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Li A, Yi Z, Ma C, Sun B, Zhao L, Cheng X, Hui L, Xia Y. Innate immune recognition in hepatitis B virus infection. Virulence 2025; 16:2492371. [PMID: 40253712 PMCID: PMC12013422 DOI: 10.1080/21505594.2025.2492371] [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: 11/28/2024] [Revised: 03/19/2025] [Accepted: 04/02/2025] [Indexed: 04/22/2025] Open
Abstract
Hepatitis B virus (HBV) remains a major global public health challenge, with approximately 254 million individuals chronically infected worldwide. The interaction between HBV and the innate immune system has garnered significant attention within the scientific community, with numerous studies exploring this relationship over the past several decades. While some research suggests that HBV infection activates the host's innate immune response, other studies indicate that HBV suppresses innate immune signaling pathways. These conflicting findings underscore the complexity of the HBV-innate immunity interaction, which remains inadequately understood. This review aims to clarify this interplay by examining it from three perspectives: (a) studies showing HBV activation of innate immunity; (b) evidence suggesting HBV suppression of innate immunity; and (c) findings that support HBV's role as a stealth virus. By synthesizing these perspectives, we aim to deepen the understanding of virus-host interactions that are crucial to HBV persistence and immune evasion, with potential implications for developing new therapeutic strategies for chronic HBV infection.
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Affiliation(s)
- Aixin Li
- School of Laboratory Medicine, Shandong Second Medical University, Weifang, China
| | - Zhengjun Yi
- School of Laboratory Medicine, Shandong Second Medical University, Weifang, China
| | - Chunqiang Ma
- School of Laboratory Medicine, Shandong Second Medical University, Weifang, China
| | - Bangyao Sun
- School of Laboratory Medicine, Shandong Second Medical University, Weifang, China
| | - Li Zhao
- School of Laboratory Medicine, Shandong Second Medical University, Weifang, China
| | - Xiaoming Cheng
- State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Medical School, Wuhan University, Wuhan, China
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Jiangxia Laboratory, Wuhan, China
- Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Lixia Hui
- School of Laboratory Medicine, Shandong Second Medical University, Weifang, China
| | - Yuchen Xia
- State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Medical School, Wuhan University, Wuhan, China
- Hubei Jiangxia Laboratory, Wuhan, China
- Pingyuan Laboratory, Henan, China
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Feng Y, Geng Y, Liu Z, Lu L, Cai C, Ding C, Dong S, Gao B. QRICH1, as a key effector of endoplasmic reticulum stress, enhances HBV in promoting HMGB1 translocation and secretion in hepatocytes. Immunobiology 2025; 230:152913. [PMID: 40383084 DOI: 10.1016/j.imbio.2025.152913] [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: 01/19/2025] [Revised: 04/24/2025] [Accepted: 05/12/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND Extracellular high mobility group box 1 (HMGB1) serves as a damage-associated molecular pattern (DAMP) and leads to diverse biological effects, including the aggravation of HBV-related liver diseases. However, mechanisms underlying HMGB1 secretion in HBV-induced hepatic injury and fibrosis remain unclear. Glutamine-rich 1 (QRICH1) is known as a critical effector of endoplasmic reticulum (ER) stress and is elevated in liver diseases. Whether QRICH1 participates in HBV-induced hepatic fibrosis warrants further investigation. Here, we explore the mechanism of HMGB1 secretion during HBV-induced hepatic fibrosis and the effect of QRICH1 on the process. METHODS In vivo experiments were conducted using a chronic recombinant cccDNA (rcccDNA) mouse model. Clinical specimens were obtained from Zhongshan Hospital, Fudan University. The levels of QRICH1 and HMGB1 were determined via immunohistochemistry. Liver collagen deposition was determined by Sirius red and Masson's trichrome staining. The serum levels of HMGB1 and indicators of liver injury were detected via ELISA. HMGB1 cyto-translocation was analyzed by Western blotting and quantitative real-time PCR (qRT-PCR). RESULTS Our findings demonstrated that ER stress promoted HBV-induced hepatic fibrosis in a mouse model. QRICH1 expression and HMGB1 secretion were elevated and positively correlated in rcccDNA mice with ER stress activation and chronic hepatitis B (CHB) patients with severe fibrosis. HBV modulated Sirtuin6 (SIRT6) expression, affecting HMGB1 cyto-translocation via acetylation regulation. Furthermore, QRICH1 enhanced HBV-induced HMGB1 translocation and secretion by regulating HMGB1 transcription. CONCLUSION HBV promotes HMGB1 acetylation and cyto-translocation by modulating SIRT6 expression. QRICH1 enhances HBV-induced HMGB1 translocation and secretion by regulating HMGB1 transcription.
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Affiliation(s)
- Ying Feng
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Yucai Geng
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Zhixiang Liu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Lin Lu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Chen Cai
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Chenke Ding
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Shuyu Dong
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Bo Gao
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China..
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Martinez-Laso J, Cervera I, Martinez-Carrasco MS, Sánchez-Menéndez C, Remesal M, Casado-Fernández G, Mateos E, Lemus-Aguilar L, Torres M, Coiras M. Truncated IFI16 mRNA transcripts can control its viral DNA defense activity. Mol Immunol 2025; 183:137-144. [PMID: 40359721 DOI: 10.1016/j.molimm.2025.05.005] [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: 02/03/2025] [Revised: 04/25/2025] [Accepted: 05/08/2025] [Indexed: 05/15/2025]
Abstract
One of the most well-known viral receptors of the group called named ALRs is IFI16 (interferon-inducible protein 16) that are responsible for responses against viral dsDNA. A pyrin domain (PYD), two HIN domains, a NLS (nuclear localization sequence), and S/T/P repeats region form the structure of IFI16. Five alternatively transcripts have been described (V1, V2, V9, V4 and Vβ) that encode five isoforms (IFI16-iso1, 2, 3, 4 and β) with different structure, localization, and function. Another four transcripts (V3, V5, V6, and V8) and 12 predicted transcripts (VX1-VX7, VX1.1-VX5.1) have also been registered in the Genebank without any structural study. In the present study, we have performed a complete study of the presence of the IFI16 transcripts in a healthy population. All the alternative transcripts described except six of the so-called predicted transcripts were found, furthermore, two new transcripts (V10, V11) were described. The main mechanisms for the regulation of mRNA from IFI16 expression are due to the insertion of non-coding regions and the loss of almost all exons. A total of nine different isoforms were found and the corresponding protein models were constructed to establish the modification of its functionality to form inflammasomes or the binding to viral DNA.
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Affiliation(s)
- Jorge Martinez-Laso
- Immunogenetics Unit. National Center of Microbiology, Instituto de Salud Carlos III, Madrid 28220, Spain.
