|
1
|
Ding L, Huang J, Huang S. The significance of antibody to hepatitis B surface antigen in infection and clearance of hepatitis B virus. Hum Vaccin Immunother 2025; 21:2445283. [PMID: 39754388 DOI: 10.1080/21645515.2024.2445283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/30/2024] [Accepted: 12/17/2024] [Indexed: 01/06/2025] Open
Abstract
One of the key features of chronic hepatitis B virus (HBV) infection is the inability to mount sufficient and coordinated adaptive immune responses against HBV. Recent studies on HBV-specific B cells and antibody to hepatitis B surface antigen (anti-HBs) have shed light on their role in the pathogenesis of chronic hepatitis B (CHB). Anti-HBs is recognized as a protective immune marker, both for HBV infection clearance and following vaccination, and it is also considered an important indicator of functional cure for CHB. Notably, functional impairment of HBV-specific B cells may be reversible. The restoration of HBV-specific B cell function, along with the induction of an anti-HBs antibody response, is regarded as pivotal for terminating chronic HBV infection and achieving functional cure. This article reviews the significance of anti-HBs in both the infection and clearance of HBV, and discusses the potential of neutralizing antibodies and therapeutic vaccines as promising future strategies.
Collapse
Affiliation(s)
- Ling Ding
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaquan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuaiwen Huang
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
2
|
Wan H, Zhang YX, Shan GY, Cheng JY, Qiao DR, Liu YY, Shi WN, Li HJ. Antiviral therapy for hepatitis B virus infection is beneficial for the prognosis hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:93983. [PMID: 39817121 PMCID: PMC11664622 DOI: 10.4251/wjgo.v17.i1.93983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 09/20/2024] [Accepted: 09/29/2024] [Indexed: 12/12/2024] Open
Abstract
In this editorial, we comment on the article by Mu et al, published in the recent issue of the World Journal of Gastrointestinal Oncology. We pay special attention to the immune tolerance mechanism caused by hepatitis B virus (HBV) infection, the pathogenesis of hepatocellular carcinoma (HCC), and the role of antiviral therapy in treating HCC related to HBV infection. HBV infection leads to systemic innate immune tolerance by directly inhibiting pattern recognition receptor recognition and antiviral signaling pathways, as well as by inhibiting the immune functions of macrophages, natural killer cells and dendritic cells. In addition, HBV leads to an immunosuppressive cascade by expressing inhibitory molecules to induce exhaustion of HBV-specific cluster of differentiation 8 + T cells, ultimately leading to long-term viral infection. The loss of immune cell function caused by HBV infection ultimately leads to HCC. Long-term antiviral therapy can improve the prognosis of patients with HCC and prevent tumor recurrence and metastasis.
Collapse
Affiliation(s)
- Hui Wan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Yu-Xin Zhang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Guan-Yue Shan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Jun-Ya Cheng
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Duan-Rui Qiao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Yi-Ying Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Wen-Na Shi
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Hai-Jun Li
- Institute of Liver Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| |
Collapse
|
|
3
|
Bertoletti A. The immune response in chronic HBV infection. J Viral Hepat 2024; 31 Suppl 2:43-55. [PMID: 38845402 DOI: 10.1111/jvh.13962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 05/14/2024] [Indexed: 12/06/2024]
Abstract
Hepatitis B virus (HBV) is an ancient virus that has evolved unique strategies to persist as a chronic infection in humans. Here, I summarize the innate and adaptive features of the HBV-host interaction, and I discuss how different profiles of antiviral immunity cannot be predicted only on the basis of virological and clinical parameters.
Collapse
Affiliation(s)
- Antonio Bertoletti
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
| |
Collapse
|
|
4
|
Jiao Q, Zhu S, Liao B, Liu H, Guo X, Wu L, Chen C, Peng L, Xie C. An NLR family member X1 mutation (p.Arg707Cys) suppresses hepatitis B virus infection in hepatocytes and favors the interaction of retinoic acid-inducible gene 1 with mitochondrial antiviral signaling protein. Arch Virol 2024; 169:238. [PMID: 39499386 PMCID: PMC11538211 DOI: 10.1007/s00705-024-06133-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 07/25/2024] [Indexed: 11/07/2024]
Abstract
NLR family member X1 (NLRX1) is an important member of the NOD-like receptor (NLR) family and plays unique roles in immune system regulation. Patients with hepatitis B virus (HBV) infection are more likely to have the NLRX1 mutation p.Arg707Cys than healthy individuals. It has been reported that NLRX1 increases the infection rate of HBV in HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). However, the role of NLRX1 mutation (p.Arg707Cys) in hepatitis remains unclear. We constructed Huh7 cells that stably overexpressed NTCP, using LV003 lentivirus. First, wild-type (WT) and mutant (MT) NLRX1 overexpression plasmids were constructed. The MT plasmid contained a point mutation at position 707 of the WT overexpression plasmid. Then, Huh7-NTCP cells were transfected with the WT or MT NLRX1 overexpression plasmid, and subsequent NLRX1 expression was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. HBV RNA levels were determined using RT-qPCR. HBsAg and HBcAg levels were confirmed immunohistochemically. Interferon alpha (IFN-α), interleukin 6 (IL-6), and type I interferon beta (IFN-β) levels were determined using enzyme-linked immunosorbent assay kits. p-p65, p-interferon regulatory factor (IRF) 3, and p-IRF7 expression levels were examined using western blot. The interaction of NLRX1 and retinoic acid-inducible gene (RIG)-1/mitochondrial antiviral signaling (MAVS) protein was confirmed by coimmunoprecipitation. The interaction of NLRX1 with IFN-α, IL-6, or IFN-β was analyzed by dual luciferase reporter gene assay. The levels of HBV RNA, HBsAg, and HBcAg in infected cells transfected with the WT NLRX1 or MT NLRX1 expression plasmid were higher than those in the untransfected control group; and these levels were lower in the cells transfected with MT NLRX1 than in those transfected with WT NLRX1. The levels of IFN-α, IFN-β, IL-6, p-p65, p-IRF3, and p-IRF7 were lower in cells transfected with WT NLRX1 or MT NLRX1 than in control cells. The levels of IFN-β, p-p65, p-IRF3, and p-IRF7 were higher in cells transfected with MT NLRX1 than in those transfected with WT NLRX1. Moreover, NLRX1 competitively inhibited RIG1 binding to MAVS, but the mutation in MT NLRX1 reduced this inhibitory effect. In addition, NLRX1 decreased the promoter activity of IFN-α, IFN-β, and IL-6. Our findings revealed that NLRX1 is a regulatory factor that inhibits the anti-HBV ability of hepatocytes and that the mutation p.Arg707Cys in NLRX1 suppresses HBV infection and activates the IFN/nuclear factor κB pathway.
Collapse
Affiliation(s)
- Qian Jiao
- Department of Hepatology, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510060, China
| | - Shu Zhu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District Guangzhou, Guangzhou, Guangdong, 510630, China
| | - Baolin Liao
- Department of Hepatology, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510060, China
| | - Huiyuan Liu
- Department of Hepatology, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510060, China
| | - Xiaoyan Guo
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District Guangzhou, Guangzhou, Guangdong, 510630, China
| | - Lina Wu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District Guangzhou, Guangzhou, Guangdong, 510630, China
| | - Chuming Chen
- Department of Infectious Diseases, Third People's Hospital of Shenzhen, Shenzhen, Guangdong, 518112, China
| | - Liang Peng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District Guangzhou, Guangzhou, Guangdong, 510630, China.
| | - Chan Xie
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District Guangzhou, Guangzhou, Guangdong, 510630, China.
| |
Collapse
|
|
5
|
Graham CT, Gordon S, Kubes P. A historical perspective of Kupffer cells in the context of infection. Cell Tissue Res 2024:10.1007/s00441-024-03924-4. [PMID: 39392500 DOI: 10.1007/s00441-024-03924-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 10/02/2024] [Indexed: 10/12/2024]
Abstract
The Kupffer cell was first discovered by Karl Wilhelm von Kupffer in 1876, labeling them as "Sternzellen." Since their discovery as the primary macrophages of the liver, researchers have gradually gained an in-depth understanding of the identity, functions, and influential role of Kupffer cells, particularly in infection. It is becoming clear that Kupffer cells perform important tissue-specific functions in homeostasis and disease. Stationary in the sinusoids of the liver, Kupffer cells have a high phagocytic capacity and are adept in clearing the bloodstream of foreign material, toxins, and pathogens. Thus, they are indispensable to host defense and prevent the dissemination of bacteria during infections. To highlight the importance of this cell, this review will explore the history of the Kupffer cell in the context of infection beginning with its discovery to the present day.
Collapse
Affiliation(s)
- Carolyn T Graham
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
| | - Siamon Gordon
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wenhua 1st Road Guishan Dist., Taoyuan, Taiwan
| | - Paul Kubes
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| |
Collapse
|
|
6
|
Chen S, Yao C, Tian N, Zhang C, Chen Y, Wang X, Jiang Y, Zhang T, Zeng T, Song Y. The interplay between persistent pathogen infections with tumor microenvironment and immunotherapy in cancer. Cancer Med 2024; 13:e70154. [PMID: 39240588 PMCID: PMC11378724 DOI: 10.1002/cam4.70154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/15/2024] [Accepted: 08/16/2024] [Indexed: 09/07/2024] Open
Abstract
BACKGROUND Chronic infections by pathogenic microorganisms play a significant role in cancer development, disrupting the body's immune system and microenvironment. This interference impairs the body's ability to eliminate these microorganisms promptly, allowing them to persist by evading immune defenses. AIMS This study aimed to explore how chronic pathogenic infections influence the immune microenvironment, impacting tumorigenesis, cancer progression, and treatment strategies. Additionally, it seeks to investigate the effects of these infections on specific immune checkpoints and identify potential targets for immunotherapy. METHODS We conducted searches, readings, and detailed analyses of key terms in databases like PubMed and Web of Science to evaluate the impact of chronic infections by pathogenic microorganisms on the immune microenvironment. RESULTS Our analysis demonstrates a significant association between persistent chronic infections by pathogenic microorganisms and tumorigenesis. Notable impacts on the immune microenvironment include changes in immune cell function and the regulation of immune checkpoints, offering insights into potential targets for cancer immunotherapy. DISCUSSION This study highlights the complex relationship between chronic infections and cancer development, presenting new opportunities for cancer immunotherapy by understanding their effects on the immune microenvironment. The influence of these infections on immune checkpoints emphasizes the crucial role of the immune system in cancer treatment. CONCLUSION Chronic infections by pathogenic microorganisms greatly affect the immune microenvironment, tumorigenesis, and cancer treatment. Unraveling the underlying mechanisms can unveil potential targets for immunotherapy, improving our comprehension of the immune response to cancer and potentially leading to more effective cancer treatments in the future.
