• RGPIN-2022-04026 Natural Sciences and Engineering Research Council of Canada

• environmental factors
• fibrosis regression
• genetic determinants
• hepatocarcinogenesis
• liver fibrosis
• signaling pathways

• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/metabolism
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Liver Cirrhosis/metabolism
• Disease Progression
• Animals
• Gene-Environment Interaction
• Hepatic Stellate Cells/metabolism
• Hepatic Stellate Cells/pathology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/metabolism
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Extracellular Matrix/metabolism
• Liver/pathology
• Liver/metabolism

• cytokine levels
• fetal alcohol spectrum disorders
• immunological development
• in utero exposure
• prenatal alcohol exposure
• toll-like receptor agonists
• umbilical cord blood

• Humans
• Female
• Pregnancy
• Fetal Blood/metabolism
• Pilot Projects
• Toll-Like Receptors/metabolism
• Toll-Like Receptors/agonists
• Cytokines/metabolism
• Cytokines/blood
• Adult
• Infant, Newborn
• Prenatal Exposure Delayed Effects/metabolism
• Leukocytes, Mononuclear/metabolism
• Leukocytes, Mononuclear/drug effects
• Male
• Ethanol/pharmacology
• Toll-Like Receptor 2/metabolism
• Toll-Like Receptor 2/agonists

• R01 AA021771 NIAAA NIH HHS
• 2R01AA021771 and P50 AA022534 NIH HHS

• Humans
• Hepatitis, Chronic
• Carcinoma, Hepatocellular
• Liver Neoplasms
• Hepatitis, Viral, Human
• Antiviral Agents/therapeutic use

• ECTZ132153 ANRS
• 22-CE15-0001 ANR

• structural biology
• biotechnology
• computational biology and bioinformatics
• drug discovery
• immunology
• microbiology
• molecular biology

• Child
• Humans
• Respiratory Syncytial Virus, Human
• Molecular Docking Simulation
• Vaccines, Combined
• Respiratory Syncytial Virus Infections
• Epitopes, B-Lymphocyte
• Antibodies, Viral

• antiviral innate immunity
• capsid proteins
• enterovirus 71
• immune activation
• toll-like receptors

• Humans
• Animals
• Mice
• Toll-Like Receptor 1
• Toll-Like Receptor 2/metabolism
• Enterovirus A, Human
• Proto-Oncogene Proteins c-akt
• Phosphatidylinositol 3-Kinases
• Toll-Like Receptor 6/metabolism
• Toll-Like Receptor 4
• Capsid Proteins
• Toll-Like Receptors
• Cell Membrane/metabolism

• National Key Research and Development Program of China
• National Natural Science Foundation of China
• Natural Science Foundation of Hebei Province

• apoptosis
• autophagy
• disease associations
• ferroptosis
• hepatocellular carcinoma

• TLR agonist
• TLR antagonist
• TLR2
• TLR4
• Toll-like receptors
• cytokines
• innate immunity
• interferons
• viral proteins
• viruses

• Viral Proteins
• Signal Transduction
• Toll-Like Receptors
• Viruses
• Receptors, Pattern Recognition
• Immunity, Innate

• F31 AI161890 NIAID NIH HHS

• Adaboost
• HCV
• SVM
• Xgboost
• protein-protein interaction
• random forest

• cellular metabolism
• hepatitis virus
• hepatocyte
• immunometabolism
• inflammation
• innate immunity
• liver diseases

• Humans
• Carcinoma, Hepatocellular
• Liver Neoplasms
• Hepatitis Viruses
• Hepatocytes
• Antiviral Agents/therapeutic use

Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals with a significant socioeconomic impact. One of the issues related to this disease is the ability of its etiological agent, foot-and-mouth disease virus (FMDV), to persist in the organism of its hosts via underlying mechanisms that remain to be elucidated. The establishment of a virus–host equilibrium via protein–protein interactions could contribute to explaining these phenomena. FMDV has indeed developed numerous strategies to evade the immune response, especially the type I interferon response. Viral proteins target this innate antiviral response at different levels, ranging from blocking the detection of viral RNAs to inhibiting the expression of ISGs. The large diversity of impacts of these interactions must be considered in the light of the in vitro models that have been used to demonstrate them, some being sometimes far from biological systems. In this review, we have therefore listed the interactions between FMDV and the interferon response as exhaustively as possible, focusing on both their biological effect and the study models used.

• Animals
• Foot-and-Mouth Disease Virus
• Foot-and-Mouth Disease
• Viral Proteins/metabolism
• Interferon Type I/metabolism
• Antiviral Agents/metabolism

Members of the Flaviviridae family are posing a significant threat to human health worldwide. Many flaviviruses are capable of inducing severe inflammation in humans. Flaviviridae nonstructural proteins, apart from their canonical roles in viral replication, have noncanonical functions strongly affecting antiviral innate immunity. Among these functions, antagonism of type I IFN is the most investigated; meanwhile, more data are accumulated on their role in the other pathways of innate response. This review systematizes the last known data on the role of Flaviviridae nonstructural proteins in molecular mechanisms of triggering inflammation, with an emphasis on their interactions with TLRs and RLRs, interference with NF-κB and cGAS-STING signaling, and activation of inflammasomes.

• Flaviviridae/metabolism
• Humans
• Immunity, Innate
• Inflammasomes
• Inflammation
• Signal Transduction

• disorder-to-order transition
• hepatitis C virus
• intrinsically disordered protein
• intrinsically disordered region
• posttranslational modifications
• protein–protein interactions
• toll-like receptors

• 838 Deputyship for Research & Innovation, Ministry of Education of Saudi Arabia

• Toll-like receptor
• cytokines
• hepatitis C virus
• infection
• innate immunity

Chikungunya virus (CHIKV) is the etiological agent of chikungunya fever (CHIKF), a self-limiting disease characterized by myalgia and severe acute or chronic arthralgia. CHIKF is associated with immunopathology and high levels of pro-inflammatory factors. CHIKV is known to have a wide range of tropism in human cell types, including keratinocytes, fibroblasts, endothelial cells, monocytes, and macrophages. Previously, we reported that CHIKV-infected monocytes-derived macrophages (MDMs) express high levels of interleukin 27 (IL27), a heterodimeric cytokine consisting of IL27p28 and EBI3 subunits, that triggers JAK-STAT signaling and promotes pro-inflammatory and antiviral response, in interferon (IFN)-independent manner. Based on the transcriptomic analysis, we now report that induction of IL27-dependent pro-inflammatory and antiviral response in CHIKV-infected MDMs relies on two signaling pathways: an early signal dependent on recognition of CHIKV-PAMPs by TLR1/2-MyD88 to activate NF-κB-complex that induces the expression of EBI3 mRNA; and second signaling dependent on the recognition of intermediates of CHIKV replication (such as dsRNA) by TLR3-TRIF, to activate IRF1 and the induction of IL27p28 mRNA expression. Both signaling pathways were required to produce a functional IL27 protein involved in the induction of ISGs, including antiviral proteins, cytokines, CC- and CXC- chemokines in an IFN-independent manner in MDMs. Furthermore, we reported that activation of TLR4 by LPS, both in human MDMs and murine BMDM, results in the induction of both subunits of IL27 that trigger strong IL27-dependent pro-inflammatory and antiviral response independent of IFNs signaling. Our findings are a significant contribution to the understanding of molecular and cellular mechanisms of CHIKV infection.

• HBV
• HCV
• cirrhosis
• hepatocellular carcinoma
• survival

• Antiviral Agents/therapeutic use
• Carcinoma, Hepatocellular/diagnostic imaging
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/physiopathology
• Carcinoma, Hepatocellular/prevention & control
• Hepatitis B, Chronic/complications
• Hepatitis B, Chronic/drug therapy
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/drug therapy
• Hepatitis D, Chronic
• Humans

• Fibrosis
• Hepatocellular carcinoma
• Kupffer cell
• Liver
• Macrophage
• Monocyte
• NASH
• Therapy

• Carcinoma, Hepatocellular/pathology
• Humans
• Kupffer Cells/pathology
• Kupffer Cells/physiology
• Liver Neoplasms
• Macrophages

• MR/W015919/1 Medical Research Council

The pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here, we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induced inflammatory cytokines and chemokines, including IL-6, IL-1β, TNFα, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and nucleocapsid (N) proteins. When stimulated with extracellular S protein, human and mouse lung epithelial cells also produced inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly were non-inflammatory, but elicited an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-κB pathway in a MyD88-dependent manner. Further, such an activation of the NF-κB pathway was abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein-induced IL-6, TNF-α, and IL-1β in wild-type, but not Tlr2-deficient mice. Notably, upon recognition of S protein, TLR2 dimerizes with TLR1 or TLR6 to activate the NF-κB pathway. Taken together, these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.