| | - Isabel Cervera
- Immunogenetics Unit. National Center of Microbiology, Instituto de Salud Carlos III, Madrid 28220, Spain
| | - Marina S Martinez-Carrasco
- Immunogenetics Unit. National Center of Microbiology, Instituto de Salud Carlos III, Madrid 28220, Spain; Pediatrics Department. Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, Madrid 28041, Spain
| | - Clara Sánchez-Menéndez
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; PhD Program in Biomedical Sciences and Public Health, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Manuel Remesal
- Department of Pharmacy and Nutrition. Faculty of Biomedical and Health Sciences. Universidad Europea de Madrid, Villaviciosa de Odón, Madrid 28670, Spain
| | - Guiomar Casado-Fernández
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; PhD Program in Health Sciences, Faculty of Sciences, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
| | - Elena Mateos
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Biomedical Research Center Network in Infectious Diseases (CIBERINFEC), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Luis Lemus-Aguilar
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; PhD Program in Biomedical Sciences and Public Health, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Montserrat Torres
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Biomedical Research Center Network in Infectious Diseases (CIBERINFEC), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Mayte Coiras
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Biomedical Research Center Network in Infectious Diseases (CIBERINFEC), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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Liu J, Zhao YX, Song YH, Zhang L, Han X, Liu L, Li M, Wang L, Wu YM, Han QZ. FTY720 alleviates HBV-mediated inflammatory liver injury through a dual role of inhibiting lymphocyte trafficking and viral replication. Int Immunopharmacol 2025; 153:114495. [PMID: 40121743 DOI: 10.1016/j.intimp.2025.114495] [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: 11/01/2024] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND The host immune response plays a critical role in clearing hepatitis B virus infection. However, in chronic hepatitis B, this response fails to eliminate the virus, leading to recurrent inflammation, liver tissue damage, and a gradual progression from hepatitis to fibrosis, and eventually, hepatocellular carcinoma. Reducing liver injury while enhancing antiviral efficacy remains a key objective in hepatitis B virus treatment development. Our previous research revealed a close association between hepatitis B virus infection and the sphingosine 1-phosphate signaling pathway. Consequently, this study aims to explore the dual role of FTY720, an immune modulator that targets sphingosine- 1-phosphate receptor, in hepatitis B virus-related liver injury. METHODS In this study, The peripheral blood leukocyte count and the expression of sphingosine 1-phosphate receptor on lymphocytes were compared between chronic hepatitis B patients and healthy controls. In vitro experiments were conducted to evaluate the direct antiviral effects of FTY720 on two hepatitis B virus models: HepG2.2.15 and Huh7 cells transfected with pUC19-HBV1.3. Additionally, the study investigated the influence of FTY720 on the chemotaxis of peripheral blood mononuclear cells induced by the supernatant of hepatitis B virus-infected HepG2-NTCP cells. An in vivo model using hepatitis B virus hyperbaric hydrodynamic injection in mice was also employed to assess the impact of FTY720 on both HBV replication and hepatic lymphocyte infiltration. RESULTS Peripheral blood lymphocyte counts were reduced, while sphingosine 1-phosphate receptor expression was elevated in chronic hepatitis B patients compared to healthy controls. Simultaneously, antiviral therapy solely utilizing nucleotide analogues could not fully restore the peripheral blood lymphocyte count in patients with chronic hepatitis B. In vitro, FTY720 effectively inhibited hepatitis B virus replication in two models: HepG2.2.15 cells containing hepatitis B virus virions and pUC19-HBV1.3-transfected Huh7 cells. Furthermore, supernatants from hepatitis B virus-infected HepG2-NTCP cells induced increased lymphocyte chemotaxis, which was suppressed by FTY720. In a hepatitis B virus mouse model, FTY720 significantly reduced viral DNA and protein levels, while also decreasing inflammatory hepatocyte necrosis, liver lymphocyte infiltration, and sphingosine 1-phosphate receptor expression on circulating lymphocytes. CONCLUSIONS These findings suggest that FTY720 can inhibit both hepatitis B virus replication and hepatitis B virus-related liver damage by modulating lymphocyte migration. Further investigation into the specific mechanisms underlying the interaction between FTY720 and hepatitis B virus is warranted.
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Affiliation(s)
- Juan Liu
- Center of Clinical Laboratory and Translational Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, PR China
| | - Yin-Xia Zhao
- Central Laboratory, Shanghai Xuhui Central Hospital/Zhongshan-Xuhui Hospital, Fudan University, Shanghai, PR China
| | - Ya-Hui Song
- Center of Clinical Laboratory and Translational Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, PR China
| | - Lu Zhang
- Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, PR China
| | - Xiu Han
- Center of Clinical Laboratory and Translational Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, PR China
| | - Le Liu
- Center of Clinical Laboratory and Translational Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, PR China
| | - Min Li
- Institute of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, PR China
| | - Lin Wang
- Center of Clinical Laboratory and Translational Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, PR China
| | - Yu-Min Wu
- Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, PR China
| | - Qing-Zhen Han
- Center of Clinical Laboratory and Translational Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, PR China.
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Ghosh A, Britto J, Chandran B, Roy A. IFI16 recruits HDAC1 and HDAC2 to deacetylate the Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA), facilitating latency. J Virol 2025; 99:e0154924. [PMID: 39927772 PMCID: PMC11915870 DOI: 10.1128/jvi.01549-24] [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: 09/03/2024] [Accepted: 01/17/2025] [Indexed: 02/11/2025] Open
Abstract
IFI16 (interferon-γ-inducible protein 16) is an innate-immune DNA sensor that detects viral dsDNA in the nucleus. It also functions as an antiviral restriction factor, playing a crucial role in regulating the latency/lytic balance of several herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV). We previously demonstrated that IFI16 achieves this by regulating the deposition of H3K9me3 marks on the KSHV genome. Here, we explored whether IFI16 impacts the KSHV latency/lytic balance through additional mechanisms. Our analysis of the IFI16 interactome revealed that IFI16 binds to the class-I HDACs, HDAC1 and HDAC2, and recruits them to the KSHV major latency protein, latency-associated nuclear antigen (LANA). Previous reports have suggested that LANA undergoes lysine acetylation through unknown mechanisms, which results in the loss of its ability to bind to the KSHV transactivator protein (RTA) promoter. However, how the LANA acetylation-deacetylation cycle is orchestrated and what effect this has on KSHV gene expression remains unknown. Here, we demonstrate that LANA, by default, undergoes post-translational acetylation, and during latency, IFI16 interacts with this acetylated LANA and recruits HDAC1/2 to it. This keeps LANA in a deacetylated form, competent in binding and repressing lytic promoters. However, during lytic reactivation, IFI16 is degraded via the proteasomal pathway, leading to the accumulation of acetylated LANA, which cannot bind to the RTA promoter. This results in the de-repression of the RTA and, subsequently, other lytic promoters, driving reactivation. These findings shed new light on the role of IFI16 in KSHV latency and suggest that KSHV utilizes the cellular IFI16-HDAC1/2 interaction to facilitate its latency. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesviruses etiologically associated with several human malignancies, including Kaposi's sarcoma, primary effusion B-cell lymphoma, and multicentric Castleman's disease. Understanding the molecular mechanisms governing the establishment and maintenance of latency in γ-herpesviruses is crucial because latency plays a pivotal role in oncogenesis and disease manifestation post-infection. Here, we have elucidated a new mechanism by which IFI16, a previously discovered antiviral restriction factor, is hijacked by KSHV to recruit class-I HDACs on latency-associated nuclear antigen (LANA), resulting in the latter's deacetylation. The acetylation status of LANA is critical for KSHV latency because it governs LANA's binding to the KSHV replication and transcription activator (RTA) promoter, an immediate-early gene crucial for lytic reactivation. Depletion of IFI16 results in the accumulation of acetylated LANA, which is incapable of maintaining latency. These newly discovered interactions between IFI16 and LANA and between IFI16 and HDAC1/2 enhance our understanding of KSHV latency regulations.
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Affiliation(s)
- Anandita Ghosh
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Jeffrey Britto
- Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Bala Chandran
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Arunava Roy
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
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Lu L, Feng Y, Geng Y, Liu Z, Wu Y, Cai C, Zhang J, Huang X, Xue T, Gao B. ATF6-mediated mild ER stress inhibits HBV transcription and replication, which is dependent on mTOR activation. Virology 2025; 604:110448. [PMID: 39956079 DOI: 10.1016/j.virol.2025.110448] [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: 11/11/2024] [Revised: 01/21/2025] [Accepted: 02/05/2025] [Indexed: 02/18/2025]
Abstract
Chronic hepatitis B (CHB) remains a serious global health problem. In our previous investigation, HBV was found to activate a mild ER stress, which facilitated the establishment of persistent HBV infection. However, the role of ER stress manipulation in HBV replication and its underlying mechanisms remain still unclear. Our data showed that mild ER stress inhibited HBV transcription and replication, while severe ER stress enhanced them. Mechanistically, in contrary to the effect on HBV replication, mild ER stress activated whereas severe ER stress inhibited mTOR signaling in HBV-infected cells. Further, mTOR signaling was revealed to be critical for mild ER stress-mediated HBV inhibition. Furthermore, ATF6 but not PERK or IRE1α was found to be involved in mild ER stress-mediated mTOR and the following HBV inhibition. Moreover, ATF6, per se, could inhibit HBV transcription and replication via activating mTOR signaling. Together, ATF6-mediated mild ER stress inhibited HBV transcription and replication through mTOR activation, which might present as an important therapeutic target for CHB patients.
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Affiliation(s)
- Lin Lu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
| | - Ying Feng
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
| | - Yucai Geng
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
| | - Zhixiang Liu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
| | - Yan Wu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
| | - Chen Cai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Shanghai, PR China
| | - Ji Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Shanghai, PR China
| | - Xingda Huang
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
| | - Tongchun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Shanghai, PR China.
| | - Bo Gao
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China.
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Ren D, Ye X, Chen R, Jia X, He X, Tao J, Jin T, Wu S, Zhang H. Activation and evasion of inflammasomes during viral and microbial infection. Cell Mol Life Sci 2025; 82:56. [PMID: 39833559 PMCID: PMC11753444 DOI: 10.1007/s00018-025-05575-2] [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: 10/03/2024] [Revised: 10/31/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025]
Abstract
The inflammasome is a cytoplasmic multiprotein complex that induces the maturation of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) or pyroptosis by activating caspases, which play critical roles in regulating inflammation, cell death, and various cellular processes. Multiple studies have shown that the inflammasome is a key regulator of the host defence response against pathogen infections. During the process of pathogenic microbe invasion into host cells, the host's innate immune system recognizes these microbes by activating inflammasomes, triggering inflammatory responses to clear the microbes and initiate immune responses. Moreover, microbial pathogens have evolved various mechanisms to inhibit or evade the activation of inflammasomes. Therefore, we review the interactions between viruses and microbes with inflammasomes during the invasion process, highlight the molecular mechanisms of inflammasome activation induced by microbial pathogen infection, and highlight the corresponding strategies that pathogens employ to evade inflammasome activity. Finally, we also discuss potential therapeutic strategies for the treatment of pathogenic microbial infections via the targeting of inflammasomes and their products.
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Affiliation(s)
- Dan Ren
- Center of Disease Immunity and Intervention, College of Medicine, Lishui University, Lishui, 323000, China
| | - Xiaoou Ye
- Center of Disease Immunity and Intervention, College of Medicine, Lishui University, Lishui, 323000, China
| | - Ruiming Chen
- Center of Disease Immunity and Intervention, College of Medicine, Lishui University, Lishui, 323000, China
| | - Xiuzhi Jia
- Center of Disease Immunity and Intervention, College of Medicine, Lishui University, Lishui, 323000, China
| | - Xianhong He
- Center of Disease Immunity and Intervention, College of Medicine, Lishui University, Lishui, 323000, China
| | - Jinhui Tao
- Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, People's Republic of China
| | - Tengchuan Jin
- Center of Disease Immunity and Intervention, College of Medicine, Lishui University, Lishui, 323000, China.
- Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, People's Republic of China.
| | - Songquan Wu
- Center of Disease Immunity and Intervention, College of Medicine, Lishui University, Lishui, 323000, China.
| | - Hongliang Zhang
- Center of Disease Immunity and Intervention, College of Medicine, Lishui University, Lishui, 323000, China.
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Li Z, Rahman N, Bi C, Mohallem R, Pattnaik A, Kazemian M, Huang F, Aryal UK, Andrisani O. RNA Helicase DDX5 in Association With IFI16 and the Polycomb Repressive Complex 2 Silences Transcription of the Hepatitis B Virus by Interferon. J Med Virol 2024; 96:e70118. [PMID: 39679735 DOI: 10.1002/jmv.70118] [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: 06/14/2024] [Revised: 10/29/2024] [Accepted: 11/26/2024] [Indexed: 12/17/2024]
Abstract
RNA helicase DDX5 is a host restriction factor for hepatitis B virus (HBV) biosynthesis. Mass spectrometry (LC-MS/MS) identified significant DDX5-interacting partners, including interferon-inducible protein 16 (IFI16) and RBBP4/7, an auxiliary subunit of polycomb repressive complex 2 (PRC2). DDX5 co-eluted with IFI16, RBBP4/7, and core PRC2 subunits in size exclusion chromatography fractions derived from native nuclear extracts. Native gel electrophoresis of DDX5 immunoprecipitants revealed a 750 kDa DDX5/IFI16/PRC2 complex, validated by nanoscale co-localization via super-resolution microscopy. Prior studies demonstrated that IFI16 suppresses HBV transcription by binding to the interferon-sensitive response element of covalently closed circular DNA (cccDNA), reducing H3 acetylation and increasing H3K27me3 levels by an unknown mechanism. Herein, we demonstrate that ectopic expression of IFI16 inhibited HBV transcription from recombinant rcccDNA, correlating with increased IFI16 binding to rcccDNA, reduced H3 acetylation, and elevated H3K27me3, determined by chromatin immunoprecipitation. Importantly, the inhibitory effect of ectopic IFI16 on HBV transcription was reversed by siRNA-mediated knockdown of DDX5 and EZH2, the methyltransferase subunit of PRC2. This reversal was associated with decreased IFI16 binding to rcccDNA, enhanced H3 acetylation, and reduced H3K27me3. Similarly, endogenous IFI16 induced by interferon-α inhibited HBV rcccDNA transcription in a DDX5- and PRC2-dependent manner. In HBV-infected HepG2-NTCP cells, the antiviral effect of interferon-α was abrogated upon knockdown of DDX5 and EZH2, underscoring the crucial role of the DDX5 complex in IFI16-mediated antiviral response. In conclusion, in response to interferon, DDX5 partners with IFI16 to bind cccDNA, directing PRC2 to epigenetically silence cccDNA chromatin, thereby regulating immune signaling and HBV transcription.
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Affiliation(s)
- Zhili Li
- Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana, USA
| | - Naimur Rahman
- Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana, USA
| | - Cheng Bi
- Department of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
| | - Rodrigo Mohallem
- Purdue Proteomics Facility, Bindley Bioscience Center, Purdue University, West Lafayette, Indiana, USA
- Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA
| | - Aryamav Pattnaik
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana, USA
- Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA
| | - Majid Kazemian
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana, USA
- Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA
- Department of Computer Science, Purdue University, West Lafayette, Indiana, USA
| | - Fang Huang
- Department of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
| | - Uma K Aryal
- Purdue Proteomics Facility, Bindley Bioscience Center, Purdue University, West Lafayette, Indiana, USA
- Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA
| | - Ourania Andrisani
- Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana, USA
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Ren C, Zhang Z, Dou Y, Sun Y, Fu Z, Wang L, Wang K, Gao C, Fan Y, Sun S, Yue X, Li C, Gao L, Liang X, Ma C, Wu Z. DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2409485. [PMID: 39498874 PMCID: PMC11672287 DOI: 10.1002/advs.202409485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/25/2024] [Indexed: 11/07/2024]
Abstract
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence, however, how the host innate immune system responds to cccDNA is still less known. Here, based on cccDNA-hepatic proteins interaction profiling, DNA sensor ATP-binding cassette subfamily F member 1 (ABCF1) is identified as a novel cccDNA-binding protein and host restriction factor for HBV replication. Mechanistically, ABCF1 recognizes cccDNA by KKx4 motif and forms phase-separated condensates by the poly-glutamine (PolyQ) region of the N-terminal intrinsically disordered low-complexity domain (LCD). Subsequently, ABCF1-cccDNA phase separation not only activates the type I/III interferon (IFN-I/III) pathway but also prevents Pol II accumulation on cccDNA to inhibit HBV transcription. In turn, to sustain viral replication, HBV reduces ABCF1 expression by HBx-mediated ubiquitination and degradation of SRY-box transcription factor 4（SOX4）, leading to defects in SOX4-mediated upregulation of ABCF1 transcription. Taken together, the study shows that ABCF1 interacts with cccDNA to form phase separation that dually drives innate immune signaling and HBV transcriptional inhibition. These findings shed new light on the understanding of host defense against cccDNA and provide a novel promising therapeutic strategy for HBV infection.
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Affiliation(s)
- Caiyue Ren
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Zhaoying Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Yutong Dou
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Yang Sun
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Zhendong Fu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Liyuan Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Kai Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Chengjiang Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Yuchen Fan
- Department of HepatologyQilu HospitalCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Shuguo Sun
- Department of Human Anatomy, Histology and EmbryologySchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei430030China
| | - Xuetian Yue
- Department of Cellular BiologySchool of Basic Medical SciencesShandong UniversityJinanShandong250012China
| | - Chunyang Li
- Key Laboratory for Experimental Teratology of the Ministry of EducationDepartment of Histology and EmbryologySchool of Basic Medical SciencesShandong UniversityJinanShandong250012China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Zhuanchang Wu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
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10
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Feng R, Li D, Yan Z, Li X, Xie J. EMCV VP2 degrades IFI16 through Caspase-dependent apoptosis to evade IFI16-STING pathway. Virol J 2024; 21:296. [PMID: 39551733 PMCID: PMC11571899 DOI: 10.1186/s12985-024-02568-8] [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: 01/09/2024] [Accepted: 11/03/2024] [Indexed: 11/19/2024] Open
Abstract
Interferon (IFN)-γ inducible protein 16 (IFI16), a key DNA sensor, triggers downstream STING-dependent type I interferon (IFN-I) production and antiviral immunity. However, how the IFI16-STING signaling pathway is regulated by EMCV infection is still not well elucidated. In this study, we investigated the interaction between IFI16 and EMCV. Results indicated EMCV infection suppressed IFI16 expression in A549 cells. This study reveals that IFI16 plays an active role in combating EMCV. Screening viral proteins in conjunction with IFI16, we found that the EMCV VP2 protein hinders the antiviral response mediated by IFI16 by causing degradation of the IFI16 protein via the caspase-dependent apoptosis pathway. Our study communicates the antiviral role of the IFI16-STING pathway during EMCV infection. Importantly, this study unveils the novel mechanism by which VP2 counteracts the innate immune signaling activated by foreign DNA.
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Affiliation(s)
- Ruofei Feng
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Biomedical Research Center, Northwest Minzu University, Lanzhou, China
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Dianyu Li
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Biomedical Research Center, Northwest Minzu University, Lanzhou, China
- College of Life Science and Engineering, Northwest Minzu University, No. 1 Xibeixincun, Lanzhou, 730030, China
| | - Zhenfang Yan
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Biomedical Research Center, Northwest Minzu University, Lanzhou, China
- College of Life Science and Engineering, Northwest Minzu University, No. 1 Xibeixincun, Lanzhou, 730030, China
| | - Xiangrong Li
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
- Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
| | - Jingying Xie
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
- College of Life Science and Engineering, Northwest Minzu University, No. 1 Xibeixincun, Lanzhou, 730030, China.
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11
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Zhang L, Song YH, Liu J, Zhao YX, Zhou RR, Xu JC, He J, Lu YL, Gan WJ, Lu XS, Li M, Zhou P, Wang L, Han QZ. Hepatitis B Virus Increases SphK1-S1P Synthesis by Promoting the Availability of the Transcription Factor USF1. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:1499-1507. [PMID: 39400236 PMCID: PMC11533153 DOI: 10.4049/jimmunol.2400088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 09/10/2024] [Indexed: 10/15/2024]
Abstract
Hepatitis B virus (HBV) is the most common chronic viral infection globally, affecting ∼360 million people and causing about 1 million deaths annually due to end-stage liver disease or hepatocellular carcinoma. Current antiviral treatments rarely achieve a functional cure for chronic hepatitis B, highlighting the need for improved monitoring and intervention strategies. This study explores the role of the sphingosine kinase 1 (SphK1)-sphingosine-1-phosphate (S1P) axis in HBV-related liver injury. We investigated the association between serum S1P concentration and HBV DNA levels in chronic hepatitis B patients, finding a significant positive correlation. Additionally, SphK1 was elevated in liver tissues of HBV-positive hepatocellular carcinoma patients, particularly in HBsAg-positive regions. HBV infection models in HepG2-sodium taurocholate cotransporting polypeptide cells confirmed that HBV enhances SphK1 expression and S1P production. Inhibition of HBV replication through antiviral agents and the CRISPR-Cas9 system reduced SphK1 and S1P levels. Further, we identified the transcription factor USF1 as a key regulator of SphK1 expression during HBV infection. USF1 binds to the SphK1 promoter, increasing its transcriptional activity, and is upregulated in response to HBV infection. In vivo studies in mice demonstrated that HBV exposure promotes the expression of USF1 and SphK1-S1P. These findings suggest that the SphK1-S1P axis, regulated by HBV-induced USF1, could serve as a potential biomarker and therapeutic target for HBV-related liver injury.
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Affiliation(s)
- Lu Zhang
- Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, People’s Republic of China
- Department of Laboratory Medicine, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ya-Hui Song
- Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, People’s Republic of China
| | - Juan Liu
- Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, People’s Republic of China
| | - Yin-Xia Zhao
- Central Laboratory, Shanghai Xuhui Central Hospital/Zhongshan–Xuhui Hospital, Fudan University, Shanghai, China
| | - Ruo-Ran Zhou
- Suzhou Medical College, Soochow University, Suzhou, Jiangsu, People’s Republic of China
| | - Jun-Chi Xu
- Fifth People’s Hospital of Suzhou, Suzhou, People’s Republic of China
| | - Jun He
- Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, First Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, People’s Republic of China
| | - You-Li Lu
- Central Laboratory, Shanghai Xuhui Central Hospital/Zhongshan–Xuhui Hospital, Fudan University, Shanghai, China
| | - Wen-Juan Gan
- Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, People’s Republic of China
| | - Xing-Sheng Lu
- Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, People’s Republic of China
| | - Min Li
- Institute of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, People’s Republic of China
| | - Peng Zhou
- Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, People’s Republic of China
| | - Lin Wang
- Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, People’s Republic of China
| | - Qing-Zhen Han
- Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, People’s Republic of China
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12
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Zeng Q, Ren Y, Wang Y, Yang J, Qin Y, Yang L, Zheng X, Huang A, Fan H. The nuclear matrix protein HNRNPU restricts hepatitis B virus transcription by promoting OAS3-based activation of host innate immunity. J Med Virol 2024; 96:e29805. [PMID: 39011773 DOI: 10.1002/jmv.29805] [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: 02/29/2024] [Revised: 05/24/2024] [Accepted: 07/04/2024] [Indexed: 07/17/2024]
Abstract
Heterogeneous nuclear protein U (HNRNPU) plays a pivotal role in innate immunity by facilitating chromatin opening to activate immune genes during host defense against viral infection. However, the mechanism by which HNRNPU is involved in Hepatitis B virus (HBV) transcription regulation through mediating antiviral immunity remains unknown. Our study revealed a significant decrease in HNRNPU levels during HBV transcription, which depends on HBx-DDB1-mediated degradation. Overexpression of HNRNPU suppressed HBV transcription, while its knockdown effectively promoted viral transcription, indicating HNRNPU as a novel host restriction factor for HBV transcription. Mechanistically, HNRNPU inhibits HBV transcription by activating innate immunity through primarily the positive regulation of the interferon-stimulating factor 2'-5'-oligoadenylate synthetase 3, which mediates an ribonuclease L-dependent mechanism to enhance innate immune responses. This study offers new insights into the host immune regulation of HBV transcription and proposes potential targets for therapeutic intervention against HBV infection.
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Affiliation(s)
- Qiqi Zeng
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yi Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yanyan Wang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Jiaxin Yang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yi Qin
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Lijuan Yang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xinrui Zheng
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ailong Huang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hui Fan
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
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13
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Liu D, Yang J, Cristea IM. Liquid-liquid phase separation in innate immunity. Trends Immunol 2024; 45:454-469. [PMID: 38762334 PMCID: PMC11247960 DOI: 10.1016/j.it.2024.04.009] [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: 03/18/2024] [Revised: 04/17/2024] [Accepted: 04/24/2024] [Indexed: 05/20/2024]
Abstract
Intrinsic and innate immune responses are essential lines of defense in the body's constant surveillance of pathogens. The discovery of liquid-liquid phase separation (LLPS) as a key regulator of this primal response to infection brings an updated perspective to our understanding of cellular defense mechanisms. Here, we review the emerging multifaceted role of LLPS in diverse aspects of mammalian innate immunity, including DNA and RNA sensing and inflammasome activity. We discuss the intricate regulation of LLPS by post-translational modifications (PTMs), and the subversive tactics used by viruses to antagonize LLPS. This Review, therefore, underscores the significance of LLPS as a regulatory node that offers rapid and plastic control over host immune signaling, representing a promising target for future therapeutic strategies.
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Affiliation(s)
- Dawei Liu
- Department of Molecular Biology, Princeton University; Princeton, NJ 08544, USA
| | - Jinhang Yang
- Department of Molecular Biology, Princeton University; Princeton, NJ 08544, USA
| | - Ileana M Cristea
- Department of Molecular Biology, Princeton University; Princeton, NJ 08544, USA.
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14
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Sinha P, Thio CL, Balagopal A. Intracellular Host Restriction of Hepatitis B Virus Replication. Viruses 2024; 16:764. [PMID: 38793645 PMCID: PMC11125714 DOI: 10.3390/v16050764] [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: 04/12/2024] [Revised: 05/06/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
The hepatitis B virus (HBV) infects hepatocytes and hijacks host cellular mechanisms for its replication. Host proteins can be frontline effectors of the cell's defense and restrict viral replication by impeding multiple steps during its intracellular lifecycle. This review summarizes many of the well-described restriction factors, their mechanisms of restriction, and counteractive measures of HBV, with a special focus on viral transcription. We discuss some of the limitations and knowledge gaps about the restriction factors, highlighting how these factors may be harnessed to facilitate therapeutic strategies against HBV.
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Affiliation(s)
| | | | - Ashwin Balagopal
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (P.S.); (C.L.T.)
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15
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Roy A, Ghosh A. Epigenetic Restriction Factors (eRFs) in Virus Infection. Viruses 2024; 16:183. [PMID: 38399958 PMCID: PMC10892949 DOI: 10.3390/v16020183] [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: 12/09/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
The ongoing arms race between viruses and their hosts is constantly evolving. One of the ways in which cells defend themselves against invading viruses is by using restriction factors (RFs), which are cell-intrinsic antiviral mechanisms that block viral replication and transcription. Recent research has identified a specific group of RFs that belong to the cellular epigenetic machinery and are able to restrict the gene expression of certain viruses. These RFs can be referred to as epigenetic restriction factors or eRFs. In this review, eRFs have been classified into two categories. The first category includes eRFs that target viral chromatin. So far, the identified eRFs in this category include the PML-NBs, the KRAB/KAP1 complex, IFI16, and the HUSH complex. The second category includes eRFs that target viral RNA or, more specifically, the viral epitranscriptome. These epitranscriptomic eRFs have been further classified into two types: those that edit RNA bases-adenosine deaminase acting on RNA (ADAR) and pseudouridine synthases (PUS), and those that covalently modify viral RNA-the N6-methyladenosine (m6A) writers, readers, and erasers. We delve into the molecular machinery of eRFs, their role in limiting various viruses, and the mechanisms by which viruses have evolved to counteract them. We also examine the crosstalk between different eRFs, including the common effectors that connect them. Finally, we explore the potential for new discoveries in the realm of epigenetic networks that restrict viral gene expression, as well as the future research directions in this area.
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Affiliation(s)
- Arunava Roy
- Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA;
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16
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Zhao Q, Liu H, Tang L, Wang F, Tolufashe G, Chang J, Guo JT. Mechanism of interferon alpha therapy for chronic hepatitis B and potential approaches to improve its therapeutic efficacy. Antiviral Res 2024; 221:105782. [PMID: 38110058 DOI: 10.1016/j.antiviral.2023.105782] [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: 09/16/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
Hepatitis B virus (HBV) chronically infects 296 million people worldwide and causes more than 820,000 deaths annually due to cirrhosis and hepatocellular carcinoma. Current standard-of-care medications for chronic hepatitis B (CHB) include nucleos(t)ide analogue (NA) viral DNA polymerase inhibitors and pegylated interferon alpha (PEG-IFN-α). NAs can efficiently suppress viral replication and improve liver pathology, but not eliminate or inactivate HBV covalently closed circular DNA (cccDNA). CCC DNA is the most stable HBV replication intermediate that exists as a minichromosome in the nucleus of infected hepatocyte to transcribe viral RNA and support viral protein translation and genome replication. Consequentially, a finite duration of NA therapy rarely achieves a sustained off-treatment suppression of viral replication and life-long NA treatment is most likely required. On the contrary, PEG-IFN-α has the benefit of finite treatment duration and achieves HBsAg seroclearance, the indication of durable immune control of HBV replication and functional cure of CHB, in approximately 5% of treated patients. However, the low antiviral efficacy and poor tolerability limit its use. Understanding how IFN-α suppresses HBV replication and regulates antiviral immune responses will help rational optimization of IFN therapy and development of novel immune modulators to improve the rate of functional cure. This review article highlights mechanistic insight on IFN control of HBV infection and recent progress in development of novel IFN regimens, small molecule IFN mimetics and combination therapy of PEG-IFN-α with new direct-acting antivirals and therapeutic vaccines to facilitate the functional cure of CHB.
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Affiliation(s)
- Qiong Zhao
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Hui Liu
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Liudi Tang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Fuxuan Wang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | | | - Jinhong Chang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, PA, United States.
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17
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Roca Suarez AA, Planel S, Grand X, Couturier C, Tran T, Porcheray F, Becker J, Reynier F, Delgado A, Cascales E, Peyrot L, Tamellini A, Saliou A, Elie C, Baum C, Vuong BQ, Testoni B, Roques P, Zoulim F, Hasan U, Chemin I. Interspecies comparison of the early transcriptomic changes associated with hepatitis B virus exposure in human and macaque immune cell populations. Front Cell Infect Microbiol 2023; 13:1248782. [PMID: 37727809 PMCID: PMC10505653 DOI: 10.3389/fcimb.2023.1248782] [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: 06/27/2023] [Accepted: 08/15/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) infection affects 300 million individuals worldwide, representing a major factor for the development of hepatic complications. Although existing antivirals are effective in suppressing replication, eradication of HBV is not achieved. Therefore, a multi-faceted approach involving antivirals and immunomodulatory agents is required. Non-human primates are widely used in pre-clinical studies due to their close evolutionary relationship to humans. Nonetheless, it is fundamental to identify the differences in immune response between humans and these models. Thus, we performed a transcriptomic characterization and interspecies comparison of the early immune responses to HBV in human and cynomolgus macaques. METHODS We characterized early transcriptomic changes in human and cynomolgus B cells, T cells, myeloid and plasmacytoid dendritic cells (pDC) exposed to HBV ex vivo for 2 hours. Differentially-expressed genes were further compared to the profiles of HBV-infected patients using publicly-available single-cell data. RESULTS HBV induced a wide variety of transcriptional changes in all cell types, with common genes between species representing only a small proportion. In particular, interferon gamma signaling was repressed in human pDCs. At the gene level, interferon gamma inducible protein 16 (IFI16) was upregulated in macaque pDCs, while downregulated in humans. Moreover, IFI16 expression in pDCs from chronic HBV-infected patients anti-paralleled serum HBsAg levels. CONCLUSION Our characterization of early transcriptomic changes induced by HBV in humans and cynomolgus macaques represents a useful resource for the identification of shared and divergent host responses, as well as potential immune targets against HBV.
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Affiliation(s)
- Armando Andres Roca Suarez
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- Hepatology Institute of Lyon, Lyon, France
| | | | - Xavier Grand
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- Hepatology Institute of Lyon, Lyon, France
| | | | - Trang Tran
- BIOASTER, Institut de Recherche Technologique, Lyon, France
| | | | - Jérémie Becker
- BIOASTER, Institut de Recherche Technologique, Lyon, France
| | | | - Ana Delgado
- BIOASTER, Institut de Recherche Technologique, Lyon, France
| | | | - Loïc Peyrot
- BIOASTER, Institut de Recherche Technologique, Lyon, France
| | | | - Adrien Saliou
- BIOASTER, Institut de Recherche Technologique, Lyon, France
| | - Céline Elie
- BIOASTER, Institut de Recherche Technologique, Lyon, France
| | - Chloé Baum
- BIOASTER, Institut de Recherche Technologique, Lyon, France
| | - Bao Quoc Vuong
- Department of Biology, The City College of New York, New York, NY, United States
- The Graduate Center, The City University of New York, New York, NY, United States
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- Hepatology Institute of Lyon, Lyon, France
| | - Pierre Roques
- CEA, Institut François Jacob, Fontenay-aux-Roses, France
- Inserm, U1184, Fontenay-aux-Roses and Université Paris-Saclay, Orsay, France
- Institut Pasteur de Guinée, Conakry, Guinea
| | - Fabien Zoulim
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- Hepatology Institute of Lyon, Lyon, France
- Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| | - Uzma Hasan
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- INSERM U1111, Centre International de Recherche en Infectiologie (CIRI), Lyon, France
| | - Isabelle Chemin
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- Hepatology Institute of Lyon, Lyon, France
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18
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Fan Z, Chen R, Yin W, Xie X, Wang S, Hao C. Effects of AIM2 and IFI16 on Infectious Diseases and Inflammation. Viral Immunol 2023; 36:438-448. [PMID: 37585649 DOI: 10.1089/vim.2023.0044] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023] Open
Abstract
Both absent in melanoma 2 (AIM2) and interferon-inducible protein 16 (IFI16) are intracellular innate immune receptors that recognize double-stranded DNA released during pathogenic infection, leading to the assembly of the inflammasome. The assembly of the inflammasome results in the secretion of bioactive interleukin (IL)-1β and IL-18 and induces cell death through an inflammatory process called pyroptosis. Although the AIM2 inflammasome is generally harmful in the context of some aseptic inflammatory illnesses, it plays a protective role in infectious diseases. During inflammatory processes, there is competition between IFI16 and AIM2. In this review, we explore the impacts of IFI16 and AIM2 in infectious disease and aseptic inflammation, respectively, and how they compete.
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Affiliation(s)
- Zhen Fan
- Department of Stomatology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, P.R. China
| | - Rui Chen
- Department of Stomatology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, P.R. China
| | - Wen Yin
- Department of Stomatology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, P.R. China
| | - Xiaomei Xie
- Department of Stomatology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, P.R. China
| | - Shan Wang
- Department of Oral Pathology, School of Stomatology, Hainan Medical University, Haikou, P.R. China
- Department of Stomatology, The Second Affiliated Hospital of Hainan Medical University, Haikou, P.R. China
| | - Chunbo Hao
- Department of Stomatology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, P.R. China
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Wu N, Zheng C, Xu J, Ma S, Jia H, Yan M, An F, Zhou Y, Qi J, Bian H. Race between virus and inflammasomes: inhibition or escape, intervention and therapy. Front Cell Infect Microbiol 2023; 13:1173505. [PMID: 37465759 PMCID: PMC10351387 DOI: 10.3389/fcimb.2023.1173505] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 05/17/2023] [Indexed: 07/20/2023] Open
Abstract
The inflammasome is a multiprotein complex that further regulates cell pyroptosis and inflammation by activating caspase-1. The assembly and activation of inflammasome are associated with a variety of diseases. Accumulative studies have shown that inflammasome is a key modulator of the host's defense response to viral infection. Indeed, it has been established that activation of inflammasome occurs during viral infection. At the same time, the host has evolved a variety of corresponding mechanisms to inhibit unnecessary inflammasome activation. Therefore, here, we review and summarize the latest research progress on the interaction between inflammosomes and viruses, highlight the assembly and activation of inflammosome in related cells after viral infection, as well as the corresponding molecular regulatory mechanisms, and elucidate the effects of this activation on virus immune escape and host innate and adaptive immune defenses. Finally, we also discuss the potential therapeutic strategies to prevent and/or ameliorate viral infection-related diseases via targeting inflammasomes and its products.