Collapse
Affiliation(s)
- Si Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University; Sichuan Clinical Research Center for Laboratory Medicine; Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, People's Republic of China
| | - Caihong Yao
- Department of Laboratory Medicine, West China Hospital, Sichuan University; Sichuan Clinical Research Center for Laboratory Medicine; Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, People's Republic of China
| | - Na Tian
- Anesthesiology Department, Qingdao Eighth People's Hospital, Qingdao, People's Republic of China
| | - Chunying Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University; Sichuan Clinical Research Center for Laboratory Medicine; Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, People's Republic of China
| | - Yuemei Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University; Sichuan Clinical Research Center for Laboratory Medicine; Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, People's Republic of China
| | - Xuting Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University; Sichuan Clinical Research Center for Laboratory Medicine; Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, People's Republic of China
| | - Yue Jiang
- Department of Laboratory Medicine, West China Hospital, Sichuan University; Sichuan Clinical Research Center for Laboratory Medicine; Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, People's Republic of China
| | - Tonghao Zhang
- Department of Statistics, University of Virginia, Charlottesville, Virginia, USA
| | - Tingting Zeng
- Department of Laboratory Medicine, West China Hospital, Sichuan University; Sichuan Clinical Research Center for Laboratory Medicine; Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, People's Republic of China
| | - Yali Song
- Department of Laboratory Medicine, West China Hospital, Sichuan University; Sichuan Clinical Research Center for Laboratory Medicine; Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, People's Republic of China
| |
Collapse
|
|
7
|
Costa JP, de Carvalho A, Paiva A, Borges O. Insights into Immune Exhaustion in Chronic Hepatitis B: A Review of Checkpoint Receptor Expression. Pharmaceuticals (Basel) 2024; 17:964. [PMID: 39065812 PMCID: PMC11279883 DOI: 10.3390/ph17070964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Hepatitis B, caused by the hepatitis B virus (HBV), often progresses to chronic infection, leading to severe complications, such as cirrhosis, liver failure, and hepatocellular carcinoma. Chronic HBV infection is characterized by a complex interplay between the virus and the host immune system, resulting in immune cell exhaustion, a phenomenon commonly observed in chronic viral infections and cancer. This state of exhaustion involves elevated levels of inhibitory molecules, cells, and cell surface receptors, as opposed to stimulatory counterparts. This review aims to elucidate the expression patterns of various co-inhibitory and co-stimulatory receptors on immune cells isolated from chronic hepatitis B (CHB) patients. By analyzing existing data, the review conducts comparisons between CHB patients and healthy adults, explores the differences between HBV-specific and total T cells in CHB patients, and examines variations between intrahepatic and peripheral immune cells in CHB patients. Understanding the mechanisms underlying immune exhaustion in CHB is crucial for developing novel immunotherapeutic approaches. This detailed analysis sheds light on the immune exhaustion observed in CHB and lays the groundwork for future combined immunotherapy strategies aimed at leveraging checkpoint receptors to restore immune function and improve clinical outcomes.
Collapse
Affiliation(s)
- João Panão Costa
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal;
- CNC-UC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Armando de Carvalho
- Centro Hospitalar e Universitário de Coimbra, 3004-561 Coimbra, Portugal; (A.d.C.); (A.P.)
- Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Artur Paiva
- Centro Hospitalar e Universitário de Coimbra, 3004-561 Coimbra, Portugal; (A.d.C.); (A.P.)
| | - Olga Borges
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal;
- CNC-UC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
| |
Collapse
|
|
8
|
Kalita S, Kalita MJ, Talukdar AJ, Das PP, Dutta K, Hazarika G, Dutta S, Das P, Idris G, Kaur H, Medhi S. Altered TLR7 Expression-Mediated Immune Modulation Is Supportive of Persistent Replication and Intrauterine Transmission of HBV. Viral Immunol 2024; 37:149-158. [PMID: 38573237 DOI: 10.1089/vim.2023.0117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2024] Open
Abstract
Hepatitis B Virus (HBV) is posing as a serious public health threat mainly due to its asymptomatic nature of infection in pregnancy and vertical transmission. Viral sensing toll-like receptors (TLR) and Interleukins (IL) are important molecules in providing an antiviral state. The study aimed to assess the role of TLR7-mediated immune modulation, which might have an impact in the intrauterine transmission of HBV leading to mother to child transmission of the virus. We investigated the expression pattern of TLR7, IL-3, and IL-6 by RT-PCR in the placentas of HBV-infected pregnant women to see their role in the intrauterine transmission of HBV. We further validated the expression of TLR7 in placentas using Immunohistochemistry. Expression analysis by RT-PCR of TLR7 revealed significant downregulation among the Cord blood (CB) HBV DNA positive and negative cases with mean ± standard deviation (SD) of 0.43 ± 0.22 (28) and 1.14 ± 0.57 (44) with p = 0.001. IL-3 and IL-6 expression revealed significant upregulation in the CB HBV DNA-positive cases with p = 0.001. Multinomial logistic regression analysis revealed that TLR7 and IL-3 fold change and mother HBeAg status are important predictors for HBV mother to child transmission. Immunohistochemistry revealed the decreased expression of TLR7 in CB HBV DNA-positive cases. This study reveals that the downregulation of TLR7 in the placenta along with CB HBV DNA-positive status may lead to intrauterine transmission of HBV, which may lead to vertical transmission of HBV.
Collapse
Affiliation(s)
- Simanta Kalita
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | - Manash Jyoti Kalita
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | | | - Partha Pratim Das
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
- Multidisciplinary Research Unit, Fakhruddin Ali Ahmed Medical College and Hospital, Barpeta, India
| | - Kalpajit Dutta
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | - Gautam Hazarika
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | - Sangit Dutta
- Department of Medicine, Gauhati Medical College and Hospital, Guwahati, India
| | - Panchanan Das
- Department of Obstetrics and Gynaecology, Gauhati Medical College and Hospital, Guwahati, India
| | - Ghaznavi Idris
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| | - Harpreet Kaur
- Epidemiology and Communicable Diseases Division, Indian Council of Medical Research, New Delhi, India
| | - Subhash Medhi
- Department of Bioengineering & Technology, Gauhati University, Guwahati India
| |
Collapse
|
|
9
|
Soleiman-Meigooni S, Yarahmadi A, Kheirkhah AH, Afkhami H. Recent advances in different interactions between toll-like receptors and hepatitis B infection: a review. Front Immunol 2024; 15:1363996. [PMID: 38545106 PMCID: PMC10965641 DOI: 10.3389/fimmu.2024.1363996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 02/26/2024] [Indexed: 04/17/2024] Open
Abstract
Hepatitis B virus (HBV) B infections remain a primary global health concern. The immunopathology of the infection, specifically the interactions between HBV and the host immune system, remains somewhat unknown. It has been discovered that innate immune reactions are vital in eliminating HBV. Toll-like receptors (TLRs) are an essential category of proteins that detect pathogen-associated molecular patterns (PAMPs). They begin pathways of intracellular signals to stimulate pro-inflammatory and anti-inflammatory cytokines, thus forming adaptive immune reactions. HBV TLRs include TLR2, TLR3, TLR4, TLR7 and TLR9. Each TLR has its particular molecule to recognize; various TLRs impact HBV and play distinct roles in the pathogenesis of the disease. TLR gene polymorphisms may have an advantageous or disadvantageous efficacy on HBV infection, and some single nucleotide polymorphisms (SNPs) can influence the progression or prognosis of infection. Additionally, it has been discovered that similar SNPs in TLR genes might have varied effects on distinct populations due to stress, diet, and external physical variables. In addition, activation of TLR-interceded signaling pathways could suppress HBV replication and increase HBV-particular T-cell and B-cell reactions. By identifying these associated polymorphisms, we can efficiently advance the immune efficacy of vaccines. Additionally, this will enhance our capability to forecast the danger of HBV infection or the threat of dependent liver disease development via several TLR SNPs, thus playing a role in the inhibition, monitoring, and even treatment guidance for HBV infection. This review will show TLR polymorphisms, their influence on TLR signaling, and their associations with HBV diseases.
Collapse
Affiliation(s)
| | - Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Amir-Hossein Kheirkhah
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| |
Collapse
|
|
10
|
Ide M, Tabata N, Yonemura Y, Murai K, Wang Y, Ishida A, Honda M, Kaneko S, Ito S, Yanagawa H. Hepatitis B virus evades the immune system by suppressing the NF-κB signaling pathway with DENND2A. Microbiol Spectr 2024; 12:e0378523. [PMID: 38240571 PMCID: PMC10913737 DOI: 10.1128/spectrum.03785-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 12/08/2023] [Indexed: 03/06/2024] Open
Abstract
Overcoming hepatitis B virus (HBV) is a challenging problem because HBV deceives the host immune system. We have found that DENN domain-containing 2A (DENND2A) was essential for HBV maintenance, although its role remains unclear. In this study, we elucidate its function by screening a novel DENND2A-binding peptide, DENP4-3S. DENP4-3S exhibits homology to SAM and SH3 domain-containing protein 1 (SASH1), a scaffold protein involved in Toll-like receptor signaling that promotes proinflammatory cytokine production. We confirmed that DENND2A interacts with SASH1 specifically. Overexpression and knockdown experiments showed that overexpression of DENND2A suppressed the transcriptional activity of NF-κB, and the knockdown of DENND2A promoted it and the production of cytokines and interferons. Here, we constructed a fusion protein (10M-DEN3SN) consisting of an anti-asialoglycoprotein receptor antibody and DENP4-3S to deliver the peptide to hepatocytes specifically. 10M-DEN3SN inhibited the interaction between DENND2A and SASH1, and rescued SASH1 trapped by DENND2A, leading to the upregulation of NF-κB and its downstream signaling. In addition, 10M-DEN3SN suppressed HBV proliferation in PXB chimeric mice. These results with the DENND2A-binding peptide delivered into hepatocytes suggested the involvement of DENND2A, SASH, and NF-κB signaling pathway in the HBV infection and onset of hepatitis. In conclusion, this study indicates that HBV utilizes DENND2A and SASH1 to evade the immune system.IMPORTANCEHepatitis B virus (HBV) is a serious liver infection with no established cure, causing an abnormal host immune response. Here, we identified a novel peptide that interacts with DENN domain-containing 2A (DENND2A), a host factor essential for HBV maintenance. The resulting peptide showed sequence homology, revealing an interaction between DENND2A and the immune system regulator SASH1. This study suggests that DENND2A contributes to HBV infection by suppressing the cellular immune system by inhibiting SASH1. The DENND2A-binding peptide, incorporated into our hepatocyte-specific peptide delivery system, inhibited the DENND2A-SASH1 interaction and promoted the production of cytokines and interferons in cultured hepatocytes. As a consequence, the peptide suppressed HBV proliferation in humanized mice. We report new insights into the role of DENND2A and SASH1 in HBV maintenance and highlight the importance of the immune system.
Collapse
Affiliation(s)
- Mayuko Ide
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
| | - Noriko Tabata
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
| | - Yuko Yonemura
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
| | - Kazuhisa Murai
- Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Health Medicine, Kanazawa, Ishikawa, Japan
| | - Ying Wang
- Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Health Medicine, Kanazawa, Ishikawa, Japan
| | - Atsuya Ishida
- Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Health Medicine, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Health Medicine, Kanazawa, Ishikawa, Japan
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan
| | - Satoru Ito
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
| | - Hiroshi Yanagawa
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
| |
Collapse
|
|
11
|
Mak LY, Hui RWH, Seto WK, Yuen MF. Novel Drug Development in Chronic Hepatitis B Infection: Capsid Assembly Modulators and Nucleic Acid Polymers. Clin Liver Dis 2023; 27:877-893. [PMID: 37778775 DOI: 10.1016/j.cld.2023.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Currently approved treatment of patients with chronic hepatitis B infection is insufficient to achieve functional cure. Numerous new compounds are identified, and among many, capsid assembly modulators (CAMs) and nucleic acid polymers (NAPs) are 2 classes of virus-directing agents in clinical development. CAMs interfere with viral pregenomic RNA encapsidation and are effective in viral load reduction but have limited effects on hepatitis B surface antigen (HBsAg). NAPs prevent HBsAg release from hepatocytes and induce intracellular degradation, leading to potent suppression of serum HBsAg when combined with nucleoside analogues and pegylated interferon demonstrated by initial data, but awaiting further confirmation studies.
Collapse
Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, Pokfulam Road 102, Hong Kong, China; State Key Laboratory of Liver Research, 7/F, HK Jockey Club Building of Interdisciplinary Research, 5 Sassoon Road, Pokfulam, Hong Kong, China
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, Pokfulam Road 102, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, Pokfulam Road 102, Hong Kong, China; State Key Laboratory of Liver Research, 7/F, HK Jockey Club Building of Interdisciplinary Research, 5 Sassoon Road, Pokfulam, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, Pokfulam Road 102, Hong Kong, China; State Key Laboratory of Liver Research, 7/F, HK Jockey Club Building of Interdisciplinary Research, 5 Sassoon Road, Pokfulam, Hong Kong, China.
| |
Collapse
|
|
12
|
Lok J, Guerra Veloz MF, Agarwal K. Overview of New Targets for Hepatitis B Virus: Immune Modulators, Interferons, Bifunctional Peptides, Therapeutic Vaccines and Beyond. Clin Liver Dis 2023; 27:857-876. [PMID: 37778774 DOI: 10.1016/j.cld.2023.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Nucleos(t)ide analogs are the cornerstone of treatment against hepatitis B virus; however, they have no direct effect on its transcriptional template (ie, covalently closed circular DNA) and so functional cure is rarely achieved. Over recent years, there has been a significant improvement in our understanding of the viral life cycle and its mechanisms of immune evasion. In this review article, we will explore novel therapeutic targets, discuss the latest data from clinical trials, and highlight future research priorities.