• COVID-19
• SARS-CoV-2
• TLR2
• cytokine storm
• immunology
• inflammation
• spike protein
• viruses

• Hepatitis C
• Immune evasion
• Inflammation
• Interferons
• Toll-like receptors

• Cancer
• Fibrosis
• HSCs
• Inflammation
• KCs
• TLR2

• Klebsiella pneumoniae
• drug resistant
• human neutrophil peptide 1
• immune sterilization
• macrophages

• Fibrosis
• HBeAg
• Hepatic stellate cell
• Inflammation
• Macrophage

• PAMPs
• TLRs
• innate immunity
• viral proteins

• HBV
• HCV
• Kupffer cells
• NAFLD
• NASH
• acute liver injury
• chronic liver injury
• hepatic macrophages
• liver fibrosis
• monocyte-derived macrophages

• Animals
• Homeostasis/physiology
• Humans
• Kupffer Cells/pathology
• Liver/pathology
• Liver Diseases/pathology
• Macrophages/pathology
• Monocytes/pathology

Coevolution occurs between viruses and their hosts. The hosts need to evolve means to eliminate pathogenic virus infections, and the viruses, for their own survival and multiplication, have to develop mechanisms to escape clearance by hosts. Hepatitis C virus (HCV) of Flaviviridae is a pathogen which infects human liver and causes hepatitis, a condition of liver inflammation. Unlike most of the other flaviviruses, HCV has an excellent ability to evade host immunity to establish chronic infection. The persistent liver infection leads to chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), as well as extrahepatic HCV-related diseases. HCV genomic RNA only expresses 10 proteins, many of which bear functions, in addition to those involved in HCV life cycle, for assisting the virus to develop its persistency. HCV core protein is a structural protein which encapsulates HCV genomic RNA and assembles into nucleocapsids. The core protein is also found to exert functions to affect host inflammation and immune responses by altering a variety of host pathways. This paper reviews the studies regarding the HCV core protein-induced alterations of host immunity and inflammatory responses, as well as the involvements of the HCV core protein in pro- and anti-inflammatory cytokine stimulations, host cellular transcription, lipid metabolism, cell apoptosis, cell proliferations, immune cell differentiations, oxidative stress, and hepatocyte steatosis, which leads to liver fibrosis, cirrhosis, and HCC. Implications of roles played by the HCV core protein in therapeutic resistance are also discussed.

• SARS-CoV-2
• co-infection
• comorbidity
• drugs
• host response
• integrative genomics
• therapeutics
• vaccines

• MLP-2005,2020 Council of Scientific and Industrial Research

• Antiviral activity
• Herpes simplex virus (HSV)
• Mitogen-activated protein kinase (MAPK)
• Nuclear factor κB (NF-κB)
• Wogonin

• B cells
• HCV
• IL-10
• Immunotherapy
• Infection

• CD14
• FMDV
• IL-6
• TLR
• macrophages

• DAA
• ER stress
• HCC
• HCV
• IFN
• autophagy
• direct-acting antiviral
• endoplasmic reticulum stress
• hepatitis C virus
• hepatocellular carcinoma
• interferon

• I01 BX004516 BLRD VA
• P20 GM121288 NIGMS NIH HHS
• U54 GM104940 NIGMS NIH HHS

•

The article provides a summary on cellular receptors involved in virus immunity.

Viroporins are virus encoded proteins that alter membrane permeability and can trigger subsequent cellular signals. Oligomerization of viroporin subunits results in formation of a hydrophilic pore which facilitates ion transport across host cell membranes. These viral channel proteins may be involved in different stages of the virus infection cycle. Inflammasomes are large multimolecular complexes best recognized for their ability to control activation of caspase-1, which in turn regulates the maturation of interleukin-1 β (IL-1β) and interleukin 18 (IL-18). IL-1β was originally identified as a pro-inflammatory cytokine able to induce both local and systemic inflammation and a febrile reaction in response to infection or injury. Excessive production of IL-1β is associated with autoimmune and inflammatory diseases. Microbial derivatives, bacterial pore-forming toxins, extracellular ATP and other pathogen-associated molecular patterns trigger activation of NLRP3 inflammasomes. Recent studies have reported that viroporin activity is capable of inducing inflammasome activity and production of IL-1β, where NLRP3 is shown to be regulated by fluxes of K⁺, H⁺ and Ca²⁺ in addition to reactive oxygen species, autophagy and endoplasmic reticulum stress. The aim of this review is to present an overview of the key findings on viroporin activity with special emphasis on their role in virus immunity and as possible activators of inflammasomes.

