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Viruses May 2021Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide. Despite decades of research, the pathogenic mechanisms of hepatitis A remain... (Review)
Review
Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide. Despite decades of research, the pathogenic mechanisms of hepatitis A remain incompletely understood. As the replication of HAV is noncytopathic in vitro, a widely accepted concept has been that virus-specific cytotoxic T cells are responsible for liver injury. However, accumulating evidence suggests that natural killer (NK) cells, NKT cells, and even non-HAV-specific CD8 T cells contribute to liver damage during HAV infection. In addition, intrinsic death of virus-infected hepatocytes has been implicated as a cause of liver injury in a murine model of hepatitis A. Furthermore, genetic variations in host factors such as T cell immunoglobulin-1 (TIM1) and IL-18 binding protein (IL-18BP) have been linked to hepatitis A severity. This review summarizes the current knowledge of the mechanisms of hepatocellular injury in hepatitis A. Different mechanisms may be involved under different conditions and they are not necessarily mutually exclusive. A better understanding of these mechanisms would aid in diagnosis and treatment of diseases associated with HAV infection.
Topics: Animals; Carcinoma, Hepatocellular; Hepatitis A; Hepatitis A virus; Hepatocytes; Humans; Liver; Liver Neoplasms; Mice
PubMed: 34066709
DOI: 10.3390/v13050861 -
Journal of Vector Borne Diseases 2018Malaria, caused by the protozoan parasites of the genus Plasmodium, is a major health problem in many countries of the world. Five parasite species namely, Plasmodium... (Review)
Review
Malaria, caused by the protozoan parasites of the genus Plasmodium, is a major health problem in many countries of the world. Five parasite species namely, Plasmodium falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi, cause malaria in humans. Of these, P. falciparum and P. vivax are the most prevalent and account for the majority of the global malaria cases. In most areas of Africa, P. vivax infection is essentially absent because of the inherited lack of Duffy antigen receptor for chemokines on the surface of red blood cells that is involved in the parasite invasion of erythrocytes. Therefore, in Africa, most malaria infections are by P. falciparum and the highest burden of P. vivax infection is in Southeast Asia and South America. Plasmodium falciparum is the most virulent and as such, it is responsible for the majority of malarial mortality, particularly in Africa. Although, P. vivax infection has long been considered to be benign, recent studies have reported life-threatening consequences, including acute respiratory distress syndrome, cerebral malaria, multi-organ failure, dyserythropoiesis and anaemia. Despite exhibiting low parasite biomass in infected people due to parasite's specificity to infect only reticulocytes, P. vivax infection triggers higher inflammatory responses and exacerbated clinical symptoms than P. falciparum, such as fever and chills. Another characteristic feature of P. vivax infection, compared to P. falciparum infection, is persistence of the parasite as dormant liver-stage hypnozoites, causing recurrent episodes of malaria. This review article summarizes the published information on P. vivax epidemiology, drug resistance and pathophysiology.
Topics: Antimalarials; Asia, Southeastern; Drug Resistance; Female; Humans; Inflammation; Liver; Malaria, Vivax; Male; Plasmodium vivax; Pregnancy; Pregnancy Complications, Parasitic; Recurrence; South America
PubMed: 29916441
DOI: 10.4103/0972-9062.234620 -
ELife Jul 2021The molecular events that drive hepatitis B virus (HBV)-mediated transformation and tumorigenesis have remained largely unclear, due to the absence of a relevant primary...
The molecular events that drive hepatitis B virus (HBV)-mediated transformation and tumorigenesis have remained largely unclear, due to the absence of a relevant primary model system. Here we propose the use of human liver organoids as a platform for modeling HBV infection and related tumorigenesis. We first describe a primary ex vivo HBV-infection model derived from healthy donor liver organoids after challenge with recombinant virus or HBV-infected patient serum. HBV-infected organoids produced covalently closed circular DNA (cccDNA) and HBV early antigen (HBeAg), expressed intracellular HBV RNA and proteins, and produced infectious HBV. This ex vivo HBV-infected primary differentiated hepatocyte organoid platform was amenable to drug screening for both anti-HBV activity and drug-induced toxicity. We also studied HBV replication in transgenically modified organoids; liver organoids exogenously overexpressing the HBV receptor sodium taurocholate co-transporting polypeptide (NTCP) after lentiviral transduction were not more susceptible to HBV, suggesting the necessity for additional host factors for efficient infection. We also generated transgenic organoids harboring integrated HBV, representing a long-term culture system also suitable for viral production and the study of HBV transcription. Finally, we generated HBV-infected patient-derived liver organoids from non-tumor cirrhotic tissue of explants from liver transplant patients. Interestingly, transcriptomic analysis of patient-derived liver organoids indicated the presence of an aberrant early cancer gene signature, which clustered with the hepatocellular carcinoma (HCC) cohort on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset and away from healthy liver tissue, and may provide invaluable novel biomarkers for the development of HCC and surveillance in HBV-infected patients.
