Implication of viruses in the etiology of preeclampsia.

Preeclampsia is one of the most common disorders that poses threat to both mothers and neonates and a major contributor to perinatal morbidity and mortality worldwide. Viral infection during pregnancy is not typically considered to cause preeclampsia; however, syndromic nature of preeclampsia etiology and the immunomodulatory effects of viral infections suggest that microbes could trigger a subset of preeclampsia. Notably, SARS-CoV-2 infection is associated with an increased risk of preeclampsia. Herein, we review the potential role of viral infections in this great obstetrical syndrome. According to in vitro and in vivo experimental studies, viral infections can cause preeclampsia by introducing poor placentation, syncytiotrophoblast stress, and/or maternal systemic inflammation, which are all known to play a critical role in the development of preeclampsia. Moreover, clinical and experimental investigations have suggested a link between several viruses and the onset of preeclampsia via multiple pathways. However, the results of experimental and clinical research are not always consistent. Therefore, future studies should investigate the causal link between viral infections and preeclampsia to elucidate the mechanism behind this relationship and the etiology of preeclampsia itself.

The NF-κB RelA transcription factor is not required for CD8+ T-cell function in acute viral infection and cancer.

CD8+ T cells are critical mediators of pathogen clearance and anti-tumor immunity. Although signaling pathways leading to the activation of NF-κB transcription factors have crucial functions in the regulation of immune responses, the CD8+ T cell-autonomous roles of the different NF-κB subunits, are still unresolved. Here, we investigated the function of the ubiquitously expressed transcription factor RelA in CD8+ T-cell biology using a novel mouse model and gene-edited human cells. We found that CD8+ T cell-specific ablation of RelA markedly altered the transcriptome of ex vivo stimulated cells, but maintained the proliferative capacity of both mouse and human cells. In contrast, in vivo experiments showed that RelA deficiency did not affect the CD8+ T-cell response to acute viral infection or transplanted tumors. Our data suggest that in CD8+ T cells, RelA is dispensable for their protective activity in pathological contexts.

ECSIT facilitates memory CD8+ T cell development by mediating fumarate synthesis during viral infection and tumorigenesis.

Memory CD8+ T cells play a crucial role in infection and cancer and mount rapid responses to repeat antigen exposure. Although memory cell transcriptional programmes have been previously identified, the regulatory mechanisms that control the formation of CD8+ T cells have not been resolved. Here we report ECSIT as an essential mediator of memory CD8+ T cell differentiation. Ablation of ECSIT in T cells resulted in loss of fumarate synthesis and abrogated TCF-1 expression via demethylation of the TCF-1 promoter by the histone demethylase KDM5, thereby impairing memory CD8+ T cell development in a cell-intrinsic manner. In addition, ECSIT expression correlated positively with stem-like memory progenitor exhausted CD8+ T cells and the survival of patients with cancer. Our study demonstrates that ECSIT-mediated fumarate synthesis stimulates TCF-1 activity and memory CD8+ T cell development during viral infection and tumorigenesis and highlights the utility of therapeutic fumarate analogues and PD-L1 inhibition for tumour immunotherapy.

The host mannose-6-phosphate pathway and viral infection.

Viruses, despite their simple structural composition, engage in intricate and complex interactions with their hosts due to their parasitic nature. A notable demonstration of viral behavior lies in their exploitation of lysosomes, specialized organelles responsible for the breakdown of biomolecules and clearance of foreign substances, to bolster their own replication. The man-nose-6-phosphate (M6P) pathway, crucial for facilitating the proper transport of hydrolases into lysosomes and promoting lysosome maturation, is frequently exploited for viral manipulation in support of replication. Recently, the discovery of lysosomal enzyme trafficking factor (LYSET) as a pivotal regulator within the lysosomal M6P pathway has introduced a fresh perspective on the intricate interplay between viral entry and host factors. This groundbreaking revelation illuminates unexplored dimensions of these interactions. In this review, we endeavor to provide a thorough overview of the M6P pathway and its intricate interplay with viral factors during infection. By consolidating the current understanding in this field, our objective is to establish a valuable reference for the development of antiviral drugs that selectively target the M6P pathway.

DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response.

Detection of cytosolic nucleic acids by pattern recognition receptors, including STING and RIG-I, leads to the activation of multiple signalling pathways that culminate in the production of type I interferons (IFNs) which are vital for host survival during virus infection. In addition to protective immune modulatory functions, type I IFNs are also associated with autoimmune diseases. Hence, it is important to elucidate the mechanisms that govern their expression. In this study, we identified a critical regulatory function of the DUSP4 phosphatase in innate immune signalling. We found that DUSP4 regulates the activation of TBK1 and ERK1/2 in a signalling complex containing DUSP4, TBK1, ERK1/2 and IRF3 to regulate the production of type I IFNs. Mice deficient in DUSP4 were more resistant to infections by both RNA and DNA viruses but more susceptible to malaria parasites. Therefore, our study establishes DUSP4 as a regulator of nucleic acid sensor signalling and sheds light on an important facet of the type I IFN regulatory system.

The multifaceted interactions between Newcastle disease virus proteins and host proteins: a systematic review.

Newcastle disease virus (NDV) typically induces severe illness in poultry and results in significant economic losses for the worldwide poultry sector. NDV, an RNA virus with a single-stranded negative-sense genome, is susceptible to mutation and immune evasion during viral transmission, thus imposing enormous challenges to avian health and poultry production. NDV is composed of six structural proteins and two nonstructural proteins that exert pivotal roles in viral infection and antiviral responses by interacting with host proteins. Nowadays, there is a particular focus on the mechanisms of virus-host protein interactions in NDV research, yet a comprehensive overview of such research is still lacking. Herein, we briefly summarize the mechanisms regarding the effects of virus-host protein interaction on viral infection, pathogenesis, and host immune responses. This review can not only enhance the present comprehension of the mechanism underlying NDV and host interplay, but also furnish a point of reference for the advancement of antiviral measures.

The population context is a driver of the heterogeneous response of epithelial cells to interferons.

Isogenic cells respond in a heterogeneous manner to interferon. Using a micropatterning approach combined with high-content imaging and spatial analyses, we characterized how the population context (position of a cell with respect to neighboring cells) of epithelial cells affects their response to interferons. We identified that cells at the edge of cellular colonies are more responsive than cells embedded within colonies. We determined that this spatial heterogeneity in interferon response resulted from the polarized basolateral interferon receptor distribution, making cells located in the center of cellular colonies less responsive to ectopic interferon stimulation. This was conserved across cell lines and primary cells originating from epithelial tissues. Importantly, cells embedded within cellular colonies were not protected from viral infection by apical interferon treatment, demonstrating that the population context-driven heterogeneous response to interferon influences the outcome of viral infection. Our data highlights that the behavior of isolated cells does not directly translate to their behavior in a population, placing the population context as one important factor influencing heterogeneity during interferon response in epithelial cells.

EFHD2 cooperates with E3 ubiquitin ligase Smurf1 to facilitate virus infection by promoting the degradation of TRAF6 in teleost fish.

The ubiquitin-proteasome system is one of the most important protein stability regulation systems. It can precisely regulate host immune responses by targeting signaling proteins. TRAF6 is a crucial E3 ubiquitin ligase in host antiviral signaling pathway. Here, we discovered that EF-hand domain-containing protein D2 (EFHD2) collaborated with the E3 ubiquitin ligase Smurf1 to potentiate the degradation of TRAF6, hence facilitating RNA virus Siniperca chuatsi rhabdovirus infection. The mechanism analysis revealed that EFHD2 interacted with Smurf1 and enhanced its protein stability by impairing K48-linked polyubiquitination of Smurf1, thereby promoting Smurf1-catalyzed degradation of TRAF6. This study initially demonstrated a novel mechanism by which viruses utilize host EFHD2 to achieve immune escape and provided a new perspective on the exploration of mammalian innate immunity.IMPORTANCEViruses induce host cells to activate several antiviral signaling pathways. TNF receptor-associated factor 6 (TRAF6) plays an essential role in these pathways. Numerous studies have been done on the mechanisms of TRAF6-mediated resistance to viral invasion. However, little is known about the strategies that viruses employ to antagonize TRAF6-mediated antiviral signaling pathway. Here, we discovered that EFHD2 functions as a host factor to promote viral replication. Mechanistically, EFHD2 potentiates Smurf1 to catalyze the ubiquitin-proteasomal degradation of TRAF6 by promoting the deubiquitination and stability of Smurf1, which in turn inhibits the production of proinflammatory cytokines and interferons. Our study also provides a new perspective on mammalian resistance to viral invasion.

Signaling pathways regulating the immune function of cochlear supporting cells and their involvement in cochlear pathophysiology.