Collapse
Affiliation(s)
- James Lok
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | | | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK.
| |
Collapse
|
|
13
|
Bao Z, Chen X, Li Y, Jiang W, Pan D, Ma L, Wu Y, Chen Y, Chen C, Wang L, Zhao S, Wang T, Lu WY, Ma C, Wang S. The hepatic GABAergic system promotes liver macrophage M2 polarization and mediates HBV replication in mice. Antiviral Res 2023; 217:105680. [PMID: 37494980 DOI: 10.1016/j.antiviral.2023.105680] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 07/17/2023] [Accepted: 07/23/2023] [Indexed: 07/28/2023]
Abstract
Macrophages display functional phenotypic plasticity. Hepatitis B virus (HBV) infection induces polarizations of liver macrophages either to M1-like pro-inflammatory phenotype or to M2-like anti-inflammatory phenotype. Gamma-aminobutyric acid (GABA) signaling exists in various non-neuronal cells including hepatocytes and some immune cells. Here we report that macrophages express functional GABAergic signaling components and activation of type A GABA receptors (GABAARs) promotes M2-polarization thus advancing HBV replication. Notably, intraperitoneal injection of GABA or the GABAAR agonist muscimol increased HBV replication in HBV-carrier mice that were generated by hydrodynamical injection of adeno-associated virus/HBV1.2 plasmids (pAAV/HBV1.2). The GABA-augmented HBV replication in HBV-carrier mice was significantly reduced by the GABAAR inhibitor picrotoxin although picrotoxin had no significant effect on serum HBsAg levels in control HBV-carrier mice. Depletion of liver macrophages by liposomal clodronate treatment also significantly reduced the GABA-augmented HBV replication. Yet adoptive transfer of liver macrophages isolated from GABA-treated donor HBV-carrier mice into the liposomal clodronate-pretreated recipient HBV-carrier mice restored HBV replication. Moreover, GABA or muscimol treatment increased the expression of "M2" cytokines in macrophages, but had no direct effect on HBV replication in the HepG2.2.15 cells, HBV1.3-transfected Huh7, HepG2, or HepaRG cells, or HBV-infected Huh7-NTCP cells. Taken together, these results suggest that increasing GABA signaling in the liver promotes HBV replication in HBV-carrier mice by suppressing the immunity of liver macrophages, but not by increasing the susceptibility of hepatocytes to HBV infection. Our study shows that a previously unknown GABAergic system in liver macrophage has an essential role in HBV replication.
Collapse
Affiliation(s)
- Ziyou Bao
- Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Xiaotong Chen
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan, China
| | - Yan Li
- Translational Medical Research Centre, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Wenshan Jiang
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Di Pan
- Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, China; Department of Physiology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Lushun Ma
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Paediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Yunxiao Wu
- Department of Physiology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Yunling Chen
- Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, China; Department of Physiology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Chaojia Chen
- Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Liyuan Wang
- Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Songbo Zhao
- Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Tixiao Wang
- Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Wei-Yang Lu
- Department of Physiology and Pharmacology, Robarts Research Institute, University of Western Ontario, Canada.
| | - Chunhong Ma
- Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, China.
| | - Shuanglian Wang
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
| |
Collapse
|
|
14
|
Schlaak JF. Current Therapy of Chronic Viral Hepatitis B, C and D. J Pers Med 2023; 13:964. [PMID: 37373953 DOI: 10.3390/jpm13060964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The majority of chronic viral hepatitis cases are induced via infection with the hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). These patients are at increased risk for progressive liver disease leading to cirrhosis as well as hepatocellular carcinoma (HCC). HBV infection is well controlled by the currently available nucleosides as well as nucleotides, and the development of cirrhosis can be prevented. Additionally, it has been shown that HBV-induced liver fibrosis can regress during successful antiviral treatment; however, a "functional cure", i.e., loss of HBsAg, is a rare event when these drugs are used. Therefore, novel therapeutic strategies are aiming at the selective suppression of HBsAg levels in combination with immunostimulation. The development of directly acting antivirals (DAAs) has revolutionized HCV therapy, as almost all patients can be cured via this treatment. Additionally, DAA therapy has few, if any, side effects, and is generally well tolerated by patients. HDV remains the most challenging type of chronic viral hepatitis. Although novel therapeutic options have recently been approved, response rates are still less favorable compared to HBV and HCV. This review discusses current and future options for the treatment of chronic HBV, HCV, and HDV infection.
Collapse
Affiliation(s)
- Jörg F Schlaak
- Department of Internal Medicine, Ameos Hospital Oberhausen, Wilhelmstr. 34, 46145 Oberhausen, Germany
| |
Collapse
|
|
15
|
Schefczyk S, Luo X, Liang Y, Trippler M, Lu M, Wedemeyer H, Schmidt HH, Broering R. Poly(I:C) Induces Distinct Liver Cell Type-Specific Responses in Hepatitis B Virus-Transgenic Mice In Vitro, but Fails to Induce These Signals In Vivo. Viruses 2023; 15:v15051203. [PMID: 37243287 DOI: 10.3390/v15051203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/12/2023] [Accepted: 05/13/2023] [Indexed: 05/28/2023] Open
Abstract
Immunopathology in hepatitis B virus (HBV) infection is driven by innate and adaptive immunity. Whether the hepatitis B surface antigen (HBsAg) affects hepatic antiviral signalling was investigated in HBV-transgenic mouse models that either accumulate (Alb/HBs, Tg[Alb1HBV]Bri44), lack (Tg1.4HBV-s-mut3) or secrete (Tg1.4HBV-s-rec (F1, Tg1.4HBV-s-mut × Alb/HBs) the HBsAg. Herein, the responsiveness of TLR3 and RIG-I in primary parenchymal and non-parenchymal liver cells was determined in vitro and in vivo. Cell type-specific and mouse strain-dependent interferon, cytokine and chemokine expression were observed by LEGENDplex™ and validated by quantitative PCR. In vitro, the hepatocytes, liver sinusoidal endothelial cells and Kupffer cells of Tg1.4HBV-s-rec mice showed poly(I:C) susceptibilities similar to the wild-type controls, while in the remaining leucocyte fraction the interferon, cytokine and chemokine induction was reduced. On the contrary, poly(I:C)-injected 1.4TgHBV-s-rec mice showed suppressed interferon, cytokine and chemokine levels in hepatocytes but increased levels in the leucocyte fraction. Thus, we concluded that liver cells of Tg1.4HBV-s-rec mice, which produce HBV particles and release the HBsAg, responded to exogenous TLR3/RIG-I stimuli in vitro but exhibited a tolerogenic environment in vivo.
Collapse
Affiliation(s)
- Stefan Schefczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Xufeng Luo
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Yaojie Liang
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Martin Trippler
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
| | - Hartmut H Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| |
Collapse
|
|
16
|
Ruta S, Grecu L, Iacob D, Cernescu C, Sultana C. HIV-HBV Coinfection-Current Challenges for Virologic Monitoring. Biomedicines 2023; 11:biomedicines11051306. [PMID: 37238976 DOI: 10.3390/biomedicines11051306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
HIV-HBV coinfected patients have higher rates of liver-related morbidity, hospitalizations, and mortality compared to HBV or HIV mono-infected ones. Clinical studies have shown an accelerated progression of liver fibrosis and an increased incidence of HCC, resulting from the combined action of HBV replication, immune-mediated hepatocytolysis, and HIV-induced immunosuppression and immunosenescence. Antiviral therapy based on dually active antiretrovirals is highly efficient, but late initiation, global disparities in accessibility, suboptimal regimens, and adherence issues may limit its impact on the development of end-stage liver disease. In this paper, we review the mechanisms of liver injuries in HIV-HBV coinfected patients and the novel biomarkers that can be used for treatment monitoring in HIV-HBV coinfected persons: markers that assess viral suppression, markers for liver fibrosis evaluation, and predictors of oncogenesis.
Collapse
Affiliation(s)
- Simona Ruta
- Virology Discipline, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Emerging Viral Diseases, "Stefan S. Nicolau" Institute of Virology, 030304 Bucharest, Romania
| | - Laura Grecu
- Department of Emerging Viral Diseases, "Stefan S. Nicolau" Institute of Virology, 030304 Bucharest, Romania
| | - Diana Iacob
- Department for the Prevention and Control of Healthcare Associated Infections, Emergency University Hospital, 050098 Bucharest, Romania
| | | | - Camelia Sultana
- Virology Discipline, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Emerging Viral Diseases, "Stefan S. Nicolau" Institute of Virology, 030304 Bucharest, Romania
| |
Collapse
|
|
17
|
Mak LY, Hui RWH, Cheung KS, Fung J, Seto WK, Yuen MF. Advances in determining new treatments for hepatitis B infection by utilizing existing and novel biomarkers. Expert Opin Drug Discov 2023; 18:401-416. [PMID: 36943183 DOI: 10.1080/17460441.2023.2192920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
INTRODUCTION Chronic hepatitis B (CHB) infection is a major global health threat and accounts for significant liver-related morbidity and mortality. An improved understanding of how hepatitis B virus (HBV) interacts with the host immune system allows the discovery of novel biomarkers and new treatment options. Viral biomarkers including hepatitis B surface antigen (HBsAg) and newer ones like HBV RNA and hepatitis B core-related antigen appear to be useful to select patients who are likely to benefit from cessation of long-term antiviral therapy. These markers can also help to confirm target engagement for novel compounds, and efficacy in HBsAg reduction and seroclearance is deemed essential as this is how the current treatment endpoint of functional cure is defined. AREAS COVERED In this review, the authors discuss the current standard of care and the gaps between such standard and the ideal goals for treatment in CHB. The authors highlight novel viral and immunological biomarkers that are potentially useful to evaluate treatment response. Novel treatment approaches in relation to these novel biomarkers are also evaluated. EXPERT OPINION Novel serum viral biomarkers and immunological markers are indispensable in the HBV functional cure program. These will likely become part of standard monitoring soon.
Collapse
Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
| | - Ka-Shing Cheung
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
| | - James Fung
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong
| |
Collapse
|
|
18
|
Hall SAL, Burns GS, Mooney BJ, Millen R, Morris R, Vogrin S, Sundararajan V, Ratnam D, Levy MT, Lubel JS, Nicoll AJ, Strasser SI, Sievert W, Desmond PV, Ngu MC, Angus P, Sinclair M, Meredith C, Matthews G, Revill PA, Jackson K, Littlejohn M, Bowden S, Locarnini SA, Thompson AJ, Visvanathan K. Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways. J Infect Dis 2022; 227:123-132. [PMID: 36108079 DOI: 10.1093/infdis/jiac375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 09/02/2022] [Accepted: 09/13/2022] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. METHODS Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. RESULTS Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. CONCLUSIONS Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.
Collapse
Affiliation(s)
- Samuel A L Hall
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia.,Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Gareth S Burns
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia.,Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Benjamin J Mooney
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Rosemary Millen
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Rachel Morris
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Sara Vogrin
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | | | - Dilip Ratnam
- Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Australia
| | - Miriam T Levy
- Gastroenterology Department of Liverpool Hospital, Sydney, Australia
| | - John S Lubel
- Department of Gastroenterology, Alfred Health, Melbourne, Australia.,Central Clinical School, Monash University, The Alfred Centre, Melbourne, Australia
| | - Amanda J Nicoll
- Gastroenterology Department of Eastern Health, Melbourne, Australia
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.,Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - William Sievert
- Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Australia.,Department of Medicine, Monash University, Melbourne, Australia
| | - Paul V Desmond
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
| | - Meng C Ngu
- Gastroenterology Department of Concord Repatriation General Hospital, Sydney, Australia
| | - Peter Angus
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
| | - Marie Sinclair
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
| | | | - Gail Matthews
- Department of infectious Disease, St Vincent's Hospital Sydney, SydneyAustralia
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Stephen A Locarnini
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Alexander J Thompson
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia.,Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Kumar Visvanathan
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia.,Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| |
Collapse
|
|
19
|
Many Ways to Communicate-Crosstalk between the HBV-Infected Cell and Its Environment. Pathogens 2022; 12:pathogens12010029. [PMID: 36678377 PMCID: PMC9866324 DOI: 10.3390/pathogens12010029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/19/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
Chronic infection with the hepatitis B virus (HBV) affects an estimated 257 million people worldwide and can lead to liver diseases such as cirrhosis and liver cancer. Viral replication is generally considered not to be cytopathic, and although some HBV proteins may have direct carcinogenic effects, the majority of HBV infection-related disease is related to chronic inflammation resulting from disrupted antiviral responses and aberrant innate immune reactions. Like all cells, healthy and HBV-infected cells communicate with each other, as well as with other cell types, such as innate and adaptive immune cells. They do so by both interacting directly and by secreting factors into their environment. Such factors may be small molecules, such as metabolites, single viral proteins or host proteins, but can also be more complex, such as virions, protein complexes, and extracellular vesicles. The latter are small, membrane-enclosed vesicles that are exchanged between cells, and have recently gained a lot of attention for their potential to mediate complex communication and their potential for therapeutic repurposing. Here, we review how HBV infection affects the communication between HBV-infected cells and cells in their environment. We discuss the impact of these interactions on viral persistence in chronic infection, as well as their relation to HBV infection-related pathology.
Collapse
|
|
20
|
Ciaston I, Dobosz E, Potempa J, Koziel J. The subversion of toll-like receptor signaling by bacterial and viral proteases during the development of infectious diseases. Mol Aspects Med 2022; 88:101143. [PMID: 36152458 PMCID: PMC9924004 DOI: 10.1016/j.mam.2022.101143] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/29/2022] [Accepted: 09/09/2022] [Indexed: 02/05/2023]
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that respond to pathogen-associated molecular patterns (PAMPs). The recognition of specific microbial ligands by TLRs triggers an innate immune response and also promotes adaptive immunity, which is necessary for the efficient elimination of invading pathogens. Successful pathogens have therefore evolved strategies to subvert and/or manipulate TLR signaling. Both the impairment and uncontrolled activation of TLR signaling can harm the host, causing tissue destruction and allowing pathogens to proliferate, thus favoring disease progression. In this context, microbial proteases are key virulence factors that modify components of the TLR signaling pathway. In this review, we discuss the role of bacterial and viral proteases in the manipulation of TLR signaling, highlighting the importance of these enzymes during the development of infectious diseases.
Collapse
Affiliation(s)
- Izabela Ciaston
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Ewelina Dobosz
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Jan Potempa
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Department of Oral Health and Systemic Disease, University of Louisville School of Dentistry, University of Louisville, Louisville, KY, USA.
| | - Joanna Koziel
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
| |
Collapse
|
|
21
|
Diaz O, Vidalain PO, Ramière C, Lotteau V, Perrin-Cocon L. What role for cellular metabolism in the control of hepatitis viruses? Front Immunol 2022; 13:1033314. [PMID: 36466918 PMCID: PMC9713817 DOI: 10.3389/fimmu.2022.1033314] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/02/2022] [Indexed: 11/26/2023] Open
Abstract
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. As part of research efforts in the field of immunometabolism, it has also been shown that metabolic changes induced by viruses could have a direct impact on the innate antiviral response. Conversely, detection of viral components by innate immunity receptors not only triggers the activation of the antiviral defense but also induces in-depth metabolic reprogramming that is essential to support immunological functions. Altogether, these complex triangular interactions between viral components, innate immunity and hepatocyte metabolism may explain why chronic hepatitis infections progressively lead to liver inflammation and progression to cirrhosis, fibrosis and hepatocellular carcinoma (HCC). In this manuscript, we first present a global overview of known connections between the innate antiviral response and cellular metabolism. We then report known molecular mechanisms by which hepatitis viruses interfere with cellular metabolism in hepatocytes and discuss potential consequences on the innate immune response. Finally, we present evidence that drugs targeting hepatocyte metabolism could be used as an innovative strategy not only to deprive viruses of key metabolites, but also to restore the innate antiviral response that is necessary to clear infection.
Collapse
Affiliation(s)
- Olivier Diaz
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Pierre-Olivier Vidalain
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Christophe Ramière
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
- Laboratoire de Virologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Vincent Lotteau
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Laure Perrin-Cocon
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| |
Collapse
|
|
22
|
Yin GQ, Chen KP, Gu XC. Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment. World J Gastroenterol 2022; 28:5784-5800. [PMID: 36353205 PMCID: PMC9639659 DOI: 10.3748/wjg.v28.i40.5784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/08/2022] [Accepted: 10/10/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health issue. Interferon-α (IFN-α) treatment has been used to treat hepatitis B for over 20 years, but fewer than 5% of Asians receiving IFN-α treatment achieve functional cure. Thus, IFN-α retreatment has been introduced to enhance antiviral function. In recent years, immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks, in-cluding both innate and adaptive immunity, triggering immune responses that control HBV replication. However, heterogeneity of the immune system to control HBV infection, particularly HBV-specific CD8+ T cell heterogeneity, has consequ-ential effects on T cell-based immunotherapy for treating HBV infection. Altogether, the host’s genetic variants, negative-feedback regulators and HBV components affecting the immune system's ability to control HBV. In this study, we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-α treatment and retreatment.
Collapse
Affiliation(s)
- Guo-Qing Yin
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ke-Ping Chen
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Xiao-Chun Gu
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| |
Collapse
|
|
23
|
Yang G, Wan P, Zhang Y, Tan Q, Qudus MS, Yue Z, Luo W, Zhang W, Ouyang J, Li Y, Wu J. Innate Immunity, Inflammation, and Intervention in HBV Infection. Viruses 2022; 14:2275. [PMID: 36298831 PMCID: PMC9609328 DOI: 10.3390/v14102275] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/12/2022] [Accepted: 10/15/2022] [Indexed: 07/30/2023] Open
Abstract
Hepatitis B virus (HBV) infection is still one of the most dangerous viral illnesses. HBV infects around 257 million individuals worldwide. Hepatitis B in many individuals ultimately develops hepatocellular carcinoma (HCC), which is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide. The innate immunity acts as the first line of defense against HBV infection through activating antiviral genes. Along with the immune responses, pro-inflammatory cytokines are triggered to enhance the antiviral responses, but this may result in acute or chronic liver inflammation, especially when the clearance of virus is unsuccessful. To a degree, the host innate immune and inflammatory responses dominate the HBV infection and liver pathogenesis. Thus, it is crucial to figure out the signaling pathways involved in the activation of antiviral factors and inflammatory cytokines. Here, we review the interplay between HBV and the signal pathways that mediates innate immune responses and inflammation. In addition, we summarize current therapeutic strategies for HBV infection via modulating innate immunity or inflammation. Characterizing the mechanisms that underlie these HBV-host interplays might provide new approaches for the cure of chronic HBV infection.
Collapse
Affiliation(s)
- Ge Yang
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Pin Wan
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Yaru Zhang
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
| | - Qiaoru Tan
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Muhammad Suhaib Qudus
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Zhaoyang Yue
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Wei Luo
- Clinical Research Institute, The First People’s Hospital, Foshan 528000, China
| | - Wen Zhang
- Guangdong Longfan Biological Science and Technology, Foshan 528315, China
| | - Jianhua Ouyang
- Guangdong Longfan Biological Science and Technology, Foshan 528315, China
| | - Yongkui Li
- Foshan Institute of Medical Microbiology, Foshan 528315, China
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
- Guangdong Longfan Biological Science and Technology, Foshan 528315, China
| | - Jianguo Wu
- Foshan Institute of Medical Microbiology, Foshan 528315, China
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| |
Collapse
|
|
24
|
Xie X, Karakoese Z, Ablikim D, Ickler J, Schuhenn J, Zeng X, Feng X, Yang X, Dittmer U, Yang D, Sutter K, Liu J. IFNα subtype-specific susceptibility of HBV in the course of chronic infection. Front Immunol 2022; 13:1017753. [PMID: 36311794 PMCID: PMC9616162 DOI: 10.3389/fimmu.2022.1017753] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/27/2022] [Indexed: 11/28/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a major health problem worldwide and remains hard to be cured. Therapy with interferon (IFN) α is an important method for the clinical treatment of chronic hepatitis B. IFNα exhibits direct antiviral effects as well as immunomodulatory activities, which can induce sustained antiviral responses in part of the treated chronic hepatitis B patients. Numerous IFNα subtypes with high sequence identity between 76-96% exist which are characterized by diverse, non-redundant biological activities. Our previous studies have demonstrated that the clinically approved IFNα2 is not the most effective subtype for the anti-HBV treatment among all IFNα subtypes. So far very little is known about the IFNα subtype expression pattern during early HBV infection and the IFNα subtype-specific susceptibility during persistent HBV infection as well as its related cellular mechanism. Here we determined the Ifna subtype mRNA expression during acute and chronic HBV infection by using the well-established hydrodynamic injection (HDI) mouse model and we revealed a transient but strong expression of a panel of Ifna subtypes in the spleen of HBV persistent replication mice compared to HDI controls. Immunotherapy with distinct IFNα subtypes controlled chronic HBV infection. IFNα subtype-mediated antiviral response and immune activation were comprehensively analyzed in an AAV-HBV persistent infection murine model and murine IFNα2 was identified as the most effective subtype in suppression of HBV replication. Further analysis of the immune response revealed a strong immunomodulatory activity of murine IFNα2 on splenic and intrahepatic NK and T cell activation during persistent HBV infection. Taken together, our data provide IFNα subtype-specific differences in the antiviral and immunomodulatory effector responses and a strong expression of all IFNα subtypes in the spleen during persistent HBV infection in mice. This knowledge will support the development of novel immunotherapeutic strategies for chronic hepatitis B infection.
Collapse
Affiliation(s)
- Xiaohong Xie
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gastroenterology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Zehra Karakoese
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Dilhumare Ablikim
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Julia Ickler
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Jonas Schuhenn
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Xiaoqing Zeng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ulf Dittmer
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Kathrin Sutter
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Kathrin Sutter, ; Jia Liu,
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Kathrin Sutter, ; Jia Liu,
| |
Collapse
|
|
25
|
Chang KC, Chua HH, Chen YH, Tsuei DJ, Lee MH, Chiang CL, Jeng YM, Wu JF, Chen HL, Hsu HY, Ni YH, Chang MH. Hepatitis B virus X gene impacts on the innate immunity and immune-tolerant phase in chronic hepatitis B virus infection. Liver Int 2022; 42:2154-2166. [PMID: 35762289 DOI: 10.1111/liv.15348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 03/09/2022] [Accepted: 06/24/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS The immunologic features involved in the immune-tolerant phase of chronic hepatitis B (CHB) virus (HBV) infection are unclear. The hepatitis B virus X (HBx) protein disrupts IFN-β induction by downregulating MAVS and may destroy subsequent HBV-specific adaptive immunity. We aimed to analyse the impacts of genetic variability of HBx in CHB patients on the immune-tolerant phase during long-term follow-up. METHODS Children with CHB in the immune-tolerant phase were recruited and followed longitudinally. HBx gene sequencing of infecting HBV strains was performed, and the effects of HBx mutations on the immune-tolerant phase were assessed. Restoration of the host immune response to end the immune-tolerant phase was investigated by immunoblotting, immunostaining, ELISA and reporter assays of MAVS/IFN-β signalling in liver cell lines, patient liver tissues and the HBV plasmid replication system. RESULTS A total of 173 children (median age, 6.92 years) were recruited. Patients carrying HBx R87G, I127V and R87G + I127V double mutations exhibited higher cumulative incidences of immune-tolerant phase breakthrough (p = .011, p = .006 and p = .017 respectively). Cells transfected with HBx R87G and I127V mutants and pHBV1.3-B6.3 replicons containing the HBx R87G and I127V mutations exhibited statistically increased levels of IFN-β, especially under poly(I:C) stimulation or Flag-MAVS cotransfection. HA-HBx wild-type interacted with Flag-MAVS and enhanced its ubiquitination, but this ability was diminished in the R87G and I127V mutants. CONCLUSIONS HBx suppresses IFN-β induction. R87G and I127V mutation restored IFN-β production by preventing MAVS degradation, contributing to curtailing the HBV immune-tolerant phase in CHB patients.
Collapse
Affiliation(s)
- Kai-Chi Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Huey-Huey Chua
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Ya-Hui Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Daw-Jen Tsuei
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Mei-Hui Lee
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Cheng-Lun Chiang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yung-Ming Jeng
- Department of Pathology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Medical Education and Bioethics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Medical Education and Bioethics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Medical Microbiota Center, College of Medicine, National Taiwan University, Taipei, Taiwan.,Center of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| |
Collapse
|
|
26
|
Medical Advances in Hepatitis D Therapy: Molecular Targets. Int J Mol Sci 2022; 23:ijms231810817. [PMID: 36142728 PMCID: PMC9506394 DOI: 10.3390/ijms231810817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/25/2022] Open
Abstract
An approximate number of 250 million people worldwide are chronically infected with hepatitis B virus, making them susceptible to a coinfection with hepatitis D virus. The superinfection causes the most severe form of a viral hepatitis and thus drastically worsens the course of the disease. Until recently, the only available therapy consisted of interferon-α, only eligible for a minority of patients. In July 2020, the EMA granted Hepcludex conditional marketing authorization throughout the European Union. This first-in-class entry inhibitor offers the promise to prevent the spread in order to gain control and eventually participate in curing hepatitis B and D. Hepcludex is an example of how understanding the viral lifecycle can give rise to new therapy options. Sodium taurocholate co-transporting polypeptide, the virus receptor and the target of Hepcludex, and other targets of hepatitis D therapy currently researched are reviewed in this work. Farnesyltransferase inhibitors such as Lonafarnib, targeting another essential molecule in the HDV life cycle, represent a promising target for hepatitis D therapy. Farnesyltransferase attaches a farnesyl (isoprenyl) group to proteins carrying a C-terminal Ca1a2X (C: cysteine, a: aliphatic amino acid, X: C-terminal amino acid) motif like the large hepatitis D virus antigen. This modification enables the interaction of the HBV/HDV particle and the virus envelope proteins. Lonafarnib, which prevents this envelopment, has been tested in clinical trials. Targeting the lifecycle of the hepatitis B virus needs to be considered in hepatitis D therapy in order to cure a patient from both coexisting infections. Nucleic acid polymers target the hepatitis B lifecycle in a manner that is not yet understood. Understanding the possible targets of the hepatitis D virus therapy is inevitable for the improvement and development of a sufficient therapy that HDV patients are desperately in need of.
Collapse
|
|
27
|
Kayesh MEH, Hashem MA, Sanada T, Kitab B, Rashid MHO, Akter L, Ezzikouri S, Murakami S, Ogawa S, Tanaka Y, Kohara M, Tsukiyama-Kohara K. Characterization of innate immune response to hepatitis B virus genotype F acute infection in tree shrew (Tupaia belangeri) model. FRONTIERS IN VIROLOGY 2022; 2. [DOI: 10.3389/fviro.2022.926831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Hepatitis B virus (HBV) infection is a global public health problem. The clinical outcomes of HBV infections are influenced by host as well as viral factors, including viral genotypes and subgenotypes. The interplay between HBV and host innate immunity remains unclear because of the lack of a suitable small animal model. Tree shrews (Tupaia belangeri) have been utilized as a useful animal model for hepatitis viruses such as hepatitis B and C viruses. In this study, we characterized acute infections by HBV genotype F (HBV-F) wild type (Wt) and mutant type (Mt) viruses in adult tree shrews. Serum alanine aminotransferase levels were measured before and post- infection 7 and 14 dpi. Both HBV-F-Wt and Mt were detected in the HBV-F-infected tree shrew serum and liver tissue at 7 and 14 dpi. We examined the intrahepatic expression patterns of Toll-like receptors (TLRs) (TLR1–9 mRNAs), cGAS, several transcription factors such as STAT1, STAT2, IRF7, HNF4, PD-L1, and cytokines, including IFN-β, IFN-γ, IL-6, and TNF-α in HBV-F Wt/Mt-infected tree shrews. When compared with uninfected animal group, significant suppression of TLR8 in HBV-F-Wt infected animals and significant suppression of PD-L1 in both HBV-F-Wt and Mt infected animals were observed. Thus, tree shrew can be a useful animal model to characterize HBV-F pathogenesis.
Collapse
|
|
28
|
Du Y, Wu J, Liu J, Zheng X, Yang D, Lu M. Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection. Front Immunol 2022; 13:965018. [PMID: 35967443 PMCID: PMC9372436 DOI: 10.3389/fimmu.2022.965018] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/30/2022] [Indexed: 12/03/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains to be a substantial global burden, especially for end-stage liver diseases. It is well accepted that HBV-specific T and B cells are essential for controlling HBV infection. Toll-like receptors (TLRs) represent one of the major first-line antiviral defenses through intracellular signaling pathways that induce antiviral inflammatory cytokines and interferons, thereby shaping adaptive immunity. However, HBV has evolved strategies to counter TLR responses by suppressing the expression of TLRs and blocking the downstream signaling pathways, thus limiting HBV-specific adaptive immunity and facilitating viral persistence. Recent studies have stated that stimulation of the TLR signaling pathway by different TLR agonists strengthens host innate immune responses and results in suppression of HBV replication. In this review, we will discuss how TLR-mediated responses shape HBV-specific adaptive immunity as demonstrated in different experimental models. This information may provide important insight for HBV functional cure based on TLR agonists as immunomodulators.
Collapse
Affiliation(s)
- Yanqin Du
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jun Wu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Mengji Lu,
| |
Collapse
|
|
29
|
Clinical impact and mechanisms of hepatitis B virus infection concurrent with non-alcoholic fatty liver disease. Chin Med J (Engl) 2022; 135:1653-1663. [PMID: 35940901 PMCID: PMC9509100 DOI: 10.1097/cm9.0000000000002310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
ABSTRACT Chronic hepatitis B (CHB) virus infection is an important threat to global health despite the administration of vaccines and the use of antiviral treatments. In recent years, as the prevalence of obesity and metabolic syndrome has increased, non-alcoholic fatty liver disease (NAFLD) in patients with CHB has become more common. Both diseases can lead to liver fibrosis and even hepatocellular carcinoma, but the risk of dual etiology, outcome, and CHB combined with NAFLD is not fully elucidated. In this review, we assess the overlapping prevalence of NAFLD and CHB, summarize recent studies of clinical and basic research related to potential interactions, and evaluate the progressive changes of treatments for CHB patients with NAFLD. This review increases the understanding of the relationship and mechanisms of interaction between steatosis and hepatitis B virus infection, and it provides new strategies for the future clinical management and treatment of CHB combined with NAFLD.
Collapse
|
|
30
|
Wildum S, Korolowicz KE, Suresh M, Steiner G, Dai L, Li B, Yon C, De Vera Mudry MC, Regenass-Lechner F, Huang X, Hong X, Murreddu MG, Kallakury BV, Young JAT, Menne S. Toll-Like Receptor 7 Agonist RG7854 Mediates Therapeutic Efficacy and Seroconversion in Woodchucks With Chronic Hepatitis B. Front Immunol 2022; 13:884113. [PMID: 35677037 PMCID: PMC9169629 DOI: 10.3389/fimmu.2022.884113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/22/2022] [Indexed: 01/04/2023] Open
Abstract
Conventional treatment of chronic hepatitis B (CHB) is rarely curative due to the immunotolerant status of patients. RG7854 is an oral double prodrug of a toll-like receptor 7 (TLR7) agonist that is developed for the treatment of CHB. The therapeutic efficacy, host immune response, and safety of RG7854 were evaluated in the woodchuck model of CHB. Monotreatment with the two highest RG7854 doses and combination treatment with the highest RG7854 dose and entecavir (ETV) suppressed viral replication, led to loss of viral antigens, and induced seroconversion in responder woodchucks. Since viral suppression and high-titer antibodies persisted after treatment ended, this suggested that a sustained antiviral response (SVR) was induced by RG7854 in a subset of animals. The SVR rate, however, was comparable between both treatment regimens, suggesting that the addition of ETV did not enhance the therapeutic efficacy of RG7854 although it augmented the proliferation of blood cells in response to viral antigens and magnitude of antibody titers. The induction of interferon-stimulated genes in blood by RG7854/ETV combination treatment demonstrated on-target activation of TLR7. Together with the virus-specific blood cell proliferation and the transient elevations in liver enzymes and inflammation, this suggested that cytokine-mediated non-cytolytic and T-cell mediated cytolytic mechanisms contributed to the SVR, in addition to the virus-neutralizing effects by antibody-producing plasma cells. Both RG7854 regimens were not associated with treatment-limiting adverse effects but accompanied by dose-dependent, transient neutropenia and thrombocytopenia. The study concluded that finite, oral RG7854 treatment can induce a SVR in woodchucks that is based on the retrieval of antiviral innate and adaptive immune responses. This supports future investigation of the TLR7 agonist as an immunotherapeutic approach for achieving functional cure in patients with CHB.
Collapse
Affiliation(s)
- Steffen Wildum
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Kyle E Korolowicz
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Manasa Suresh
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Guido Steiner
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Lue Dai
- Roche Pharma, Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China
| | - Bin Li
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Changsuek Yon
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | | | | | - Xu Huang
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Xupeng Hong
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G Murreddu
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bhaskar V Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC, United States
| | - John A T Young
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| |
Collapse
|
|
31
|
Magri A, Harris JM, D'Arienzo V, Minisini R, Jühling F, Wing PAC, Rapetti R, Leutner M, Testoni B, Baumert TF, Zoulim F, Balfe P, Pirisi M, McKeating JA. Inflammatory Gene Expression Associates with Hepatitis B Virus cccDNA- but Not Integrant-Derived Transcripts in HBeAg Negative Disease. Viruses 2022; 14:1070. [PMID: 35632812 PMCID: PMC9146050 DOI: 10.3390/v14051070] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/11/2022] [Accepted: 05/11/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global health problem that presents as a spectrum of liver disease, reflecting an interplay between the virus and the host immune system. HBV genomes exist as episomal covalently closed circular DNA (cccDNA) or chromosomal integrants. The relative contribution of these genomes to the viral transcriptome in chronic hepatitis B (CHB) is not well-understood. We developed a qPCR method to estimate the abundance of HBV cccDNA- and integrant-derived viral transcripts and applied this to a cohort of patients diagnosed with CHB in the HBe antigen negative phase of disease. We noted a variable pattern of HBV transcripts from both DNA templates, with preS1/S2 mRNAs predominating and a significant association between increasing age and the expression of integrant-derived mRNAs, but not with inflammatory status. In contrast, cccDNA-derived transcripts were associated with markers of liver inflammation. Analysis of the inflammatory hepatic transcriptome identified 24 genes significantly associated with cccDNA transcriptional activity. Our study uncovers an immune gene signature that associates with HBV cccDNA transcription and increases our understanding of viral persistence.
