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The recent outbreak of Zika virus (ZIKV) was associated with birth defects and pregnancy loss when maternal infection occurs in early pregnancy, but specific mechanisms driving placental insufficiency and subsequent ZIKV-mediated pathogenesis remain unclear. Here we show, using large scale metabolomics, that ZIKV infection reprograms placental lipidome by impairing the lipogenesis pathways. ZIKV-induced metabolic alterations provide building blocks for lipid droplet biogenesis and intracellular membrane rearrangements to support viral replication. Furthermore, lipidome reprogramming by ZIKV is paralleled by the mitochondrial dysfunction and inflammatory immune imbalance, which contribute to placental damage. In addition, we demonstrate the efficacy of a commercially available inhibitor in limiting ZIKV infection, provides a proof-of-concept for blocking congenital infection by targeting metabolic pathways. Collectively, our study provides mechanistic insights on how ZIKV targets essential hubs of the lipid metabolism that may lead to placental dysfunction and loss of barrier function. Zika virus (ZIKV) infection of pregnant women is associated with pregnancy loss and birth defects, but molecular insights for the aetiology are scarce. Here the authors show that ZIKV reprograms the host lipidome to facilitate viral replication, induce mitochondria dysfunction, and cause immune imbalance, thereby identifying a potential target for ZIKV therapy.

The positive effects of therapeutic human allogeneic cardiac stem/progenitor cells (hCPC) in terms of cardiac repair/regeneration are very likely mediated by paracrine effects. Our previous studies revealed the advantageous immune interactions of allogeneic hCPC and proposed them as part of the positive paracrine effects occurring upon their application postmyocardial infarction (MI). Currently, extracellular vesicles/exosomes (EV/Exs) released by stem/progenitor cells are also proposed as major mediators of paracrine effects of therapeutic cells. Along this line, we evaluated contribution of EV/Exs released by therapeutic hCPC to the benefit of their successful allogeneic clinical application. Through tailored allogeneic in vitro human assay models mimicking the clinical setting, we demonstrate that hCPC‐released EV/Exs were rapidly and efficiently up‐taken by chief cellular actors of cardiac repair/regeneration. This promoted MAPK/Erk1/2 activation, migration, and proliferation of human leukocyte antigens (HLA)‐mismatched hCPC, mimicking endogenous progenitor cells and cardiomyocytes, and enhanced endothelial cell migration, growth, and organization into tube‐like structures through activation of several signaling pathways. EV/Exs also acted as pro‐survival stimuli for HLA‐mismatched monocytes tuning their phenotype toward an intermediate anti‐inflammatory pro‐angiogenic phenotype. Thus, while positively impacting the intrinsic regenerative and angiogenic programs, EV/Exs released by therapeutic allogeneic hCPC can also actively contribute to shaping MI‐inflammatory environment, which could strengthen the benefits of hCPC allogeneic interactions. Collectively, our data might forecast the application of allogeneic hCPC followed by their cell‐free EV/Exs as a strategy that will not only elicit the cell‐contact mediated reparative/regenerative immune response but also have the desired long‐lasting effects through the EV/Exs. Stem Cells Translational Medicine 2019;8:911&924 Extracellular vesicles/exosomes released from therapeutic cardiac stem/progenitor cells regulate the activity of chief cellular actors of cardiac repair/regeneration. Using a tailored in vitro human model mimicking the clinical allogeneic settings, this study provides the human proof‐of‐concept of the active contribution of extracellular vesicles/exosomes to the wholesome reparative/regenerative benefit of therapeutic cells.

Hepatitis E virus (HEV) infection, particularly HEV genotype 1 (HEV-1), can result in fulminant hepatic failure and severe placental diseases, but mechanisms underlying genotype-specific pathogenicity are unclear and appropriate models are lacking. Here, we model HEV-1 infection ex vivo at the maternal-fetal interface using the decidua basalis and fetal placenta, and compare its effects to the less-pathogenic genotype 3 (HEV-3). We demonstrate that HEV-1 replicates more efficiently than HEV-3 both in tissue explants and stromal cells, produces more infectious progeny virions and causes severe tissue alterations. HEV-1 infection dysregulates the secretion of several soluble factors. These alterations to the cytokine microenvironment correlate with viral load and contribute to the tissue damage. Collectively, this study characterizes an ex vivo model for HEV infection and provides insights into HEV-1 pathogenesis during pregnancy that are linked to high viral replication, alteration of the local secretome and induction of tissue injuries. Hepatitis E virus (HEV) infection can result in severe placental disease, but mechanisms underlying pathogenicity are poorly understood. Here, the authors develop an ex vivo model for HEV infection at the maternal-fetal interface and compare pathogenicity of different HEV genotypes.