Topics: Carcinoma, Hepatocellular; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Liver; Liver Neoplasms; Living Donors; Models, Biological; Organoids; Virus Replication
PubMed: 34328417
DOI: 10.7554/eLife.60747 -
World Journal of Gastroenterology Nov 2018Liver injury is a characteristic feature of human immunodeficiency virus (HIV) infection, which is the second most common cause of mortality in HIV-infected patients.... (Review)
Review
Liver injury is a characteristic feature of human immunodeficiency virus (HIV) infection, which is the second most common cause of mortality in HIV-infected patients. Now it is recognized that liver plays a key role in HIV infection pathogenesis. Antiretroviral therapy (ART), which suppresses HIV infection in permissive immune cells, is less effective in hepatocytes, thereby making these cells a silent reservoir of HIV infection. In addition to direct hepatotoxic effects of HIV, certain ART treatment modalities provide hepatotoxic effects. The exact mechanisms of HIV-triggered chronic hepatitis progression are not elucidated, but the liver is adversely affected by HIV-infection and liver cells are prominently involved in HIV-elicited injury. These effects are potentiated by second hits like alcohol. Here, we will focus on the incidence of HIV, clinical evidence of HIV-related liver damage, interactions between HIV and liver cells and the role of alcohol and co-infection with hepatotropic viruses in liver inflammation and fibrosis progression.
Topics: Alcohol Drinking; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Coinfection; Disease Progression; HIV; HIV Infections; Hepacivirus; Hepatitis B; Hepatitis B virus; Hepatitis C; Hepatocytes; Humans; Incidence; Liver; Liver Cirrhosis
PubMed: 30479460
DOI: 10.3748/wjg.v24.i42.4728 -
Journal of Gastroenterology and... Aug 2013Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect and replicate primarily in human hepatocytes. Few reliable and easy accessible animal models are available for... (Review)
Review
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect and replicate primarily in human hepatocytes. Few reliable and easy accessible animal models are available for studying the immune system's contribution to the liver disease progression during hepatitis virus infection. Humanized mouse models reconstituted with human hematopoietic stem cells (HSCs) have been developed to study human immunology, human immunodeficiency virus 1 infection, and immunopathogenesis. However, a humanized mouse model engrafted with both human immune and human liver cells is needed to study infection and immunopathogenesis of HBV/HCV infection in vivo. We have recently developed the humanized mouse model with both human immune and human liver cells (AFC8-hu HSC/Hep) to study immunopathogenesis and therapy of HCV infection in vivo. In this review, we summarize the current models of HBV/HCV infection and their limitations in immunopathogenesis. We will then present our recent findings of HCV infection and immunopathogenesis in the AFC8-hu HSC/Hep mouse, which supports HCV infection, human T-cell response and associated liver pathogenesis. Inoculation of humanized mice with primary HCV isolates resulted in long-term HCV infection. HCV infection induced elevated infiltration of human immune cells in the livers of HCV-infected humanized mice. HCV infection also induced HCV-specific T-cell immune response in lymphoid tissues of humanized mice. Additionally, HCV infection induced liver fibrosis in humanized mice. Anti-human alpha smooth muscle actin (αSMA) staining showed elevated human hepatic stellate cell activation in HCV-infected humanized mice. We discuss the limitation and future improvements of the AFC8-hu HSC/Hep mouse model and its application in evaluating novel therapeutics, as well as studying both HCV and HBV infection, human immune responses, and associated human liver fibrosis and cancer.
Topics: Animals; Disease Models, Animal; Fibrosis; Hepacivirus; Hepatic Stellate Cells; Hepatitis B; Hepatitis B virus; Hepatitis C; Humans; Liver; Mice; Mice, SCID; Mice, Transgenic; T-Lymphocytes
PubMed: 23855307
DOI: 10.1111/jgh.12092 -
Frontiers in Immunology 2021The non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is an important component of NF-κB transcription complex.... (Review)
Review
The non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is an important component of NF-κB transcription complex. Activation of this pathway mediates the development and function of host immune system involved in inflammation and viral infection. During hepatitis B virus (HBV) infection, there is a complex interaction between infected hepatocytes and the immune cells, which can hinder antiviral immune responses and is associated with pathological changes in liver tissue. Consistently, the host immune system is closely related to the severity of liver damage and the level of viral replication. Previous studies indicated that the non-canonical NF-κB signaling pathway was affected by HBV and might play an important regulatory role in the antiviral immunity. Therefore, systematically elucidating the interplay between HBV and non-canonical NF-κB signaling will contribute the discovery of more potential therapeutic targets and novel drugs to treat HBV infection.
Topics: Animals; Antiviral Agents; Hepatitis B; Hepatitis B virus; Host-Pathogen Interactions; Humans; Liver; NF-kappa B; Signal Transduction
PubMed: 34659217
DOI: 10.3389/fimmu.2021.730684 -
World Journal of Gastroenterology Nov 2015This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus... (Review)
Review
This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis.