The inner ear, including the cochlea, used to be regarded as an immune-privileged site because of its immunologically isolated environment caused by the blood-labyrinthine barrier. Cochlear resident macrophages, which originate from the yolk sac or fetal liver during the embryonic stage and are maintained after birth, are distributed throughout various regions of the cochlear duct. Intriguingly, these cells are absent in the organ of Corti, where hair cells (HCs) and supporting cells (SCs) are located, except for a limited number of ionized calcium-binding adapter molecule 1 (Iba1)-positive cells. Instead, SCs exert glial functions varying from a quiescent to an emergency state. Notably, SCs acquire the nature of macrophages and begin to secrete inflammatory cytokines during viral infection in the organ of Corti, which is ostensibly unprotected owing to the lack of general resident macrophages. This review provides an overview of both positive and negative functions of SCs enabled to acquire macrophage phenotypes upon viral infection focusing on the signaling pathways that regulate these functions. The former function protects HCs from viral infection by inducting type I interferons, and the latter function induces HC death by necroptosis, leading to sensorineural hearing loss. Thus, SCs play contradictory roles as immune cells with acquired macrophage phenotypes; thereby, they are favorable and unfavorable to HCs, which play a pivotal role in hearing function.

A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome.

Of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ~ 10% develop the chronic post-viral debilitating condition, long COVID (LC). Although LC is a heterogeneous condition, about half of cases have typical post-viral fatigue with onset and symptoms that are very similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A key question is whether these conditions are closely related. ME/CFS is a post-stressor fatigue condition that arises from multiple triggers. To investigate the pathophysiology of LC, a pilot study of patients (n = 6) and healthy controls (n = 5) has used quantitative proteomics to discover changes in peripheral blood mononuclear cell (PBMC) proteins. A principal component analysis separated all long COVID patients from healthy controls. Analysis of 3131 proteins identified 162 proteins differentially regulated, of which 37 were related to immune functions, and 21 to mitochondrial functions. Markov cluster analysis identified clusters involved in immune system processes, and two aspects of gene expression-spliceosome and transcription. These results were compared with an earlier dataset of 346 differentially regulated proteins in PBMC's from ME/CFS patients (n = 9) analysed by the same methodology. There were overlapping protein clusters and enriched molecular pathways particularly in immune functions, suggesting the two conditions have similar immune pathophysiology as a prominent feature, and mitochondrial functions involved in energy production were affected in both conditions.

Viruses and Cajal Bodies: A Critical Cellular Target in Virus Infection?

Nuclear bodies (NBs) are dynamic structures present in eukaryotic cell nuclei. They are not bounded by membranes and are often considered biomolecular condensates, defined structurally and functionally by the localisation of core components. Nuclear architecture can be reorganised during normal cellular processes such as the cell cycle as well as in response to cellular stress. Many plant and animal viruses target their proteins to NBs, in some cases triggering their structural disruption and redistribution. Although not all such interactions have been well characterised, subversion of NBs and their functions may form a key part of the life cycle of eukaryotic viruses that require the nucleus for their replication. This review will focus on Cajal bodies (CBs) and the viruses that target them. Since CBs are dynamic structures, other NBs (principally nucleoli and promyelocytic leukaemia, PML and bodies), whose components interact with CBs, will also be considered. As well as providing important insights into key virus-host cell interactions, studies on Cajal and associated NBs may identify novel cellular targets for development of antiviral compounds.

Mitochondrial Oxidative Phosphorylation in Viral Infections.

Mitochondria have been identified as the "powerhouse" of the cell, generating the cellular energy, ATP, for almost seven decades. Research over time has uncovered a multifaceted role of the mitochondrion in processes such as cellular stress signaling, generating precursor molecules, immune response, and apoptosis to name a few. Dysfunctional mitochondria resulting from a departure in homeostasis results in cellular degeneration. Viruses hijack host cell machinery to facilitate their own replication in the absence of a bonafide replication machinery. Replication being an energy intensive process necessitates regulation of the host cell oxidative phosphorylation occurring at the electron transport chain in the mitochondria to generate energy. Mitochondria, therefore, can be an attractive therapeutic target by limiting energy for viral replication. In this review we focus on the physiology of oxidative phosphorylation and on the limited studies highlighting the regulatory effects viruses induce on the electron transport chain.

Identification of differences in CD4+ T-cell gene expression between people with asthma and healthy controls.