The outbreak of the Zika Virus (ZIKV) and its association with fetal abnormalities have raised worldwide concern. However, the cellular tropism and the mechanisms of ZIKV transmission to the fetus during early pregnancy are still largely unknown. Therefore, we ex vivo modeled the ZIKV transmission at the maternal-fetal interface using organ culture from first trimester pregnancy samples. Here, we provide evidence that ZIKV strain circulating in Brazil infects and damages tissue architecture of the maternal decidua basalis , the fetal placenta and umbilical cord. We also show that ZIKV replicates differentially in a wide range of maternal and fetal cells, including decidual fibroblasts and macrophages, trophoblasts, Hofbauer cells as well as umbilical cord mesenchymal stem cells. The striking cellular tropism of ZIKV and its cytopathic-induced tissue injury during the first trimester of pregnancy could provide an explanation for the irreversible congenital damages.

The natural cytotoxicity receptors NKp46/NCR1, NKp44/NCR2 and NKp30/NCR3 are critical for natural killer (NK) cell functions. Their genes are transcribed into several splice variants whose physiological relevance is not yet fully understood. Here we report that decidua basalis NK (dNK) cells of the pregnant uterine mucosa and peripheral blood NK (pNK) cells, two functionally distinct subsets of the physiological NK cell pool, display differential expression of NKp30/NCR3 and NKp44/NCR2 splice variants. The presence of cytokines that are enriched within the decidual microenvironment is sufficient to convert the splice variant profile of pNK cells into one similar to that of dNK cells. This switch is associated with decreased cytotoxic function and major adaptations to the secretome, hallmarks of the decidual phenotype. Thus, NKp30/NCR3 and NKp44/NCR2 splice variants delineate functionally distinct NK cell subsets. To our knowledge, this is the first conclusive evidence underlining the physiological importance of NCR splice variants. Decidual natural killer (NK) cells from the pregnant uterus play an important role in the physiology of pregnancy and differ functionally from peripheral blood NK cells. Siewiera et al . reveal that this is partly due to the differential expression of splice variants of natural cytotoxicity receptors by these two cell subsets.

Hepatitis E virus (HEV), a leading cause of acute and chronic viral hepatitis, poses a persistent global health challenge. A deeper mechanistic understanding of virus–host interactions is critical for identifying therapeutic targets to mitigate HEV-associated disease. In this study, we employ a systems biology framework to comprehensively map metabolic and bioenergetic alterations induced by HEV genotypes 1 and 3 in HepG2/C3a-MAVS-KD cells, a robust model of HEV infection, enabling reliable assessment of virus- and host-driven cellular changes. Our analyses reveal extensive remodelling of host metabolism, including reprogramming of the tricarboxylic acid (TCA) cycle, mitochondrial oxidative phosphorylation (OXPHOS), fatty acid metabolism, and β-oxidation—pathways that collectively sustain the energetic and biosynthetic demands of viral infection. HEV infection also reshapes the cellular lipidome, increasing levels of long-chain neutral lipids and lipid droplet abundance, alongside elevated levels of pro-inflammatory oxylipins. Functional metabolic assays demonstrate a reliance on lipid-fuelled OXPHOS rather than glycolysis for efficient HEV infection. These findings uncover critical host metabolic dependencies exploited by HEV and offer a conceptual framework for targeting metabolic hubs as a therapeutic strategy against HEV infection. Author Summary: Viruses are obligate intracellular pathogens that reprogramme host cellular machinery to their advantage. Yet, the extent to which Hepatitis E virus (HEV) infection orchestrates metabolic reprogramming, and the implications of these changes for viral fitness, remain poorly defined. By integrating large-scale proteomics with lipid metabolic profiling, we delineate molecular strategies through which HEV subverts host lipid metabolism and mitochondrial function. Our findings provide mechanistic insight into how HEV infection modulates host metabolic pathways to its advantage, highlighting potential targets for therapeutic intervention. Graphical Abstract

