Killer Timing:The Temporal Uterine Natural Killer Cell Differentiation Pathway and Implications for Female Reproductive Health

Natural killer (NK) cells are the predominant maternal uterine immune cell component, and they densely populate uterine mucosa to promote key changes in the post-ovulatory endometrium and in early pregnancy. It is broadly accepted that (a) immature, inactive endometrial NK (eNK) cells in the pre-ovulatory endometrium become activated and transition into decidual NK (dNK) cells in the secretory stage, peri-implantation endometrium, and continue to mature into early pregnancy; and (b) that secretory-stage and early pregnancy dNK cells promote uterine vascular growth and mediate trophoblast invasion, but do not exert their killing function. However, this may be an overly simplistic view. Evidence of specific dNK functional killer roles, as well as opposing effects of dNK cells on the uterine vasculature before and after conception, indicates the presence of a transitory secretory-stage dNK cell (s-dNK) phenotype with a unique angiodevelopmental profile during the peri-implantation period, that is that is functionally distinct from the angiomodulatory dNK cells that promote vessel destabilisation and vascular cell apoptosis to facilitate uterine vascular changes in early pregnancy. It is possible that abnormal activation and differentiation into the proposed transitory s-dNK phenotype may have implications in uterine pathologies ranging from infertility to cancer, as well as downstream effects on dNK cell differentiation in early pregnancy. Further, dysregulated transition into the angiomodulatory dNK phenotype in early pregnancy will likely have potential repercussions for adverse pregnancy outcomes, since impaired dNK function is associated with several obstetric complications. A comprehensive understanding of the uterine NK cell temporal differentiation pathway may therefore have important translational potential due to likely NK phenotypic functional implications in a range of reproductive, obstetric, and gynaecological pathologies

Epigenetic reprogramming of the zygote in mice and men: on your marks, get set, go!

Gametogenesis (spermatogenesis and oogenesis) is accompanied by the acquisition of gender-specific epigenetic marks, such as DNA methylation, histone modifications and regulation by small RNAs, to form highly differentiated, but transcriptionally silent cell-types in preparation for fertilisation. Upon fertilisation, extensive global epigenetic reprogramming takes place to remove the previously acquired epigenetic marks and produce totipotent zygotic states. It is the aim of this review to delineate the cellular and molecular events involved in maternal, paternal and zygotic epigenetic reprogramming from the time of gametogenesis, through fertilisation, to the initiation of zygotic genome activation for preimplantation embryonic development. Recent studies have begun to uncover the indispensable functions of epigenetic players during gametogenesis, fertilisation and preimplantation embryo development, and a more comprehensive understanding of these early events will be informative for increasing pregnancy success rates, adding particular value to assisted fertility programmes

Upper respiratory tract mucosal immunity for SARS-CoV-2 vaccines

SARS-CoV-2 vaccination significantly reduces morbidity and mortality, but has less impact on viral transmission rates, thus aiding viral evolution; and the longevity of vaccine-induced immunity rapidly declines. Immune responses in respiratory tract mucosal tissues are crucial for early control of infection, and can generate long-term antigen-specific protection with prompt recall responses. However, currently approved SARS-CoV-2 vaccines are not amenable to adequate respiratory mucosal delivery, particularly in the upper airways, which could account for the high vaccine breakthrough infection rates and limited duration of vaccine-mediated protection. In view of these drawbacks, we outline a strategy that has the potential to enhance both the efficacy and durability of existing SARS-CoV-2 vaccines, by inducing robust memory responses in the upper respiratory tract mucosa

Does autonomous macrophage-driven inflammation promote alveolar damage in COVID-19?

SARS-CoV-2 has caused devastating effects with over 550 million infections by July 2022 and approximately 6.4 million deaths [1]. Societal and economic impacts will reverberate for years, with continuous evolution of SARS-CoV-2 as it persistently spreads through the human population as exemplified by reduced activity of vaccines and monoclonals against Omicron BA.4 or BA.5 subvariants [2]. A greater understanding of pathogenesis and more tailored therapeutic approaches are therefore essential

Severe COVID-19 versus multisystem inflammatory syndrome:comparing two critical outcomes of SARS-CoV-2 infection

peer reviewedSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with diverse host response immunodynamics and variable inflammatory manifestations. Several immune-modulating risk factors can contribute to a more severe coronavirus disease 2019 (COVID-19) course with increased morbidity and mortality. The comparatively rare post-infectious multisystem inflammatory syndrome (MIS) can develop in formerly healthy individuals, with accelerated progression to life-threatening illness. A common trajectory of immune dysregulation forms a continuum of the COVID-19 spectrum and MIS; however, severity of COVID-19 or the development of MIS is dependent on distinct aetiological factors that produce variable host inflammatory responses to infection with different spatiotemporal manifestations, a comprehensive understanding of which is necessary to set better targeted therapeutic and preventative strategies for both

COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.

Funder: Bundesministerium für Bildung und ForschungFunder: Bundesministerium für Bildung und Forschung (BMBF)We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective

The role of decidual natural killer cells in pregnancy

During pregnancy, maternal uterine spiral arteries are remodelled from minimal flow, high resistance vessels into large diameter, low resistance, high flow vessels. This change is crucial for delivery of adequate blood supply to the developing fetus, and is impaired in pregnancies complicated by pre-eclampsia. In early pregnancy, fetal trophoblasts invade into the decidua and remodel the spiral arteries. However, decidual natural killer (dNK) cells accumulate around spiral arteries and are present ahead of trophoblast invasion. Their presence is continuous during trophoblast invasion and spiral artery remodelling. A functional role for dNK in remodelling has not yet been defined. Measurement of uterine artery resistance indices (RI), by Doppler ultrasound at 9-14 weeks of gestation, was used to identify pregnancies with 21 % risk (high RI). Following surgical termination of pregnancy, CD56+ dNK cells were isolated and comparisons made between cells from normal and high RI pregnancies. dNK cell-secreted factors and receptor expression were characterised by proteome profiler arrays, multiplex assays, flow cytometry and western blot analysis. Differences between the two groups were detected in several factors, including angiogenin, endostatin, hepatocyte growth factor (HGF), placental growth factor (PIG F), the soluble interleukin-2 receptor (sIL-2R), active matrix metalloproteinases (MMPs), tumour necrosis factor (TNF)-α, Fas ligand (FasL) and TNF-related apoptosis inducing ligand (TRAIL). dNK effects on trophoblasts and vascular cells were investigated by eo- culture studies to model the interactions at the maternal-fetal interface. Normal RI dNK solube factors were able to promote trophoblast motility (an important component of invasion), to a greater extent than high RI dNK, and a function for dNK-secreted HGF in promoting trophoblast motility was determined. Normal RI dNK caused destabilisation of endothelial cell tube-like structures, partly through TNF-α, whereas this effect was not seen with high RI dNK. Normal RI dNK cells also induced vascular cell apoptosis partly via FasL, while high RI dNK cells did not. These studies demonstrate a functional role for dNK in regulating trophoblast motility and vascular cell remodelling, events of importance in a successful pregnancy. The ability of dNK to regulate these events in pregnancies at higher risk of pre-eclampsia is impaired, which may contribute to the poor remodelling seen in these pregnancies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

COVID19 Disease Map, a computational knowledge repository of virus–host interaction mechanisms

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective