Pharmacological induction of the hypoxia response pathway in Huh7 hepatoma cells limits proliferation but increases resilience under metabolic stress.

The hypoxia response pathway enables adaptation to oxygen deprivation. It is mediated by hypoxia-inducible factors (HIF), which promote metabolic reprogramming, erythropoiesis, angiogenesis and tissue remodeling. This led to the successful development of HIF-inducing drugs for treating anemia and some of these molecules are now in clinic.

Dengue Virus dependence on glucokinase activity and glycolysis Confers Sensitivity to NAD(H) biosynthesis inhibitors.

Viruses have developed sophisticated strategies to control metabolic activity of infected cells in order to supply replication machinery with energy and metabolites. Dengue virus (DENV), a mosquito-borne flavivirus responsible for dengue fever, is no exception. Previous reports have documented DENV interactions with metabolic pathways and shown in particular that glycolysis is increased in DENV-infected cells.

[Role of cellular metabolism in the control of chronic viral hepatitis].

Hepatitis viruses modify the cellular metabolism of hepatocytes by interacting with specific enzymes such as glucokinase. The metabolic changes induced by viruses can have a direct impact on the innate antiviral response. The complex interactions between viral components, innate immunity, and hepatocyte metabolism explain why chronic hepatitis infections lead to liver inflammation, progressing to cirrhosis, fibrosis, and hepatocellular carcinoma.

An inventory of adjuvants used for vaccination in horses: the past, the present and the future.

Vaccination is one of the most widely used strategies to protect horses against pathogens. However, available equine vaccines often have limitations, as they do not always provide effective, long-term protection and booster injections are often required. In addition, research efforts are needed to develop effective vaccines against emerging equine pathogens.

What role for cellular metabolism in the control of hepatitis viruses?

Hepatitis B, C and D viruses (HBV, HCV, HDV, respectively) specifically infect human hepatocytes and often establish chronic viral infections of the liver, thus escaping antiviral immunity for years. Like other viruses, hepatitis viruses rely on the cellular machinery to meet their energy and metabolite requirements for replication. Although this was initially considered passive parasitism, studies have shown that hepatitis viruses actively rewire cellular metabolism through molecular interactions with specific enzymes such as glucokinase, the first rate-limiting enzyme of glycolysis.

Hamster organotypic kidney culture model of early-stage SARS-CoV-2 infection highlights a two-step renal susceptibility.

Kidney pathology is frequently reported in patients hospitalized with COVID-19, the pandemic disease caused by the Severe acute respiratory coronavirus 2 (SARS-CoV-2). However, due to a lack of suitable study models, the events occurring in the kidney during the earliest stages of infection remain unknown. We have developed hamster organotypic kidney cultures (OKCs) to study the early stages of direct renal infection.

Targeting the liver X receptor with dendrogenin A differentiates tumour cells to secrete immunogenic exosome-enriched vesicles.

Tumour cells are characterized by having lost their differentiation state. They constitutively secrete small extracellular vesicles (sEV) called exosomes when they come from late endosomes. Dendrogenin A (DDA) is an endogenous tumour suppressor cholesterol-derived metabolite.

Domain 2 of Hepatitis C Virus Protein NS5A Activates Glucokinase and Induces Lipogenesis in Hepatocytes.

Hepatitis C virus (HCV) relies on cellular lipid metabolism for its replication, and actively modulates lipogenesis and lipid trafficking in infected hepatocytes. This translates into an intracellular accumulation of triglycerides leading to liver steatosis, cirrhosis and hepatocellular carcinoma, which are hallmarks of HCV pathogenesis. While the interaction of HCV with hepatocyte metabolic pathways is patent, how viral proteins are able to redirect central carbon metabolism towards lipogenesis is unclear.

A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity.

During the cancerous transformation of normal hepatocytes into hepatocellular carcinoma (HCC), the enzyme catalyzing the first rate-limiting step of glycolysis, namely the glucokinase (GCK), is replaced by the higher affinity isoenzyme, hexokinase 2 (HK2). Here, we show that in HCC tumors the highest expression level of HK2 is inversely correlated to GCK expression, and is associated to poor prognosis for patient survival. To further explore functional consequences of the GCK-to-HK2 isoenzyme switch occurring during carcinogenesis, HK2 was knocked-out in the HCC cell line Huh7 and replaced by GCK, to generate the Huh7-GCK/HK2 cell line.

The current landscape of coronavirus-host protein-protein interactions.

In less than 20 years, three deadly coronaviruses, SARS-CoV, MERS-CoV and SARS-CoV-2, have emerged in human population causing hundreds to hundreds of thousands of deaths. Other coronaviruses are causing epizootic representing a significant threat for both domestic and wild animals. Members of this viral family have the longest genome of all RNA viruses, and express up to 29 proteins establishing complex interactions with the host proteome.

Toll-like Receptor 4-Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1α and Increased Hexokinase II Expression.

Cell metabolism now appears as an essential regulator of immune cells activation. In particular, TLR stimulation triggers metabolic reprogramming of dendritic cells (DCs) with an increased glycolytic flux, whereas inhibition of glycolysis alters their functional activation. The molecular mechanisms involved in the control of glycolysis upon TLR stimulation are poorly understood for human DCs.

TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection.

Dysregulated Toll-like receptor (TLR)-4 activation is involved in acute systemic sepsis, chronic inflammatory diseases, such as atherosclerosis and diabetes, and in viral infections, such as influenza infection. Thus, therapeutic control of the TLR4 signalling pathway is of major interest. Here we tested the activity of the small-molecule synthetic TLR4 antagonist, FP7, in vitro on human monocytes and monocyte-derived dendritic cells (DCs) and in vivo during influenza virus infection of mice.

Extended interaction network of procollagen C-proteinase enhancer-1 in the extracellular matrix.

PCPE-1 (procollagen C-proteinase enhancer-1) is an extracellular matrix glycoprotein that can stimulate procollagen processing by procollagen C-proteinases such as BMP-1 (bone morphogenetic protein 1). PCPE-1 interacts with several proteins in addition to procollagens and BMP-1, suggesting that it could be involved in biological processes other than collagen maturation. We thus searched for additional partners of PCPE-1 in the extracellular matrix, which could provide new insights into its biological roles.

HCV core-mediated activation of latent TGF-β via thrombospondin drives the crosstalk between hepatocytes and stromal environment.

Background & Aims: The mechanisms by which fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) develop during chronic hepatitis C virus (HCV) infection are not fully understood. We previously observed that HCV core protein induced a TGF-β-dependent epithelial mesenchymal transition, a process contributing to the promotion of cell invasion and metastasis by impacting TGF-β1 signalling. Here we investigated HCV core capacity to drive increased expression of the active form of TGF-β1n transgenic mice and hepatoma cell lines.

The interactomes of influenza virus NS1 and NS2 proteins identify new host factors and provide insights for ADAR1 playing a supportive role in virus replication.

Influenza A NS1 and NS2 proteins are encoded by the RNA segment 8 of the viral genome. NS1 is a multifunctional protein and a virulence factor while NS2 is involved in nuclear export of viral ribonucleoprotein complexes. A yeast two-hybrid screening strategy was used to identify host factors supporting NS1 and NS2 functions.

Hepatitis C virus/human interactome identifies SMURF2 and the viral protease as critical elements for the control of TGF-β signaling.

TGF-β signaling induces epithelial to mesenchymal transition (EMT) and plays an important role in hepatocellular carcinoma (HCC) development. Clinical observations indicate that hepatitis C virus (HCV) chronic infection, which is a major cause of HCC, induces TGF-β signaling perturbations. Here, we investigate the mechanisms by which HCV nonstructural proteins interfere with TGF-β signaling, in human hepatoma cell lines expressing HCV subgenomic replicon.

Modified lipoproteins provide lipids that modulate dendritic cell immune function.

Both physiological and pathological situations can result in biochemical changes of low-density lipoproteins (LDL). Because they can deliver signals to dendritic cells (DC), these modified lipoproteins now appear as regulators of the immune response. Among these modified lipoproteins, oxidized LDL (oxLDL) that accumulate during inflammatory conditions have been extensively studied.

Human group X secreted phospholipase A2 induces dendritic cell maturation through lipoprotein-dependent and -independent mechanisms.

Objective: Increased secreted phospholipase A(2) (sPLA(2)) activity has been documented in several inflammatory disorders. Among sPLA(2)s, the human group X (hGX)-sPLA(2) has the highest catalytic activity towards phosphatidylcholine (PC), the major phospholipid of cell membranes and blood lipoproteins. hGX-sPLA(2) has been detected in human atherosclerotic lesions, indicating that sPLA(2)s are an important link between lipids and inflammation, both involved in atherosclerosis.

High plasma level of nucleocapsid-free envelope glycoprotein-positive lipoproteins in hepatitis C patients.

Unlabelled: Hepatitis C virus (HCV) particles associate viral and lipoprotein moieties to form hybrid lipoviral particles (LVPs). Cell culture-produced HCV (HCVcc) and ex vivo-characterized LVPs primarily differ by their apolipoprotein (apo) B content, which is low for HCVcc, but high for LVPs. Recombinant nucleocapsid-free subviral LVPs are assembled and secreted by apoB-producing cell lines.

High-density lipoprotein phospholipids interfere with dendritic cell Th1 functional maturation.

Lipoproteins are both lipid carriers in the blood and regulators of essential biological processes. Several studies demonstrated that lipoproteins modified during pathological conditions could alter dendritic cell (DC) maturation. Here the immune function of non-pathological lipoproteins is addressed by analysing their impact on human DC maturation triggered by TLR ligands.

Single lysophosphatidylcholine components exhibit adjuvant activities in vitro and in vivo.

Improving vaccine immunogenicity by developing new adjuvant formulations has long been a goal of vaccinologists. It has previously been shown that a natural mix of lysophosphatidylcholine (LPC) from chicken eggs promotes mature dendritic cell (DC) generation in vitro and primes antigen-specific immune responses in mice. In the present study, we dissected the adjuvant potentials of five individual LPC components found in the chicken egg mixture.

Secretion of hepatitis C virus envelope glycoproteins depends on assembly of apolipoprotein B positive lipoproteins.

The density of circulating hepatitis C virus (HCV) particles in the blood of chronically infected patients is very heterogeneous. The very low density of some particles has been attributed to an association of the virus with apolipoprotein B (apoB) positive and triglyceride rich lipoproteins (TRL) likely resulting in hybrid lipoproteins known as lipo-viro-particles (LVP) containing the viral envelope glycoproteins E1 and E2, capsid and viral RNA. The specific infectivity of these particles has been shown to be higher than the infectivity of particles of higher density.

Transactivation of the hepatitis B virus core promoter by the nuclear receptor FXRalpha.

Hepatitis B virus (HBV) core promoter activity is positively and negatively regulated by nuclear receptors, a superfamily of ligand-activated transcription factors, via cis-acting sequences located in the viral genome. In this study, we investigated the role of farnesoid X receptor alpha (FXRalpha) in modulating transcription from the HBV core promoter. FXRalpha is a liver-enriched nuclear receptor activated by bile acids recognizing hormone response elements by forming heterodimers with retinoid X receptor alpha (RXRalpha).

Th1 disabled function in response to TLR4 stimulation of monocyte-derived DC from patients chronically-infected by hepatitis C virus.

Background: Lack of protective antibodies and inefficient cytotoxic responses are characteristics of chronic hepatitis C infection. A defect in dendritic cell (DC) function has thus been suspected, but this remains a controversial issue.

Methods And Findings: Here we show that monocyte-derived DC (MoDC) from chronically-infected patients can mature in response to TLR1/2, TLR2/6 or TLR3 ligands.