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Affiliation(s)
- Nijin Wu
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Chunzhi Zheng
- Shandong Provincial Hospital for Skin Diseases and Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jiarui Xu
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Shujun Ma
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Huimin Jia
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Meizhu Yan
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Fuxiang An
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yi Zhou
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jianni Qi
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Hongjun Bian
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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Zhao L, Yuan H, Wang Y, Geng Y, Yun H, Zheng W, Yuan Y, Lv P, Hou C, Zhang H, Sun J, Sun L, Suo Y, Wang S, Zhang N, Lu W, Yang G, Zhang X. HBV confers innate immune evasion through triggering HAT1/acetylation of H4K5/H4K12/miR-181a-5p or KPNA2/cGAS-STING/IFN-I signaling. J Med Virol 2023; 95:e28966. [PMID: 37466313 DOI: 10.1002/jmv.28966] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 06/13/2023] [Accepted: 07/06/2023] [Indexed: 07/20/2023]
Abstract
Viral immune evasion is crucial to the pathogenesis of hepatitis B virus (HBV) infection. However, the role of HBV in the modulation of innate immune evasion is poorly understood. A liver-specific histone acetyltransferase 1 (Hat1) knockout (KO) mouse model and HAT1 KO cell line were established. Immunohistochemistry staining, Western blot analysis, Southern blot analysis, Northern blot analysis, immunofluorescence assays, enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, and chromatin immunoprecipitation assays were performed in the livers of mouse models, primary human hepatocytes, HepG2-NTCP, and Huh7 and HepG2 cell lines. HBV-elevated HAT1 increased the expression of miR-181a-5p targeting cyclic GMP-AMP synthase (cGAS) messenger RNA 3' untranslated regions through modulating acetylation of H4K5 and H4K12 in vitro and in vivo, leading to the inability of cGAS-stimulator of interferon genes (STING) pathway and type I interferon (IFN-I) signaling. Additionally, HBV-elevated HAT1 promoted the expression of KPNA2 through modulating acetylation of H4K5 and H4K12 in the system, resulting in nuclear translocation of cGAS, HBx was responsible for the events by HAT1, suggesting that HBV-elevated HAT1 controls the cGAS-STING pathway and IFN-I signaling to modulate viral innate immune evasion. HBV confers innate immune evasion through triggering HAT1/acetylation of H4K5/H4K12/miR-181a-5p or KPNA2/cGAS-STING/IFN-I signaling. Our finding provides new insights into the mechanism by which HBV drives viral innate immune evasion.
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Affiliation(s)
- Lina Zhao
- Department of Gastrointestinal Cancer Biology, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
| | - Hongfeng Yuan
- Department of Gastrointestinal Cancer Biology, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
| | - Yufei Wang
- Department of Gastrointestinal Cancer Biology, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
| | - Yu Geng
- Department of Cancer Research, Institute of Molecular Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Haolin Yun
- Department of Cancer Research, Institute of Molecular Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Wei Zheng
- Department of Cancer Research, Institute of Molecular Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Ying Yuan
- Department of Cancer Research, Institute of Molecular Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Pan Lv
- Department of Gastrointestinal Cancer Biology, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
| | - Chunyu Hou
- Department of Gastrointestinal Cancer Biology, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
| | - Huihui Zhang
- Department of Gastrointestinal Cancer Biology, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
| | - Jiao Sun
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Linlin Sun
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Yuhong Suo
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Shuai Wang
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Ningning Zhang
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Wei Lu
- Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Guang Yang
- Department of Gastrointestinal Cancer Biology, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
| | - Xiaodong Zhang
- Department of Gastrointestinal Cancer Biology, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
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21
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Zheng P, Dou Y, Wang Q. Immune response and treatment targets of chronic hepatitis B virus infection: innate and adaptive immunity. Front Cell Infect Microbiol 2023; 13:1206720. [PMID: 37424786 PMCID: PMC10324618 DOI: 10.3389/fcimb.2023.1206720] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 06/06/2023] [Indexed: 07/11/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major global public health risk that threatens human life and health, although the number of vaccinated people has increased. The clinical outcome of HBV infection depends on the complex interplay between viral replication and the host immune response. Innate immunity plays an important role in the early stages of the disease but retains no long-term immune memory. However, HBV evades detection by the host innate immune system through stealth. Therefore, adaptive immunity involving T and B cells is crucial for controlling and clearing HBV infections that lead to liver inflammation and damage. The persistence of HBV leads to immune tolerance owing to immune cell dysfunction, T cell exhaustion, and an increase in suppressor cells and cytokines. Although significant progress has been made in HBV treatment in recent years, the balance between immune tolerance, immune activation, inflammation, and fibrosis in chronic hepatitis B remains unknown, making a functional cure difficult to achieve. Therefore, this review focuses on the important cells involved in the innate and adaptive immunity of chronic hepatitis B that target the host immune system and identifies treatment strategies.
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Affiliation(s)
- Peiyu Zheng
- Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan, China
- Graduate School of Shanxi Medical University, Taiyuan, China
| | - Yongqing Dou
- Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Qinying Wang
- Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan, China
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22
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Wang ZL, Zheng JR, Yang RF, Huang LX, Chen HS, Feng B. An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients: High-sensitivity Quantitative HBsAg Loss. J Clin Transl Hepatol 2023; 11:197-206. [PMID: 36406318 PMCID: PMC9647097 DOI: 10.14218/jcth.2022.00289] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/12/2022] [Accepted: 08/02/2022] [Indexed: 12/04/2022] Open
Abstract
In the era of antiviral therapy, the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus (HBV) replication to the pursuit of serological clearance of HBs surface antigen (HBsAg). Based on the life cycle of HBV, HBsAg originates from covalently closed circular DNA (cccDNA) and integrated HBV DNA, thus reflecting their transcriptional activity. Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA. HBsAg loss improves the recovery of abnormal immune function, which in turn, may further promote the clearance of residual viruses. Combined with functional cure and the great improvement of clinical outcomes, the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B (CHB). For many other risk factors besides HBV itself, patients with HBsAg loss still need regular monitoring. In this review, we summarized the evolution of CHB treatment, the origin of serum HBsAg, the pattern of HBsAg seroclearance, and the effect of HBsAg loss on immune function and disease outcomes. In addition, we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.
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Affiliation(s)
| | | | - Rui-Feng Yang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Lin-Xiang Huang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Hong-Song Chen
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Bo Feng
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
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23
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He M, Chu T, Wang Z, Feng Y, Shi R, He M, Feng S, Lu L, Cai C, Fang F, Zhang X, Liu Y, Gao B. Inhibition of macrophages inflammasome activation via autophagic degradation of HMGB1 by EGCG ameliorates HBV-induced liver injury and fibrosis. Front Immunol 2023; 14:1147379. [PMID: 37122751 PMCID: PMC10140519 DOI: 10.3389/fimmu.2023.1147379] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/29/2023] [Indexed: 05/02/2023] Open
Abstract
Background Liver fibrosis is a reversible wound-healing response that can lead to end-stage liver diseases without effective treatment, in which HBV infection is a major cause. However, the underlying mechanisms for the development of HBV-induced fibrosis remains elusive, and efficacious therapies for this disease are still lacking. In present investigation, we investigated the effect and mechanism of green tea polyphenol epigallocatechin-3-gallate (EGCG) on HBV-induced liver injury and fibrosis. Methods The effect of EGCG on liver fibrosis was examined in a recombinant cccDNA (rcccDNA) chronic HBV mouse model by immunohistochemical staining, Sirius red and Masson's trichrome staining. The functional relevance between high mobility group box 1 (HMGB1) and inflammasome activation and the role of EGCG in it were analyzed by Western blotting. The effect of EGCG on autophagic flux was determined by Western blotting and flow cytometric analysis. Results EGCG treatment efficiently was found to alleviate HBV-induced liver injury and fibrosis in a recombinant cccDNA (rcccDNA) chronic HBV mouse model, a proven suitable research platform for HBV-induced fibrosis. Mechanistically, EGCG was revealed to repress the activation of macrophage NLRP3 inflammasome, a critical trigger of HBV-induced liver fibrosis. Further study revealed that EGCG suppressed macrophage inflammasome through downregulating the level of extracellular HMGB1. Furthermore, our data demonstrated that EGCG treatment downregulated the levels of extracellular HMGB1 through activating autophagic degradation of cytoplasmic HMGB1 in hepatocytes. Accordingly, autophagy blockade was revealed to significantly reverse EGCG-mediated inhibition on extracellular HMGB1-activated macrophage inflammasome and thus suppress the therapeutic effect of EGCG on HBV-induced liver injury and fibrosis. Conclusion EGCG ameliorates HBV-induced liver injury and fibrosis via autophagic degradation of cytoplasmic HMGB1 and the subsequent suppression of macrophage inflammasome activation. These data provided a new pathogenic mechanism for HBV-induced liver fibrosis involving the extracellular HMGB1-mediated macrophage inflammasome activation, and also suggested EGCG administration as a promising therapeutic strategy for this disease.