Topics: Bacterial Infections; Bacterial Translocation; Diagnosis, Differential; Hepacivirus; Hepatitis C; Host-Pathogen Interactions; Humans; Inflammation Mediators; Liver; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Predictive Value of Tests; Prognosis; Risk Factors; Signal Transduction
PubMed: 26556984
DOI: 10.3748/wjg.v21.i41.11522 -
Liver International : Official Journal... May 2020The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), the pathogen of 2019 novel coronavirus disease (COVID-19), has posed a serious threat to global public... (Review)
Review
The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), the pathogen of 2019 novel coronavirus disease (COVID-19), has posed a serious threat to global public health. The WHO has declared the outbreak of SARS-CoV-2 infection an international public health emergency. Lung lesions have been considered as the major damage caused by SARS-CoV-2 infection. However, liver injury has also been reported to occur during the course of the disease in severe cases. Similarly, previous studies have shown that liver damage was common in the patients infected by the other two highly pathogenic coronavirus - severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), and associated with the severity of diseases. In this review, the characteristics and mechanism of liver injury caused by SARS-CoV, MERS-CoV as well as SARS-CoV-2 infection were summarized, which may provide help for further studies on the liver injury of COVID-19.
Topics: Betacoronavirus; COVID-19; Coronavirus Infections; Disease Progression; Humans; Liver; Middle East Respiratory Syndrome Coronavirus; Pandemics; Pneumonia, Viral; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2
PubMed: 32170806
DOI: 10.1111/liv.14435 -
Human Pathology Feb 2020Infection with the hepatitis E virus (HEV) is one of the most common causes, if not the most common, of acute hepatitis worldwide. In the last decade, we have learned... (Review)
Review
Infection with the hepatitis E virus (HEV) is one of the most common causes, if not the most common, of acute hepatitis worldwide. In the last decade, we have learned that, in addition to the endemically and epidemically occurring form of hepatitis E, which is predominantly transmitted by contaminated drinking water and constitutes a significant health problem in resource-poor countries, there is a globally existing form of hepatitis E, which is a zoonosis and as such is primarily transmitted by the consumption of contaminated meat products. Although in most cases hepatitis E is subclinical or mild and self-limiting, pregnant women and patients with liver cirrhosis may have severe, occasionally even fatal disease, and immunocompromised individuals may develop chronic hepatitis E. Considering the substantial global health burden caused by HEV infection, it is surprising how limited our knowledge of hepatitis E pathology still is. In this article, we describe localization studies on HEV infection and discuss their implications for everyday diagnostics. Furthermore, we outline and discuss the spectrum of histologic changes, which can be found in HEV infection in various clinical contexts.
Topics: Biopsy; Hepatitis E; Hepatitis E virus; Host-Pathogen Interactions; Humans; Immunohistochemistry; Liver; Predictive Value of Tests; Prognosis; Viral Proteins
PubMed: 31666196
DOI: 10.1016/j.humpath.2019.10.003 -
World Journal of Gastroenterology Sep 2015Hepatitis C virus (HCV) is a hepatotrophic virus and a major cause of chronic liver disease, including hepatocellular carcinoma, worldwide. The life cycle of HCV is... (Review)
Review
Hepatitis C virus (HCV) is a hepatotrophic virus and a major cause of chronic liver disease, including hepatocellular carcinoma, worldwide. The life cycle of HCV is closely associated with the metabolism of lipids and lipoproteins. The main function of lipoproteins is transporting lipids throughout the body. Triglycerides, free cholesterol, cholesteryl esters, and phospholipids are the major components of the transported lipids. The pathway of HCV assembly and secretion is closely linked to lipoprotein production and secretion, and the infectivity of HCV particles largely depends on the interaction of lipoproteins. Moreover, HCV entry into hepatocytes is strongly influenced by lipoproteins. The key lipoprotein molecules mediating these interactions are apolipoproteins. Apolipoproteins are amphipathic proteins on the surface of a lipoprotein particle, which help stabilize lipoprotein structure. They perform a key role in lipoprotein metabolism by serving as receptor ligands, enzyme co-factors, and lipid transport carriers. Understanding the association between the life cycle of HCV and lipoprotein metabolism is important because each step of the life cycle of HCV that is associated with lipoprotein metabolism is a potential target for anti-HCV therapy. In this article, we first concisely review the nature of lipoprotein and its metabolism to better understand the complicated interaction of HCV with lipoprotein. Then, we review the outline of the processes of HCV assembly, secretion, and entry into hepatocytes, focusing on the association with lipoproteins. Finally, we discuss the clinical aspects of disturbed lipid/lipoprotein metabolism and the significance of dyslipoproteinemia in chronic HCV infection with regard to abnormal apolipoproteins.
Topics: Animals; Hepacivirus; Hepatitis C, Chronic; Humans; Lipoproteins; Liver; Virus Internalization
PubMed: 26420957
DOI: 10.3748/wjg.v21.i36.10299