Collapse
Affiliation(s)
- Andrea Magri
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
| | - James M Harris
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
| | | | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Frank Jühling
- Institut de Recherche sur les Maladies Virales et Hépatiques, University of Strasbourg and Inserm, UMR_S1110, F-67000 Strasbourg, France
| | - Peter A C Wing
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX1 4BH, UK
| | - Rachele Rapetti
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Monica Leutner
- Department of Diagnostic Services and Supportive Therapies, ASL Verbano-Cusio-Ossola, 28887 Omegna, Italy
| | - Barbara Testoni
- Cancer Research Center of Lyon, UMR INSERM 1052, 69008 Lyon, France
| | - Thomas F Baumert
- Institut de Recherche sur les Maladies Virales et Hépatiques, University of Strasbourg and Inserm, UMR_S1110, F-67000 Strasbourg, France
- Pôle Hépato-Digestif, Institut Hopitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- Institut Universitaire de France, 75005 Paris, France
| | - Fabien Zoulim
- Cancer Research Center of Lyon, UMR INSERM 1052, 69008 Lyon, France
| | - Peter Balfe
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Jane A McKeating
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX1 4BH, UK
| |
Collapse
|
|
32
|
Wu S, Yi W, Gao Y, Deng W, Bi X, Lin Y, Yang L, Lu Y, Liu R, Chang M, Shen G, Hu L, Zhang L, Li M, Xie Y. Immune Mechanisms Underlying Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B Patients With Viral Coinfection. Front Immunol 2022; 13:893512. [PMID: 35634301 PMCID: PMC9130599 DOI: 10.3389/fimmu.2022.893512] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 04/11/2022] [Indexed: 12/28/2022] Open
Abstract
It is considered that chronic hepatitis B patients have obtained functional cure if they get hepatitis B surface antigen (HBsAg) seroclearance after treatment. Serum HBsAg is produced by cccDNA that is extremely difficult to clear and dslDNA that is integrated with host chromosome. High HBsAg serum level leads to failure of host immune system, which makes it unable to produce effective antiviral response required for HBsAg seroclerance. Therefore, it is very difficult to achieve functional cure, and fewer than 1% of chronic hepatitis B patients are cured with antiviral treatment annually. Some chronic hepatitis B patients are coinfected with other chronic viral infections, such as HIV, HCV and HDV, which makes more difficult to cure. However, it is found that the probability of obtaining HBsAg seroclearance in patients with coinfection is higher than that in patients with HBV monoinfection, especially in patients with HBV/HIV coinfection who have an up to 36% of HBsAg 5-year-seroclerance rate. The mechanism of this interesting phenomenon is related to the functional reconstruction of immune system after antiretroviral therapy (ART). The quantity increase and function recovery of HBV specific T cells and B cells, and the higher level of cytokines and chemokines such as IP-10, GM-CSF, promote HBsAg seroclearance. This review summarizes recent studies on the immune factors that have influence on HBsAg seroconversion in the chronic hepatitis B patients with viral coinfection, which might provide new insights for the development of therapeutic approaches to partially restore the specific immune response to HBV and other viruses.
Collapse
Affiliation(s)
- Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| |
Collapse
|
|
33
|
Li J, Yu M, Zong R, Fan C, Ren F, Wu W, Li C. Deacetylation of Notch1 by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization. Am J Physiol Gastrointest Liver Physiol 2022; 322:G459-G471. [PMID: 35234049 DOI: 10.1152/ajpgi.00338.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic macrophages are involved in both pathogen clearance and immunopathogenesis. Emerging evidence demonstrates that macrophage polarization plays a critical role in hepatitis B virus (HBV)-induced immune impairment and liver pathology. However, it remains largely unknown as to how HBV infection facilitates M2 macrophage polarization. Here, a mouse HBV infection model was established by hydrodynamic injection with a vector containing 1.3-fold overlength HBV genome via the tail vein. Coculture experiments with HBV-producing HepG2.2.15 cells and macrophages were established in vitro. We found that HBV-inhibited M1 while enhancing M2 markers, which was accompanied by decreased proinflammatory tumor necrosis factor-α (TNF-α) and augmented anti-inflammatory IL-10 expression. Furthermore, both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) secretion contributed to HBV-triggered macrophage polarization from M1 toward M2 phenotype. Mechanistically, HBsAg and HBeAg could upregulate the sirtuins 1 (SIRT1) deacetylase expression, which in turn promote deacetylation of the Notch1 intracellular domain (NICD), leading to increased Akt phosphorylation and decreased NF-κB nuclear translocation in macrophages. Our findings suggest that NICD deacetylation by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, raising the possibility of targeting SIRT1/Notch1 pathway in macrophages to treat HBV immune evasion and chronic HBV infection.NEW & NOTEWORTHY This study identified a previously unrecognized molecular mechanism of HBV-mediated suppression of innate immune responses. We demonstrate that deacetylation of NICD by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, which may aid in the development of new macrophage-based immunotherapy for chronic HBV infection and related diseases.
Collapse
Affiliation(s)
- Jiahui Li
- Department of Anatomy and Histology Embryology, Jinzhou Medical University, Jinzhou, People's Republic of China.,Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China.,Department of Anatomy, Youjiang Medical University for Nationalities, Baise, People's Republic of China
| | - Mengxue Yu
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| | - Ruobin Zong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| | - Chengpeng Fan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| | - Fu Ren
- Department of Anatomy, Shenyang Medical College, Shenyang, People's Republic of China
| | - Wei Wu
- Institute of Humanities and Social Sciences, Shenyang University, Shenyang, People's Republic of China
| | - Changyong Li
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| |
Collapse
|
|
34
|
Zhang X, Su H, Yu H, Ding J, Deng W, Qin B, Zhou C, Dou J, Guo M. A Polysaccharide From Eupolyphaga sinensis Walker With Anti-HBV Activities In Vitro and In Vivo. Front Pharmacol 2022; 13:827128. [PMID: 35308231 PMCID: PMC8928433 DOI: 10.3389/fphar.2022.827128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/25/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatitis B virus (HBV) infection remains a major global threat to human health worldwide. Recently, the Chinese medicines with antiviral properties and low toxicity have been a concern. In our previous study, Eupolyphaga sinensis Walker polysaccharide (ESPS) has been isolated and characterized, while its antiviral effect on HBV remained unclear. The anti-HBV activity of ESPS and its regulatory pathway were investigated in vitro and in vivo. The results showed that ESPS significantly inhibited the production of HBsAg, HBeAg, and HBV DNA in the supernatants of HepG2.2.15 in a dose-dependent manner; HBV RNA and core protein expression were also decreased by ESPS. The in vivo studies using HBV transgenic mice further revealed that ESPS (20 and 40 mg/kg/2 days) significantly reduced the levels HBsAg, HBeAg, and HBV DNA in the serum, as well as HBV DNA and HBV RNA in mice liver. In addition, ESPS activated the Toll-like receptor 4 (TLR4) pathway; elevated levels of IFN-β, TNF-α, and IL-6 in the serum were observed, indicating that the anti-HBV effect of ESPS was achieved by potentiating innate immunity function. In conclusion, our study shows that ESPS is a potential anti-HBV ingredient and is of great value in the development of new anti-HBV drugs.
Collapse
Affiliation(s)
- Xue Zhang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Huiling Su
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Haifei Yu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Jialu Ding
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Wanyu Deng
- College of Life Science, Shangrao Normal University, Shangrao, China
- Department of Biliary Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bo Qin
- Shaoxing Women and Children's Hospital, Shaoxing, China
| | - Changlin Zhou
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Jie Dou
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Min Guo
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
|
35
|
Zaki MYW, Fathi AM, Samir S, Eldafashi N, William KY, Nazmy MH, Fathy M, Gill US, Shetty S. Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:1255. [PMID: 35267563 PMCID: PMC8909759 DOI: 10.3390/cancers14051255] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 02/08/2023] Open
Abstract
Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.
Collapse
Affiliation(s)
- Marco Y. W. Zaki
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Ahmed M. Fathi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Samara Samir
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt;
| | - Nardeen Eldafashi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Kerolis Y. William
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 12613, Egypt;
| | - Maiiada Hassan Nazmy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Upkar S. Gill
- Barts Liver Centre, Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London E1 2AT, UK;
| | - Shishir Shetty
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| |
Collapse
|
|
36
|
You H, Qin S, Zhang F, Hu W, Li X, Liu D, Kong F, Pan X, Zheng K, Tang R. Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection. Front Immunol 2022; 13:829923. [PMID: 35251017 PMCID: PMC8891514 DOI: 10.3389/fimmu.2022.829923] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/24/2022] [Indexed: 12/16/2022] Open
Abstract
As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.
Collapse
Affiliation(s)
- Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Suping Qin
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Fulong Zhang
- Imaging Department, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Wei Hu
- Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliate Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Dongsheng Liu
- Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliate Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Xiucheng Pan
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
| |
Collapse
|
|
37
|
Xie X, Luo J, Zhu D, Zhou W, Yang X, Feng X, Lu M, Zheng X, Dittmer U, Yang D, Liu J. HBeAg Is Indispensable for Inducing Liver Sinusoidal Endothelial Cell Activation by Hepatitis B Virus. Front Cell Infect Microbiol 2022; 12:797915. [PMID: 35174107 PMCID: PMC8842949 DOI: 10.3389/fcimb.2022.797915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background and AimsLiver sinusoidal endothelial cells (LSECs) serve as sentinel cells to detect microbial infection and actively contribute to regulating immune responses for surveillance against intrahepatic pathogens. We recently reported that hepatitis B e antigen (HBeAg) stimulation could induce LSEC maturation and abrogate LSEC-mediated T cell suppression in a TNF-α and IL27 dependent manner. However, it remains unclear how HBeAg deficiency during HBV infection influences LSEC immunoregulation function and intrahepatic HBV-specific CD8 T cell responses.MethodsThe function of LSECs in regulating effector T cell response, intrahepatic HBV-specific CD8 T cell responses and HBV viremia were characterized in both HBeAg-deficient and -competent HBV hydrodynamic injection (HDI) mouse models.ResultsLSECs isolated from HBeAg-deficient HBV HDI mice showed a reduced capacity to promote T cell immunity in vitro compared with those isolated from wild-type HBV HDI mice. HBeAg expression replenishment in HBeAg-deficient HBV HDI mice restored the HBV-induced LSEC maturation, and resulted in potent intrahepatic anti-HBV CD8 T cell responses and efficient control of HBV replication. Moreover, in vivo TNF-α, but not IL27 blockade in HBV HDI mice impaired HBV-specific CD8 T cell immunity and delayed HBV clearance.ConclusionOur study underlines that HBeAg is indispensable for HBV-induced LSEC maturation to trigger intrahepatic HBV-specific T cell activation, and provides a new mechanism to elucidate the intrahepatic immune microenvironment regulation upon HBV exposure.
Collapse
Affiliation(s)
- Xiaohong Xie
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinzhuo Luo
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Zhu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenqing Zhou
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ulf Dittmer
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jia Liu,
| |
Collapse
|
|
38
|
Werner M, Schefczyk S, Trippler M, Treckmann JW, Baba HA, Gerken G, Schlaak JF, Broering R. Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3. Viruses 2022; 14:218. [PMID: 35215812 PMCID: PMC8874605 DOI: 10.3390/v14020218] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1-9 ligands for 6-24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.
Collapse
Affiliation(s)
- Melanie Werner
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Stefan Schefczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Martin Trippler
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Juergen W. Treckmann
- Department of General-, Visceral- and Transplantation-Surgery, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
| | - Hideo A. Baba
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
| | - Guido Gerken
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
- Helios Hospital, Gastroenterology, Hepatology and Palliative Medicine, Robert-Koch-Straße 2, 42549 Velbert, Germany
| | - Joerg F. Schlaak
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
- AMEOS Hospital, St. Clemens, Internal Medicine—Hepatology, Gastroenterology, Infectiology and Diabetology, Wilhelmstr. 34, 46145 Oberhausen, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| |
Collapse
|
|
39
|
Zhao H, Han Q, Yang A, Wang Y, Wang G, Lin A, Wang X, Yin C, Zhang J. CpG-C ODN M362 as an immunoadjuvant for HBV therapeutic vaccine reverses the systemic tolerance against HBV. Int J Biol Sci 2022; 18:154-165. [PMID: 34975324 PMCID: PMC8692134 DOI: 10.7150/ijbs.62424] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 10/20/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic Hepatitis B virus (CHB) infection is a global public health problem. Oligodeoxynucleotides (ODNs) containing class C unmethylated cytosine-guanine dinucleotide (CpG-C) motifs may provide potential adjuvants for the immunotherapeutic strategy against CHB, since CpG-C ODNs stimulate both B cell and dendritic cell (DC) activation. However, the efficacy of CpG-C ODN as an anti-HBV vaccine adjuvant remains unclear. In this study, we demonstrated that CpG M362 (CpG-C ODN) as an adjuvant in anti-HBV vaccine (cHBV-vaccine) successfully and safely eliminated the virus in HBV-carrier mice. The cHBV-vaccine enhanced DC maturation both in vivo and in vitro, overcame immune tolerance, and recovered exhausted T cells in HBV-carrier mice. Furthermore, the cHBV-vaccine elicited robust hepatic HBV-specific CD8+ and CD4+ T cell responses, with increased cellular proliferation and IFN-γ secretion. Additionally, the cHBV-vaccine invoked a long-lasting follicular CXCR5+ CD8+ T cell response following HBV re-challenge. Taken together, CpG M362 in combination with rHBVvac cleared persistent HBV and achieved long-term virological control, making it a promising candidate for treating CHB.