Endotypes are characterized by the immunological, inflammatory, metabolic, and remodelling pathways that explain the mechanisms underlying the clinical presentation (phenotype) of a disease. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease caused by COL7A1 pathogenic variants. Although underscored by animal studies, the endotypes of human RDEB are poorly understood. To fill this gap, we apply systems immunology approaches using single-cell high-dimensional techniques to capture the signature of peripheral immune cells and the diversity of metabolic profiles in RDEB adults, sampled outside of any opportunistic infection and active cancer. Our study, demonstrates the particular inflammation and immunity characteristics of RDEB adults, with activated / effector T and dysfunctional natural killer cell signatures, concomitant with an overall pro-inflammatory lipid signature. Artificial intelligence prediction models and principal component analysis stress that RDEB is not solely confined to cutaneous issues but has complex systemic endotypes marked by immune dysregulation and hyperinflammation. By characterising the phenotype-endotype association in RDEB adults, our study lays the groundwork for translational interventions that could by lessening inflammation, alleviate the everlasting suffering of RDEB patients, while awaiting curative genetic therapies. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering condition caused by pathogenic variants in the COL7A1 gene and may present with different disease endotypes. In this study, the authors characterise a cohort of RDEB adults to highlight variations in immune cell phenotypes and metabolic profiles, particularly in T cells and NK cells.

Chimeric antigen receptor–engineered NK-92 (CAR-NK-92) cells emulate activated natural killer cells, combining potent innate cytotoxicity with CAR-driven antigen specificity. Their scalability and FDA approval make them attractive for universal use. However, their application in solid tumors remains limited by the immunosuppressive tumor microenvironment (TME), which is often characterized by hypoxia and nutrient deprivation. We recently demonstrated that an ATF4-inducible promoter, 2xAARE-YB, enables spatial and temporal control of CAR expression in T cells, enhancing safety by restricting expression to amino acid-deprived TME while reducing exhaustion to improve persistence. In this study, we adapted the 2xAARE-YB system for CAR-NK-92 cells. Under glucose-limited conditions, a hallmark of the TME, the system effectively regulated CAR expression, enabling potent antigen-specific cytotoxicity. In xenograft models, the nutrient-responsive 2xAARE-YB system achieved regulated intratumoral CAR expression in vivo , supporting its potential for the development of safer therapeutic strategies. Additionally, the clinically approved ER stress–inducing drug artesunate also reliably activated the circuit, offering a drug-inducible regulation of CAR expression. Collectively, these findings establish 2xAARE-YB as a dual-mode regulatory platform that enables tunable, context-dependent CAR expression in NK-92 cells. Although this approach may be more effective in HLA I-negative tumors than in HLA I-positive tumors, it represents a promising path toward safer and more adaptable CAR-NK-92 therapies tailored for the dynamic metabolic constraints of solid tumors.

Unlike other Flaviviruses, Zika virus (ZIKV) infection during the first trimester of pregnancy causes severe pregnancy outcomes including the devastating microcephaly and diseases associated with placental dysfunctions. We have previously reported that the maternal decidua basalis, the major maternal-fetal interface, serves as a replication platform enabling virus amplification before dissemination to the fetal compartment. However, the rate of congenital infection is quite low, suggesting the presence of a natural barrier against viral infection. Using primary cells from first-trimester pregnancy samples, we investigated in this study how the maternal decidua can interfere with ZIKV infection. Our study reveals that whether through their interactions with dNK cells, the main immune cell population of the first-trimester decidua, or their production of proinflammatory cytokines, decidual stromal cells (DSCs) are the main regulators of ZIKV infection during pregnancy. We also validate the functional role of AXL as a crucial receptor for ZIKV entry in DSCs and demonstrate that targeted inhibition of ligand-receptor interaction at the early stage of the infection is effective in drastically reducing virus pathogenesis at the maternal-fetal interface. Collectively, our results provide insights into the mechanisms through which ZIKV infection and spreading can be limited. The strategy of circumventing viral entry at the maternal-fetus interface limits virus dissemination to fetal tissues, thereby preventing congenital abnormalities.