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Affiliation(s)
- Minjing He
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Tianhao Chu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Ziteng Wang
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Ying Feng
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Runhan Shi
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Muyang He
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Siheng Feng
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Lin Lu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Chen Cai
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Fang Fang
- Department of Dermatology, Shanghai Eighth People’s Hospital, Shanghai, China
| | - Xuemin Zhang
- Department of Trauma Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
- *Correspondence: Bo Gao, ; Yi Liu, ; Xuemin Zhang,
| | - Yi Liu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
- *Correspondence: Bo Gao, ; Yi Liu, ; Xuemin Zhang,
| | - Bo Gao
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
- *Correspondence: Bo Gao, ; Yi Liu, ; Xuemin Zhang,
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24
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Yang Z, Sun B, Xiang J, Wu H, Kan S, Hao M, Chang L, Liu H, Wang D, Liu W. Role of epigenetic modification in interferon treatment of hepatitis B virus infection. Front Immunol 2022; 13:1018053. [PMID: 36325353 PMCID: PMC9618964 DOI: 10.3389/fimmu.2022.1018053] [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: 08/12/2022] [Accepted: 09/27/2022] [Indexed: 11/28/2022] Open
Abstract
Human hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic hepatitis. Chronic hepatitis B (CHB) is associated with hepatocellular carcinoma pathogenesis. Interferons (IFNs) have been used for the treatment of CHB for a long time, with advantages including less treatment duration and sustained virological response. Presently, various evidence suggests that epigenetic modification of the viral covalently closed circular DNA (cccDNA) and the host genome is crucial for the regulation of viral activity. This modification includes histone acetylation, DNA methylation, N6-methyladenosine, and non-coding RNA modification. IFN treatment for CHB can stimulate multiple IFN-stimulated genes for inhibiting virus replication. IFNs can also affect the HBV life cycle through epigenetic modulation. In this review, we summarized the different mechanisms through which IFN-α inhibits HBV replication, including epigenetic regulation. Moreover, the mechanisms underlying IFN activity are discussed, which indicated its potential as a novel treatment for CHB. It is proposed that epigenetic changes such as histone acetylation, DNA methylation, m6A methylation could be the targets of IFN, which may offer a novel approach to HBV treatment.
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Affiliation(s)
- Zhijing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Baozhen Sun
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jingcheng Xiang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Han Wu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Shaoning Kan
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Ming Hao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Lu Chang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Huimin Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
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White MC, Wu X, Damania B. Oncogenic viruses, cancer biology, and innate immunity. Curr Opin Immunol 2022; 78:102253. [PMID: 36240666 DOI: 10.1016/j.coi.2022.102253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 09/05/2022] [Indexed: 01/29/2023]
Abstract
Malignancies that arise as a result of viral infection account for roughly 15% of cancer cases worldwide. The innate immune system is the body's first line of defense against oncogenic viral infection and is also involved in the response against viral-driven tumors. In this review, we discuss research advances made over the last five years elucidating how the innate immune system recognizes and responds to oncogenic viruses, how these viruses have evolved to escape this immune pressure, and ways that innate immunity can inform the development of novel therapeutics against oncogenic viral infection and their associated cancers.
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Affiliation(s)
- Maria C White
- Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Xinjun Wu
- Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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26
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Suresh M, Menne S. Recent Drug Development in the Woodchuck Model of Chronic Hepatitis B. Viruses 2022; 14:v14081711. [PMID: 36016334 PMCID: PMC9416195 DOI: 10.3390/v14081711] [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: 06/17/2022] [Revised: 07/22/2022] [Accepted: 07/31/2022] [Indexed: 11/24/2022] Open
Abstract
Infection with hepatitis B virus (HBV) is responsible for the increasing global hepatitis burden, with an estimated 296 million people being carriers and living with the risk of developing chronic liver disease and cancer. While the current treatment options for chronic hepatitis B (CHB), including oral nucleos(t)ide analogs and systemic interferon-alpha, are deemed suboptimal, the path to finding an ultimate cure for this viral disease is rather challenging. The lack of suitable laboratory animal models that support HBV infection and associated liver disease progression is one of the major hurdles in antiviral drug development. For more than four decades, experimental infection of the Eastern woodchuck with woodchuck hepatitis virus has been applied for studying the immunopathogenesis of HBV and developing new antiviral therapeutics against CHB. There are several advantages to this animal model that are beneficial for performing both basic and translational HBV research. Previous review articles have focused on the value of this animal model in regard to HBV replication, pathogenesis, and immune response. In this article, we review studies of drug development and preclinical evaluation of direct-acting antivirals, immunomodulators, therapeutic vaccines, and inhibitors of viral entry, gene expression, and antigen release in the woodchuck model of CHB since 2014 until today and discuss their significance for clinical trials in patients.
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27
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Forkhead O Transcription Factor 4 Restricts HBV Covalently Closed Circular DNA Transcription and HBV Replication through Genetic Downregulation of Hepatocyte Nuclear Factor 4 Alpha and Epigenetic Suppression of Covalently Closed Circular DNA via Interacting with Promyelocytic Leukemia Protein. J Virol 2022; 96:e0054622. [PMID: 35695580 PMCID: PMC9278149 DOI: 10.1128/jvi.00546-22] [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] [Indexed: 11/20/2022] Open
Abstract
Nuclear located hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) remains the key obstacle to cure chronic hepatitis B (CHB). In our previous investigation, it was found that FoxO4 could inhibit HBV core promoter activity through downregulating the expression of HNF4α. However, the exact mechanisms whereby FoxO4 inhibits HBV replication, especially its effect on cccDNA, remain unclear. Here, our data further revealed that FoxO4 could effectively inhibit cccDNA mediated transcription and HBV replication without affecting cccDNA level. Mechanistic study showed that FoxO4 could cause epigenetic suppression of cccDNA. Although FoxO4-mediated downregulation of HNF4α contributed to inhibiting HBV core promoter activity, it had little effect on cccDNA epigenetic regulation. Further, it was found that FoxO4 could colocalize within promyelocytic leukemia protein (PML) nuclear bodies and interact with PML. Of note, PML was revealed to be critical for FoxO4-mediated inhibition of cccDNA epigenetic modification and of the following cccDNA transcription and HBV replication. Furthermore, FoxO4 was found to be downregulated in HBV-infected hepatocytes and human liver tissues, and it was negatively correlated with cccDNA transcriptional activity in CHB patients. Together, these findings highlight the role of FoxO4 in suppressing cccDNA transcription and HBV replication via genetic downregulation of HNF4α and epigenetic suppression of cccDNA through interacting with PML. Targeting FoxO4 may present as a new therapeutic strategy against chronic HBV infection. IMPORTANCE HBV cccDNA is a determining factor for viral persistence and the main obstacle for a cure of chronic hepatitis B. Strategies that target cccDNA directly are therefore of great importance in controlling persistent HBV infection. In present investigation, we found that FoxO4 could efficiently suppress cccDNA transcription and HBV replication without affecting the level of cccDNA itself. Further, our data revealed that FoxO4 might inhibit cccDNA function via a two-part mechanism: one is to epigenetically suppress cccDNA transcription via interacting with PML, and the other is to inhibit HBV core promoter activity via the genetic downregulation of HNF4α. Of note, HBV might dampen the expression of FoxO4 for its own persistent infection. We propose that manipulation of FoxO4 may present as a potential therapeutic strategy against chronic HBV infection.