Collapse
Affiliation(s)
- Huajun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Ailu Yang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Yucan Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Guan Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Ang Lin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Xiao Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Chunlai Yin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| |
Collapse
|
|
40
|
Lu YQ, Wu J, Wu XJ, Ma H, Ma YX, Zhang R, Su MN, Wu N, Chen GY, Chen HS, Pan XB. Interferon Gamma-Inducible Protein 16 of Peripheral Blood Mononuclear Cells May Sense Hepatitis B Virus Infection and Regulate the Antiviral Immunity. Front Cell Infect Microbiol 2021; 11:790036. [PMID: 34869083 PMCID: PMC8637547 DOI: 10.3389/fcimb.2021.790036] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 10/27/2021] [Indexed: 01/12/2023] Open
Abstract
Interferon gamma-inducible protein 16 (IFI16) is a DNA sensor protein, which triggers interferon-beta (IFN-β) production. However, the role of IFI16 in the innate immunity against hepatitis B virus (HBV) remains controversial. Peripheral blood mononuclear cells (PBMCs) and serum specimens were collected from 20 patients with chronic hepatitis B (CHB) receiving Peg-IFN-α2b therapy. IFI16 mRNA/protein of PBMCs and serum IFI16 at baseline and changes during Peg-IFN-α2b treatment were detected. The interaction between IFI16 and HBV DNA in the PBMCs was analyzed using chromatin immunoprecipitation assay. Leukemic T cell line CEM-C7 and HBV-replicating HepG2.2.15 cells were used to test the effects of interferon treatment and HBV replication on IFI16 expression. Compared with healthy controls, lower levels of IFI16 mRNA but more significant expression of IFI16 protein with heterogeneous degradation were detected in PBMCs of CHB patients. Early changes in IFI16 mRNA, but not IFNB mRNA of PBMCs or serum IFI16, were correlated to HBeAg seroconversion of Peg-IFN-α2b therapy. An interaction between IFI16 and HBV DNA was detected in the PBMCs. In the cultured HepG2.2.15 and CEM-C7 cells, interferons resulted in the translocalization of IFI16 from the cytoplasm to the nucleus and inhibited IFI16 degradation. IFI16 of PBMCs may play a role in sensing HBV infection, and early change in IFI16 mRNA of PBMCs is valuable to predict HBeAg seroconversion in Peg-IFN-α2b treatment. The influences on IFI16 degradation and subcellular location may present a molecular mechanism of antiviral activity of interferon.
Collapse
Affiliation(s)
- Yu-Qing Lu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Jing Wu
- School of Basic Medical Sciences, Institute of Hepatology and Metabolic Diseases, Key Laboratory of Inflammation and Immunoregulation of Hangzhou, Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Xiang-Ji Wu
- School of Basic Medical Sciences, Institute of Hepatology and Metabolic Diseases, Key Laboratory of Inflammation and Immunoregulation of Hangzhou, Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Hui Ma
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Yan-Xiu Ma
- School of Basic Medical Sciences, Institute of Hepatology and Metabolic Diseases, Key Laboratory of Inflammation and Immunoregulation of Hangzhou, Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Rong Zhang
- School of Basic Medical Sciences, Institute of Hepatology and Metabolic Diseases, Key Laboratory of Inflammation and Immunoregulation of Hangzhou, Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Meng-Nan Su
- School of Basic Medical Sciences, Institute of Hepatology and Metabolic Diseases, Key Laboratory of Inflammation and Immunoregulation of Hangzhou, Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Nan Wu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Gong-Yin Chen
- Department of Infectious Diseases & Department of Hepatology, Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Hong-Song Chen
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Xiao-Ben Pan
- School of Basic Medical Sciences, Institute of Hepatology and Metabolic Diseases, Key Laboratory of Inflammation and Immunoregulation of Hangzhou, Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Department of Infectious Diseases & Department of Hepatology, Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| |
Collapse
|
|
41
|
Xu C, Chen J, Chen X. Host Innate Immunity Against Hepatitis Viruses and Viral Immune Evasion. Front Microbiol 2021; 12:740464. [PMID: 34803956 PMCID: PMC8598044 DOI: 10.3389/fmicb.2021.740464] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/29/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatitis viruses are primary causative agents of hepatitis and represent a major source of public health problems in the world. The host innate immune system forms the first line of defense against hepatitis viruses. Hepatitis viruses are sensed by specific pathogen recognition receptors (PRRs) that subsequently trigger the innate immune response and interferon (IFN) production. However, hepatitis viruses evade host immune surveillance via multiple strategies, which help compromise the innate immune response and create a favorable environment for viral replication. Therefore, this article reviews published findings regarding host innate immune sensing and response against hepatitis viruses. Furthermore, we also focus on how hepatitis viruses abrogate the antiviral effects of the host innate immune system.
Collapse
Affiliation(s)
- Chonghui Xu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jizheng Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| |
Collapse
|
|
42
|
Xie X, Lv H, Liu C, Su X, Yu Z, Song S, Bian H, Tian M, Qin C, Qi J, Zhu Q. HBeAg mediates inflammatory functions of macrophages by TLR2 contributing to hepatic fibrosis. BMC Med 2021; 19:247. [PMID: 34649530 PMCID: PMC8518250 DOI: 10.1186/s12916-021-02085-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 08/03/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND We and others have confirmed activation of macrophages plays a critical role in liver injury and fibrogenesis during HBV infection. And we have also proved HBeAg can obviously induce the production of macrophage inflammatory cytokines compared with HBsAg and HBcAg. However, the receptor and functional domain of HBeAg in macrophage activation and its effects and mechanisms on hepatic fibrosis remain elusive. METHODS The potentially direct binding receptors of HBeAg were screened and verified by Co-IP assay. Meanwhile, the function domain and accessible peptides of HBeAg for macrophage activation were analyzed by prediction of surface accessible peptide, construction, and synthesis of truncated fragments. Furthermore, effects and mechanisms of the activation of hepatic stellate cells induced by HBeAg-treated macrophages were investigated by Transwell, CCK-8, Gel contraction assay, Phospho Explorer antibody microarray, and Luminex assay. Finally, the effect of HBeAg in hepatic inflammation and fibrosis was evaluated in both human and murine tissues by immunohistochemistry, immunofluorescence, ELISA, and detection of liver enzymes. RESULTS Herein, we verified TLR-2 was the direct binding receptor of HBeAg. Meanwhile, C-terminal peptide (122-143 aa.) of core domain in HBeAg was critical for macrophage activation. But arginine-rich domain of HBcAg hided this function, although HBcAg and HBeAg shared the same core domain. Furthermore, HBeAg promoted the proliferation, motility, and contraction of hepatic stellate cells (HSCs) in a macrophage-dependent manner, but not alone. PI3K-AKT-mTOR and p38 MAPK signaling pathway were responsible for motility phenotype of HSCs, while the Smad-dependent TGF-β signaling pathway for proliferation and contraction of them. Additionally, multiple chemokines and cytokines, such as CCL2, CCL5, CXCL10, and TNF-α, might be key mediators of HSC activation. Consistently, HBeAg induced transient inflammation response and promoted early fibrogenesis via TLR-2 in mice. Finally, clinical investigations suggested that the level of HBeAg is associated with inflammation and fibrosis degrees in patients infected with HBV. CONCLUSIONS HBeAg activated macrophages via the TLR-2/NF-κB signal pathway and further exacerbated hepatic fibrosis by facilitating motility, proliferation, and contraction of HSCs with the help of macrophages.
Collapse
Affiliation(s)
- Xiaoyu Xie
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China
| | - Huanran Lv
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China
| | - Chenxi Liu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Xiaonan Su
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Zhen Yu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Shouyang Song
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Hongjun Bian
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Miaomiao Tian
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China
| | - Chengyong Qin
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China
| | - Jianni Qi
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China. .,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China. .,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China.
| | - Qiang Zhu
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China. .,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China. .,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China. .,The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China.
| |
Collapse
|
|
43
|
Kayesh MEH, Kohara M, Tsukiyama-Kohara K. Toll-Like Receptor Response to Hepatitis B Virus Infection and Potential of TLR Agonists as Immunomodulators for Treating Chronic Hepatitis B: An Overview. Int J Mol Sci 2021; 22:10462. [PMID: 34638802 PMCID: PMC8508807 DOI: 10.3390/ijms221910462] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health problem. The immunopathology of the disease, especially the interplay between HBV and host innate immunity, is poorly understood. Moreover, inconsistent literature on HBV and host innate immunity has led to controversies. However, recently, there has been an increase in the number of studies that have highlighted the link between innate immune responses, including Toll-like receptors (TLRs), and chronic HBV infection. TLRs are the key sensing molecules that detect pathogen-associated molecular patterns and regulate the induction of pro- and anti-inflammatory cytokines, thereby shaping the adaptive immunity. The suppression of TLR response has been reported in patients with chronic hepatitis B (CHB), as well as in other models, including tree shrews, suggesting an association of TLR response in HBV chronicity. Additionally, TLR agonists have been reported to improve the host innate immune response against HBV infection, highlighting the potential of these agonists as immunomodulators for enhancing CHB treatment. In this study, we discuss the current understanding of host innate immune responses during HBV infection, particularly focusing on the TLR response and TLR agonists as immunomodulators.
Collapse
Affiliation(s)
- Mohammad Enamul Hoque Kayesh
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan;
- Department of Microbiology and Public Health, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal 8210, Bangladesh
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;
| | - Kyoko Tsukiyama-Kohara
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan;
| |
Collapse
|
|
44
|
Hirschenberger M, Hunszinger V, Sparrer KMJ. Implications of Innate Immunity in Post-Acute Sequelae of Non-Persistent Viral Infections. Cells 2021; 10:2134. [PMID: 34440903 PMCID: PMC8391718 DOI: 10.3390/cells10082134] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/12/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Non-persistent viruses classically cause transient, acute infections triggering immune responses aimed at the elimination of the pathogen. Successful viruses evolved strategies to manipulate and evade these anti-viral defenses. Symptoms during the acute phase are often linked to dysregulated immune responses that disappear once the patient recovers. In some patients, however, symptoms persist or new symptoms emerge beyond the acute phase. Conditions resulting from previous transient infection are termed post-acute sequelae (PAS) and were reported for a wide range of non-persistent viruses such as rota-, influenza- or polioviruses. Here we provide an overview of non-persistent viral pathogens reported to be associated with diverse PAS, among them chronic fatigue, auto-immune disorders, or neurological complications and highlight known mechanistic details. Recently, the emergence of post-acute sequelae of COVID-19 (PASC) or long COVID highlighted the impact of PAS. Notably, PAS of non-persistent infections often resemble symptoms of persistent viral infections, defined by chronic inflammation. Inflammation maintained after the acute phase may be a key driver of PAS of non-persistent viruses. Therefore, we explore current insights into aberrant activation of innate immune signaling pathways in the post-acute phase of non-persistent viruses. Finally, conclusions are drawn and future perspectives for treatment and prevention of PAS are discussed.
Collapse
|
|
45
|
Zheng B, Yu Y, Pan Z, Feng Y, Zhao H, Han Q, Zhang J. HBsAg Dampened STING Associated Activation of NK Cells in HBeAg-Negative CHB Patients. Int J Mol Sci 2021; 22:ijms22147643. [PMID: 34299262 PMCID: PMC8304816 DOI: 10.3390/ijms22147643] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/08/2021] [Accepted: 07/14/2021] [Indexed: 02/07/2023] Open
Abstract
NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection.