• Inflammasomes
• Inflammation
• NLRP3
• Viroporins
• Virus-immunity

• chemokines
• hepatitis C virus
• interferon-γ
• interleukin-1β
• liver endothelial cells

Hepatic macrophages are a remarkably heterogeneous population consisting of self-renewing tissue-resident phagocytes, termed Kupffer cells (KCs), and recruited macrophages derived from peritoneal cavity as well as the bone marrow. KCs are located in the liver sinusoid where they scavenge the microbe from the portal vein to maintain liver homeostasis. Liver injury may trigger hepatic recruitment of peritoneal macrophages and monocyte-derived macrophages. Studies describing macrophage accumulation have shown that hepatic macrophages are involved in the initiation and progression of various liver diseases. They act as tolerogenic antigen-presenting cells to inhibit T-cell activation by producing distinct sets of cytokines, chemokines, and mediators to maintain or resolve inflammation. Furthermore, by releasing regenerative growth factors, matrix metalloproteinase arginase, they promote tissue repair. Recent experiments found that KCs and recruited macrophages may play different roles in the development of liver disease. Given that hepatic macrophages are considerably plastic populations, their phenotypes and functions are likely switching along disease progression. In this review, we summarize current knowledge about the role of tissue-resident macrophages and recruited macrophages in pathogenesis of alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), viral hepatitis, and hepatocellular carcinoma (HCC).

• Kupffer cells
• alcoholic liver disease
• hepatic macrophages
• hepatocellular carcinoma
• non-alcoholic steatohepatitis
• viral hepatitis

Hepatic macrophages play a central role in maintaining homeostasis in the liver, as well as in the initiation and progression of liver diseases. Hepatic macrophages are mainly derived from resident hepatic macrophages called Kupffer cells or circulating bone marrow-derived monocytes. Kupffer cells are self-renewing and typically non-migrating macrophages in the liver and are stationed in the liver sinusoids in contrast to macrophages originating from circulating monocytes. Kupffer cells regulate liver homeostasis by mediating immunity against non-pathogenic blood-borne molecules, while participating in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes present in the vasculature. Monocyte-derived macrophages infiltrate into the liver tissue when metabolic or toxic damage instigates and are likely dispensable for replenishing the macrophage population in homeostasis. In recent years, different populations of hepatic macrophages have been identified with distinct phenotypes with discrete functions, far beyond the central dogma of M1 and M2 macrophages. Hepatic macrophages play a central role in the pathogenesis of acute and chronic liver failure, liver fibrosis, non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and hepatocellular carcinoma, as well as in disease resolution. The understanding of the role of hepatic macrophages in liver diseases provides opportunities for the development of targeted therapeutics for respective malignancies. This review will summarize the current knowledge of the hepatic macrophages, their origin, functions, their critical role in maintaining homeostasis and in the progression or resolution of liver diseases. Furthermore, we will provide a comprehensive overview of the therapeutic targeting strategies against hepatic macrophages developed for the treatment of liver diseases.

• Kupffer cells
• hepatic macrophages
• liver diseases
• monocytes
• targeted therapeutics

• Cytokines
• Hepatitis C virus
• IL-1
• IL-6
• Serum amyloid A
• TNF-α

• TLR
• non-severedengue
• severe dengue
• thrombocytopenia

Control of homeostasis and rapid response to tissue damage in the liver is orchestrated by crosstalk between resident and infiltrating inflammatory cells. A crucial role for myeloid cells during hepatic injury and repair has emerged where resident Kupffer cells, circulating monocytes, macrophages, dendritic cells and neutrophils control local tissue inflammation and regenerative function to maintain tissue architecture. Studies in humans and rodents have revealed a heterogeneous population of myeloid cells that respond to the local environment by either promoting regeneration or driving the inflammatory processes that can lead to hepatitis, fibrogenesis, and the development of cirrhosis and malignancy. Such plasticity of myeloid cell responses presents unique challenges for therapeutic intervention strategies and a greater understanding of the underlying mechanisms is needed. Here we review the role of myeloid cells in the establishment and progression of liver disease and highlight key pathways that have become the focus for current and future therapeutic strategies.