Functional enrichment analysis of genome-wide association study (GWAS)-summary statistics has suggested that CD4+ T-cells play an important role in asthma pathogenesis. Despite this, CD4+ T-cells are under-represented in asthma transcriptome studies. To fill the gap, 3'-RNA-Seq was used to generate gene expression data on CD4+ T-cells (isolated within 2 h from collection) from peripheral blood from participants with well-controlled asthma (n = 32) and healthy controls (n = 11). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify sets of co-expressed genes (modules) associated with the asthma phenotype. We identified three modules associated with asthma, which are strongly enriched for GWAS-identified asthma genes, antigen processing/presentation and immune response to viral infections. Through integration of publicly available eQTL and GWAS summary statistics (colocalisation), and protein-protein interaction (PPI) data, we identified PTPRC, a potential druggable target, as a putative master regulator of the asthma gene-expression profiles. Using a co-expression network approach, with integration of external genetic and PPI data, we showed that CD4+ T-cells from peripheral blood from asthmatics have different expression profiles, albeit small in magnitude, compared to healthy controls, for sets of genes involved in immune response to viral infections (upregulated) and antigen processing/presentation (downregulated).

Defining the Assembleome of the Respiratory Syncytial Virus.

During respiratory syncytial virus (RSV) particle assembly, the mature RSV particles form as filamentous projections on the surface of RSV-infected cells. The RSV assembly process occurs at the / on the cell surface that is modified by a virus infection, involving a combination of several different host cell factors and cellular processes. This induces changes in the lipid composition and properties of these lipid microdomains, and the virus-induced activation of associated Rho GTPase signaling networks drives the remodeling of the underlying filamentous actin (F-actin) cytoskeleton network. The modified sites that form on the surface of the infected cells form the nexus point for RSV assembly, and in this review chapter, they are referred to as the RSV assembleome. This is to distinguish these unique membrane microdomains that are formed during virus infection from the corresponding membrane microdomains that are present at the cell surface prior to infection. In this article, an overview of the current understanding of the processes that drive the formation of the assembleome during RSV particle assembly is given.

Myocardial Mitochondrial DNA Drives Macrophage Inflammatory Response through STING Signaling in Coxsackievirus B3-Induced Viral Myocarditis.

Coxsackievirus B3 (CVB3), a single-stranded positive RNA virus, primarily infects cardiac myocytes and is a major causative pathogen for viral myocarditis (VMC), driving cardiac inflammation and organ dysfunction. However, whether and how myocardial damage is involved in CVB3-induced VMC remains unclear. Herein, we demonstrate that the CVB3 infection of cardiac myocytes results in the release of mitochondrial DNA (mtDNA), which functions as an important driver of cardiac macrophage inflammation through the stimulator of interferon genes (STING) dependent mechanism. More specifically, the CVB3 infection of cardiac myocytes promotes the accumulation of extracellular mtDNA. Such myocardial mtDNA is indispensable for CVB3-infected myocytes in that it induces a macrophage inflammatory response. Mechanistically, a CVB3 infection upregulates the expression of the classical DNA sensor STING, which is predominantly localized within cardiac macrophages in VMC murine models. Myocardial mtDNA efficiently triggers STING signaling in those macrophages, resulting in strong NF-kB activation when inducing the inflammatory response. Accordingly, STING-deficient mice are able to resist CVB3-induced cardiac inflammation, exhibiting minimal inflammation with regard to their functional cardiac capacities, and they exhibit higher survival rates. Moreover, our findings pinpoint myocardial mtDNA as a central element driving the cardiac inflammation of CVB3-induced VMC, and we consider the DNA sensor, STING, to be a promising therapeutic target for protecting against RNA viral infections.

A novel protein encoded by circVPS13D attenuates antiviral innate immunity by targeting MAVS in teleost fish.

IMPORTANCE: The expression of circVPS13D was upregulated with SCRV invasion, which proved that circVPS13D was involved in the regulation of the antiviral immune response. Our study revealed that the existence of circVPS13D promoted the replication of SCRV. Functionally, circVPS13D negatively regulates the antiviral responses of fish. Mechanistically, we confirmed that circVPS13D inhibited RLRs antiviral signaling pathway via the encoded protein VPS13D-170aa by targeting MAVS. Our study provided novel insights into the roles of protein-coding circRNAs and supported VPS13D-170aa as a negative regulator in the antiviral immune responses of teleost fish.

Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection.

Reprogramming lipid metabolic pathways is a critical feature of activating immune responses to infection. However, how these reconfigurations occur is poorly understood. Our previous screen to identify cellular deubiquitylases (DUBs) activated during influenza virus infection revealed Usp25 as a prominent hit. Here, we show that Usp25-deleted human lung epithelial A549 cells display a >10-fold increase in pathogenic influenza virus production, which was rescued upon reconstitution with the wild type but not the catalytically deficient (C178S) variant. Proteomic analysis of Usp25 interactors revealed a strong association with Erlin1/2, which we confirmed as its substrate. Newly synthesized Erlin1/2 were degraded in Usp25-/- or Usp25C178S cells, activating Srebp2, with increased cholesterol flux and attenuated TLR3-dependent responses. Our study therefore defines the function of a deubiquitylase that serves to restrict a range of viruses by reprogramming lipid biosynthetic flux to install appropriate inflammatory responses.

Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation.

Cellular immunity mediated by CD8+ T cells plays an indispensable role in bacterial and viral clearance and cancers. However, persistent antigen stimulation of CD8+ T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors. Numerous studies have shown that glycogen synthase kinase 3 (GSK3) controls the function and development of immune cells, but whether GSK3 affects CD8+ T cells is not clearly elucidated. Here, we demonstrate that mice with deletion of Gsk3α and Gsk3ß in activated CD8+ T cells (DKO) exhibited decreased CTL differentiation and effector function during acute and chronic viral infection. In addition, DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+ T cells. Strikingly, anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice. Mechanistically, GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT, thereby in turn dampening NFAT-mediated exhaustion-related gene expression, including TOX/TOX2 and PD-1. Thus, we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.

Dengue Virus Infection Alters Inter-Endothelial Junctions and Promotes Endothelial-Mesenchymal-Transition-Like Changes in Human Microvascular Endothelial Cells.

Dengue virus (DENV) is a pathogenic arbovirus that causes human disease. The most severe stage of the disease (severe dengue) is characterized by vascular leakage, hypovolemic shock, and organ failure. Endothelial dysfunction underlies these phenomena, but the causal mechanisms of endothelial dysfunction are poorly characterized. This study investigated the role of c-ABL kinase in DENV-induced endothelial dysfunction. Silencing c-ABL with artificial miRNA or targeting its catalytic activity with imatinib revealed that c-ABL is required for the early steps of DENV infection. DENV-2 infection and conditioned media from DENV-infected cells increased endothelial expression of c-ABL and CRKII phosphorylation, promoted expression of mesenchymal markers, e.g., vimentin and N-cadherin, and decreased the levels of endothelial-specific proteins, e.g., VE-cadherin and ZO-1. These effects were reverted by silencing or inhibiting c-ABL. As part of the acquisition of a mesenchymal phenotype, DENV infection and treatment with conditioned media from DENV-infected cells increased endothelial cell motility in a c-ABL-dependent manner. In conclusion, DENV infection promotes a c-ABL-dependent endothelial phenotypic change that leads to the loss of intercellular junctions and acquisition of motility.

Biomolecular phase separation in stress granule assembly and virus infection.

Liquid-liquid phase separation (LLPS) has emerged as a crucial mechanism for cellular compartmentalization. One prominent example of this is the stress granule. Found in various types of cells, stress granule is a biomolecular condensate formed through phase separation. It comprises numerous RNA and RNA-binding proteins. Over the past decades, substantial knowledge has been gained about the composition and dynamics of stress granules. SGs can regulate various signaling pathways and have been associated with numerous human diseases, such as neurodegenerative diseases, cancer, and infectious diseases. The threat of viral infections continues to loom over society. Both DNA and RNA viruses depend on host cells for replication. Intriguingly, many stages of the viral life cycle are closely tied to RNA metabolism in human cells. The field of biomolecular condensates has rapidly advanced in recent times. In this context, we aim to summarize research on stress granules and their link to viral infections. Notably, stress granules triggered by viral infections behave differently from the canonical stress granules triggered by sodium arsenite (SA) and heat shock. Studying stress granules in the context of viral infections could offer a valuable platform to link viral replication processes and host anti-viral responses. A deeper understanding of these biological processes could pave the way for innovative interventions and treatments for viral infectious diseases. They could potentially bridge the gap between basic biological processes and interactions between viruses and their hosts.