Collapse
|
|
46
|
Wang X, Wei Z, Lan T, He Y, Cheng B, Li R, Chen H, Li F, Liu G, Jiang B, Lin Y, Lu M, Meng Z. CCDC88A/GIV promotes HBV replication and progeny secretion via enhancing endosomal trafficking and blocking autophagic degradation. Autophagy 2021; 18:357-374. [PMID: 34190023 PMCID: PMC8942511 DOI: 10.1080/15548627.2021.1934271] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatitis B virus (HBV) particles are thought to be secreted from hepatocytes through multivesicular bodies (MVBs); however, the cellular trafficking mechanisms prior to this process remain elusive. It has been reported that CCDC88A/GIV expression, which is involved in multiple aspects of vesicular trafficking, changes dynamically at different phases of chronic HBV infection. In this study, we focused on the role of CCDC88A/GIV in HBV replication. In the liver tissues of chronically HBV-infected patients, HBV infection significantly enhanced CCDC88A/GIV expression, and increased endoplasmic reticulum (ER) stress and autophagosome formation without changing endosome formation. Additionally, colocalization of SHBsAg with early endosomes (~30.2%) far exceeded that with autophagosomes (~3.2%). In hepatoma cells, CCDC88A/GIV and its downstream proteins, DNM2 (dynamin 2; a CCDC88A/GIV effector), CLTC and RAB5A significantly enhanced HBV replication and endosome formation but inhibited autophagosome formation. Blocking endocytosis disrupted HBsAg trafficking to endosomes and caused its accumulation in the ER lumen, which triggered ER stress to initiate the unfolded protein response (UPR). Therefore, HBsAg trafficking into autophagosomes was increased, and the lysosomal activity and maturation, which was inhibited by HBV infection, were restored. Meanwhile, core particles were prevented from entering MVBs. CCDC88A/GIV and its other effector, GNAI3, decreased autophagic flux by enhancing the insulin-induced AKT-MTOR pathway, thereby inhibiting HBV antigens autophagic degradation. In conclusion, CCDC88A/GIV enhanced HBV replication by increasing endosomal trafficking and reducing autophagic degradation of HBV antigens, suggesting that CCDC88A/GIV-mediated endosomal trafficking plays an important role in HBV replication and progeny secretion.Abbreviations: ACTB: actin beta; AO: acridine orange; ATF6: activating transcription factor 6; CCDC88A/GIV: coiled-coil domain containing 88A; CLTC: clathrin heavy chain; CQ: chloroquine; DAPI: 4ʹ,6-diamidino-2-phenylindole; DNM2: dynamin 2; ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleus signaling 1; EIF2A: eukaryotic translation initiation factor 2A; FBS: fetal bovine serum; GNAI3: G protein subunit alpha i3; HBV: hepatitis B virus; HBV RIs: HBV replication intermediates; HBcAg: HBV core protein; HBsAg: HBV surface antigen; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MVBs: multivesicular bodies; MTOR: mechanistic target of rapamycin kinase; PDI: protein disulfide isomerase; PHH: primary human hepatocyte; pSM2: a HBV replication-competent plasmid; HSPA5/BIP: heat shock protein family A (Hsp70) member 5; SQSTM1/p62: sequestosome 1; siRNA: small interfering RNA; SEM: standard error of the mean; UPR: unfolded protein response
Collapse
Affiliation(s)
- Xueyu Wang
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Zhiqiang Wei
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Tingyu Lan
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Yulin He
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Bin Cheng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Ruimin Li
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Hongxia Chen
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Fahong Li
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Department of Infectious Diseases,Huashan Hospital, Fudan University, Shanghai, China
| | - Guohua Liu
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Bin Jiang
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Yong Lin
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Zhongji Meng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| |
Collapse
|
|
47
|
Campos-Valdez M, Monroy-Ramírez HC, Armendáriz-Borunda J, Sánchez-Orozco LV. Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability. Viruses 2021; 13:v13061167. [PMID: 34207116 PMCID: PMC8235420 DOI: 10.3390/v13061167] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022] Open
Abstract
The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.
Collapse
Affiliation(s)
- Marina Campos-Valdez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Hugo C. Monroy-Ramírez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Juan Armendáriz-Borunda
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Campus Guadalajara, Zapopan 45201, Jalisco, México
| | - Laura V. Sánchez-Orozco
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Correspondence: ; Tel.: +52-33-3954-5677
| |
Collapse
|
|
48
|
Vaillant A. HBsAg, Subviral Particles, and Their Clearance in Establishing a Functional Cure of Chronic Hepatitis B Virus Infection. ACS Infect Dis 2021; 7:1351-1368. [PMID: 33302622 DOI: 10.1021/acsinfecdis.0c00638] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In diverse viral infections, the production of excess viral particles containing only viral glycoproteins (subviral particles or SVP) is commonly observed and is a commonly evolved mechanism for immune evasion. In hepatitis B virus (HBV) infection, spherical particles contain the hepatitis B surface antigen, outnumber infectious virus 10 000-100 000 to 1, and have diverse inhibitory effects on the innate and adaptive immune response, playing a major role in the chronic nature of HBV infection. The current goal of therapies in development for HBV infection is a clinical outcome called functional cure, which signals a persistent and effective immune control of the infection. Although removal of spherical SVP (and the HBsAg they carry) is an important milestone in achieving functional cure, this outcome is rarely achieved with current therapies due to distinct mechanisms for assembly, secretion, and persistence of SVP, which are poorly targeted by direct acting antivirals or immunotherapies. In this Review, the current understanding of the distinct mechanisms involved in the production and persistence of spherical SVP in chronic HBV infection and their immunoinhibitory activity will be reviewed as well as current therapies in development with the goal of clearing spherical SVP and achieving functional cure.
Collapse
Affiliation(s)
- Andrew Vaillant
- Replicor Inc., 6100 Royalmount Avenue, Montreal, Quebec H8Y 3E6, Canada
| |
Collapse
|
|
49
|
Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition. Semin Immunopathol 2021; 43:535-548. [PMID: 34019142 PMCID: PMC8443521 DOI: 10.1007/s00281-021-00864-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/30/2021] [Indexed: 12/16/2022]
Abstract
Chronic infections with human hepatitis viruses continue to be a major health burden worldwide. Despite the availability of an effective prophylactic vaccine against the hepatitis B virus (HBV) and of antiviral agents efficiently suppressing HBV replication, more than 250 million people are currently chronically infected with this hepatotropic DNA virus, and resolution of chronic hepatitis B (CHB) is rarely achieved. Moreover, coinfection with the hepatitis D virus (HDV), a human RNA satellite virus requiring the envelope proteins of HBV for productive viral spreading, substantially aggravates the disease course of CHB. The molecular mechanisms by which these viruses interact with each other and with the intrinsic innate responses of the hepatocytes are not fully understood. While HBV appears to avoid innate immune recognition, HDV elicits a strong enhancement of innate responses. Notwithstanding, such induction does not hamper HDV replication but contributes to liver inflammation and pathogenesis. Intriguingly, HDV appears to influence the ability of T cells to recognize infected hepatocytes by boosting antigen presentation. This review focuses on current knowledge regarding how these viruses can shape and counteract the intrinsic innate responses of the hepatocytes, thus affecting the immune system and pathogenesis. Understanding the distinct strategies of persistence that HBV and HDV have evolved is central for advancing the development of curative therapies.
Collapse
|
|
50
|
Hsu YC, Yeh ML, Wong GLH, Chen CH, Peng CY, Buti M, Enomoto M, Xie Q, Trinh H, Preda C, Liu L, Cheung KS, Yeo YH, Hoang J, Huang CF, Riveiro-Barciela M, Kozuka R, Istratescu D, Tsai PC, Accarino EV, Lee DH, Wu JL, Huang JF, Dai CY, Cheung R, Chuang WL, Yuen MF, Wong VWS, Yu ML, Nguyen MH. Incidences and Determinants of Functional Cure during Entecavir or Tenofovir Disoproxil Fumarate for Chronic Hepatitis B. J Infect Dis 2021; 224:1890-1899. [PMID: 33999179 DOI: 10.1093/infdis/jiab241] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 05/10/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Long-term incidences and baseline determinants of functional cure (HBsAg seroclearance) during entecavir (ETV) or tenofovir disoproxil fumarate (TDF) treatment are incompletely understood. METHODS This is an international multicenter cohort study of treatment-naïve chronic hepatitis B (CHB) patients who initiated on ETV or TDF without baseline malignancy. Patients were observed for HBsAg seroclearance until death or loss to follow-up. We calculated the incidences and explored the baseline determinants of HBsAg seroclearance using competing risk regression. RESULTS The analysis included 4,769 patients (median age, 50 years; 69.05% male), with a median follow-up of 5.16 years (26,614.47 person-years). HBsAg clearance occurred in 58 patients, yielding a 10-year cumulative incidence of 2.11% (95% CI, 1.54 -- 2.88%) and an annual rate of 0.22% (95% CI, 0.17--0.28%). Baseline predictors included low-level viremia with HBV DNA <2,000 IU/mL (adjusted sub-distribution HR [aSHR], 3.14; 95% CI, 1.80--5.49), elevated serum alanine aminotransferase (ALT) >200 U/L (aSHR, 3.68; 95% CI, 2.07--6.53), serum bilirubin (aSHR, 1.11 per mg/dL; 95% CI, 1.06--1.17), and fatty liver (aSHR, 1.84; 95% CI, 1.03--3.29). CONCLUSION HBsAg seroclearance rarely occurs in CHB patients treated with ETV or TDF and is associated with low-level viremia, ALT flare, bilirubin level, and fatty liver.
Collapse
Affiliation(s)
- Yao-Chun Hsu
- Center for Liver Diseases and School of Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.,Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan.,Institute of Biomedical Informatics, National Yang-Ming University, New Taipei, Taiwan.,Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Ming-Lun Yeh
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, School of Medicine and Hepatitis Research Center, College of Medicine, and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chien-Hung Chen
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Maria Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Valle d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain and CIBERehd, Instituto Carlos III, Madrid, Spain
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huy Trinh
- San Jose Gastroenterology, San Jose, California, United States of America
| | - Carmen Preda
- Institutul Clinic Fundeni-Gastroenterologie si Hepatologie, Bucuresti, Romania
| | - Li Liu
- Department of Infection Disease, the Third Hospital of Kumming City, Kumming, China
| | - Ka-Shing Cheung
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
| | - Yee Hui Yeo
- Department of Medicine, Stanford University Medical Center, Palo Alto, California, United States of America
| | - Joseph Hoang
- Department of Medicine, Stanford University Medical Center, Palo Alto, California, United States of America
| | - Chung-Feng Huang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, School of Medicine and Hepatitis Research Center, College of Medicine, and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mar Riveiro-Barciela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Valle d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain and CIBERehd, Instituto Carlos III, Madrid, Spain
| | - Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Doina Istratescu
- Institutul Clinic Fundeni-Gastroenterologie si Hepatologie, Bucuresti, Romania
| | - Pei-Chien Tsai
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, School of Medicine and Hepatitis Research Center, College of Medicine, and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Elena Vargas Accarino
- Liver Unit, Department of Internal Medicine, Hospital Universitari Valle d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain and CIBERehd, Instituto Carlos III, Madrid, Spain
| | - Dong-Hyun Lee
- Department of Gastroenterology, Good Gang-An Hospital, Busan, South Korea
| | - Jia-Ling Wu
- Department of Public Health, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Jee Fu Huang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, School of Medicine and Hepatitis Research Center, College of Medicine, and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, School of Medicine and Hepatitis Research Center, College of Medicine, and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ramsey Cheung
- Department of Medicine, Stanford University Medical Center, Palo Alto, California, United States of America
| | - Wan-Long Chuang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, School of Medicine and Hepatitis Research Center, College of Medicine, and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Man-Fung Yuen
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ming-Lung Yu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, School of Medicine and Hepatitis Research Center, College of Medicine, and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Department of Medicine, Stanford University Medical Center, Palo Alto, California, United States of America.,Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California, United States of America
| |
Collapse
|