• circulating monocytes
• cirrhosis
• fibrosis
• hepatitis (general)
• hepatocellular carcinoma
• macrophage
• myeloid derived suppressor cell (MDSC)
• neutrophil (PMN)

Background and Aims: Polymorphisms in the immune response genes can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation and cancer pathogenesis. This study aimed to investigate the association of polymorphisms in PD-1 (PDCD1), IFNL3 (IL28B), and TLR2 immune related genes in chronic HCV patients with different hepatic and lymphoproliferative HCV-related diseases.

Methods: Selected PDCD1, IFNL3, and TLR2 genes were tested by molecular approaches in 450 HCV-positive patients with increasing severity of underlying liver diseases [including chronic infection (CHC), cirrhosis and hepatocellular carcinoma (HCC)], in 238 HCV-positive patients with lymphoproliferative diseases [such as cryoglobulinemia and non-Hodgkin lymphoma (NHL)] and in 94 blood donors (BD).

Results: While the rs12979860 IFNL3 T allele was found a good marker associated with HCV-outcome together with the rs111200466 TLR2 del variant, the rs10204525 PD-1.6 A allele was found to have an insignificant role in patients with HCV-related hepatic disorders. Though in Asian patients the combination of IFNL3 and PD-1.6 markers better define the HCV-related outcomes, in our series of Caucasian patients the PD-1.6 A-allele variant was observed very rarely.

Conclusion: Differences in the incidence of HCV-related HCC and clinical response between Asians and Europeans may be partially due to the distribution of PD-1.6 genotype that we found divergent between these two populations. On the other hand, we confirmed in this study that the polymorphic variants within IFNL3 and TLR2 immune response genes are significantly associated with HCV-related disease progression in our cohort of Italian patients.

• IFNL3
• PD-1
• TLR2
• cirrhosis
• gene polymorphism
• hepatitis virus C
• hepatocellular carcinoma
• lymphoproliferative disorders

• Classical swine fever virus
• Innate immune
• Non-structural proteins
• Porcine monocyte-derived macrophages
• Toll-like receptors

The mononuclear phagocyte system (MPS), which consists of monocytes, dendritic cells (DCs), and macrophages, plays a vital role in the innate immune defense against pathogens. Hepatitis C virus (HCV) is efficient in evading the host immunity, thereby facilitating its development into chronic infection. Chronic HCV infection is the leading cause of end-stage liver diseases, liver cirrhosis, and hepatocellular carcinoma. Acquired immune response was regarded as the key factor to eradicate HCV. However, innate immunity can regulate the acquired immune response. Innate immunity-derived cytokines shape the adaptive immunity by regulating T-cell differentiation, which determines the outcome of acute HCV infection. Inhibition of HCV-specific T-cell responses is one of the most important strategies for immune system evasion. It is meaningful to illustrate the role of innate immune response in HCV infection. With the MPS being the important factor in innate immunity, therefore, understanding the role of the MPS in HCV infection will shed light on the pathophysiology of chronic HCV infection. In this review, we outline the impact of HCV infection on the MPS and cytokine production. We discuss how HCV is detected by the MPS and describe the function and impairment of MPS components in HCV infection.

• Mononuclear phagocyte system
• Hepatitis C virus
• Monocyte
• Dendritic cell
• Macrophage

• Adaptive Immunity/immunology
• Hepacivirus/immunology
• Hepatitis C, Chronic/immunology
• Hepatitis C, Chronic/virology
• Humans
• Immunity, Innate/immunology
• Mononuclear Phagocyte System/immunology

• cytomegalovirus
• latency
• miRNA

• HCV
• acetaldehyde
• apoptotic bodies
• ethanol
• fibrosis
• liver inflammation

• Apoptosis/genetics
• Cells, Cultured
• Disease Progression
• Ethanol/toxicity
• Hepacivirus/pathogenicity
• Hepatic Stellate Cells/pathology
• Hepatic Stellate Cells/virology
• Hepatocytes/pathology
• Hepatocytes/virology
• Humans
• Inflammation/chemically induced
• Inflammation/pathology
• Inflammation/virology
• Liver/pathology
• Liver/virology
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/pathology
• Liver Cirrhosis/virology
• Macrophages/pathology
• Macrophages/virology

• K01 AA026864 NIAAA NIH HHS
• R24 OD018546 NIH HHS

• Hepatic myofibroblasts
• Hepatic stellate cells
• Liver biopsy
• Liver fibrosis
• Transient elestography

• Acute hepatitis
• Akt
• MAPK
• TLR2
• TRIAC

• Inflammation
• fibrosis
• interferon treatment
• macrophages
• sofosbuvir

• Comorbidities
• DAAs
• HCV
• Treatment