus that facilitate placentation and foetal growth. The complex interactions between maternal immunity, placentation and offspring health have only just started to be revealed. A better understanding of how the maternal immune system contributes to pregnancy complications will help to improve women’s and offspring’s health. We have discovered that the immune pathway involving the NKG2A receptor is key for optimal foetal growth, placental gene expression and brain development [5]. The goals of this proposal are to: 1. determine gene networks downstream of the NKG2A pathway; We will determine differentially expressed genes (DEGs) in human uNK cells educated or not through NKG2A by bulk RNA-Seq. Functions and roles of selected DEGs will be determined in established cellular assays and in NK-specific Cre-loxP mutant mice. Readouts will be NK cell activity, trophoblast migration and differentiation; utero-placental flow, placental gene expression and foetal organ development. To determine underlying mechanisms of how prenatal perturbations of maternal immunity affect offspring’s health, we have established models of gestational cytomegalovirus and influenza infection, which do not infect the foetus but affect maternal immunity, altering birth weight (unpublished). We will analyse gene expression and epigenetic alterations in offspring brain and immune cells by using single cells by scRNA-Seq and ATAC-Seq. New artificial intelligence-supported tools (SmartKages®) will be used to quantitatively phenotyping offspring cognition and behaviour. Deep flow cytometry phenotyping and responses to pathogens will be measured to assess offspring immunity. Treatments to enhance maternal immunity and achieve optimal foetal development are unavailable. We will identify components of the NKG2A pathway. Our unpublished preliminary data show that one component of the pathway is targetable by existing drugs. Drugs may ultimately be administered to pregnant women genetically predisposed to underutilise the NKG2A pathway. These may boost uterine lymphocytes, stimulate blood flow to the placenta, promoting healthy gestation, optimal foetal growth and offspring health. The NKG2A pathway is also relevant to cancer immunotherapies and immunity to HIV and SARS-Cov-2. |
|
|
References
|
|