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IFN-α inhibits HBV transcription and replication by promoting HDAC3-mediated de-2-hydroxyisobutyrylation of histone H4K8 on HBV cccDNA minichromosome in liver. Acta Pharmacol Sin 2022; 43:1484-1494. [PMID: 34497374 PMCID: PMC9160025 DOI: 10.1038/s41401-021-00765-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023]
Abstract
The epigenetic modification of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a crucial role in cccDNA transcription and viral persistence. Interferon-α (IFN-α) is a pivotal agent against HBV cccDNA. However, the mechanism by which IFN-α modulates the epigenetic regulation of cccDNA remains poorly understood. In this study, we report that IFN-α2b enhances the histone deacetylase 3 (HDAC3)-mediated de-2-hydroxyisobutyrylation of histone H4 lysine 8 (H4K8) on HBV cccDNA minichromosome to restrict the cccDNA transcription in liver. By screening acetyltransferases and deacetylases, we identified that HDAC3 was an effective restrictor of HBV transcription and replication. Moreover, we found that HDAC3 was able to mediate the de-2-hydroxyisobutyrylation of H4K8 in HBV-expressing hepatoma cells. Then, the 2-hydroxyisobutyrylation of histone H4K8 (H4K8hib) was identified on the HBV cccDNA minichromosome, promoting the HBV transcription and replication. The H4K8hib was regulated by HDAC3 depending on its deacetylase domain in the system. The low level of HDAC3 and high level of H4K8hib were observed in the liver tissues from HBV-infected human liver-chimeric mice. The levels of H4K8hib on HBV cccDNA minichromosome were significantly elevated in the liver biopsy specimens from clinical hepatitis B patients, which was consistent with the high transcriptional activity of cccDNA. Strikingly, IFN-α2b effectively facilitated the histone H4K8 de-2-hydroxyisobutyrylation mediated by HDAC3 on the HBV cccDNA minichromosome in primary human hepatocytes and hepatoma cells, leading to the inhibition of HBV transcription and replication. Our finding provides new insights into the mechanism by which IFN-α modulates the epigenetic regulation of HBV cccDNA minichromosome.
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29
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Huérfano S, Šroller V, Bruštíková K, Horníková L, Forstová J. The Interplay between Viruses and Host DNA Sensors. Viruses 2022; 14:v14040666. [PMID: 35458396 PMCID: PMC9027975 DOI: 10.3390/v14040666] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/21/2022] [Accepted: 03/21/2022] [Indexed: 12/12/2022] Open
Abstract
DNA virus infections are often lifelong and can cause serious diseases in their hosts. Their recognition by the sensors of the innate immune system represents the front line of host defence. Understanding the molecular mechanisms of innate immunity responses is an important prerequisite for the design of effective antivirotics. This review focuses on the present state of knowledge surrounding the mechanisms of viral DNA genome sensing and the main induced pathways of innate immunity responses. The studies that have been performed to date indicate that herpesviruses, adenoviruses, and polyomaviruses are sensed by various DNA sensors. In non-immune cells, STING pathways have been shown to be activated by cGAS, IFI16, DDX41, or DNA-PK. The activation of TLR9 has mainly been described in pDCs and in other immune cells. Importantly, studies on herpesviruses have unveiled novel participants (BRCA1, H2B, or DNA-PK) in the IFI16 sensing pathway. Polyomavirus studies have revealed that, in addition to viral DNA, micronuclei are released into the cytosol due to genotoxic stress. Papillomaviruses, HBV, and HIV have been shown to evade DNA sensing by sophisticated intracellular trafficking, unique cell tropism, and viral or cellular protein actions that prevent or block DNA sensing. Further research is required to fully understand the interplay between viruses and DNA sensors.
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30
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Jiang S, Wang X, Chen K, Yang P. Establishment of an inducible cell line for Hepatitis B virus genotype C2 and its pharmacological responses to interferons. Pharmacol Res 2022; 178:106142. [PMID: 35218895 DOI: 10.1016/j.phrs.2022.106142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/17/2022] [Accepted: 02/22/2022] [Indexed: 11/16/2022]
Abstract
Hepatitis B virus (HBV) genotype C is closely associated with poor prognosis, contributing greatly to heavy chronic hepatitis B (CHB)-related liver disease burden in China and worldwide. However, the mechanistic studies on genotype C of HBV remain largely limited, partially because of a long-term lack of genotype C HBV-based stable cell tools. According to a bioinformatic analysis on the sub-genotype C2 HBV that is predominantly endemic in China, we selected 17.3 strain as a representative isolate. With a Tet-off gene expression system, an inducible viral replication and virion production of genotype C2 HBV were achieved in a cell line carrying persistent rcDNA-cccDNA recycling, termed HepG2-17.3, can be useful for virological studies on genotype C2 HBV. Additionally, this cell line has been formatted into cell-based assay that permits particular pharmacological screening of drug candidates, such as interferon regimens, for evaluations of the inhibitory effects on genotype C2 HBV replication.
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Affiliation(s)
- Shaodong Jiang
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xin Wang
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Kaili Chen
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Pengyuan Yang
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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31
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Fan X, Jiao L, Jin T. Activation and Immune Regulation Mechanisms of PYHIN Family During Microbial Infection. Front Microbiol 2022; 12:809412. [PMID: 35145495 PMCID: PMC8822057 DOI: 10.3389/fmicb.2021.809412] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/09/2021] [Indexed: 11/29/2022] Open
Abstract
The innate immune system defenses against pathogen infections via patten-recognition receptors (PRRs). PRRs initiate immune responses by recognizing pathogen-associated molecular patterns (PAMPs), including peptidoglycan, lipopolysaccharide, and nucleic acids. Several nucleic acid sensors or families have been identified, such as RIG-I-like receptors (RLRs), Toll-like receptors (TLRs), cyclic GMP-AMP synthase (cGAS), and PYHIN family receptors. In recent years, the PYHIN family cytosolic DNA receptors have increased attention because of their important roles in initiating innate immune responses. The family members in humans include Absent in melanoma 2 (AIM2), IFN-γ inducible protein 16 (IFI16), interferon-inducible protein X (IFIX), and myeloid cell nuclear differentiation antigen (MNDA). The PYHIN family members are also identified in mice, including AIM2, p202, p203, p204, and p205. Herein, we summarize recent advances in understanding the activation and immune regulation mechanisms of the PYHIN family during microbial infection. Furthermore, structural characterizations of AIM2, IFI16, p202, and p204 provide more accurate insights into the signaling mechanisms of PYHIN family receptors. Overall, the molecular details will facilitate the development of reagents to defense against viral infections.
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Affiliation(s)
- Xiaojiao Fan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lianying Jiao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
- Institute of Molecular and Translational Medicine, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China
- *Correspondence: Lianying Jiao,
| | - Tengchuan Jin
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Center for Excellence in Molecular Cell Science, Shanghai, China
- Tengchuan Jin,
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32
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STING signaling activation inhibits HBV replication and attenuates the severity of liver injury and HBV-induced fibrosis. Cell Mol Immunol 2022; 19:92-107. [PMID: 34811496 PMCID: PMC8752589 DOI: 10.1038/s41423-021-00801-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/22/2021] [Indexed: 01/03/2023] Open
Abstract
The covalently closed circular DNA (cccDNA) of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases, including liver fibrosis. Stimulator of interferon genes (STING), a master regulator of DNA-mediated innate immune activation, is a potential therapeutic target for viral infection and virus-related diseases. In this study, agonist-induced STING signaling activation in macrophages was revealed to inhibit cccDNA-mediated transcription and HBV replication via epigenetic modification in hepatocytes. Notably, STING activation could efficiently attenuate the severity of liver injury and fibrosis in a chronic recombinant cccDNA (rcccDNA) mouse model, which is a proven suitable research platform for HBV-induced fibrosis. Mechanistically, STING-activated autophagic flux could suppress macrophage inflammasome activation, leading to the amelioration of liver injury and HBV-induced fibrosis. Overall, the activation of STING signaling could inhibit HBV replication through epigenetic suppression of cccDNA and alleviate HBV-induced liver fibrosis through the suppression of macrophage inflammasome activation by activating autophagic flux in a chronic HBV mouse model. This study suggests that targeting the STING signaling pathway may be an important therapeutic strategy to protect against persistent HBV replication and HBV-induced fibrosis.
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33
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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.
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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
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34
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Li D, Xie L, Qiao Z, Zhu J, Yao H, Qin Y, Yan Y, Chen Z, Ma F. IFI16 Isoforms with Cytoplasmic and Nuclear Locations Play Differential Roles in Recognizing Invaded DNA Viruses. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:2699-2709. [PMID: 34750204 DOI: 10.4049/jimmunol.2100398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 09/27/2021] [Indexed: 11/19/2022]
Abstract
IFN-γ-inducible protein 16 (IFI16) recognizes viral DNAs from both nucleus-replicating viruses and cytoplasm-replicating viruses. Isoform 2 of IFI16 (IFI16-iso2) with nuclear localization sequence (NLS) has been studied extensively as a well-known DNA sensor. However, the characteristics and functions of other IFI16 isoforms are almost unknown. Here, we find that IFI16-iso1, with exactly the same length as IFI16-iso2, lacks the NLS and locates in the cytoplasm. To distinguish the functions of IFI16-iso1 and IFI16-iso2, we have developed novel nuclear viral DNA mimics that can be recognized by the nuclear DNA sensors, including IFI16-iso2 and hnRNPA2B1. The hexanucleotide motif 5'-AGTGTT-3' DNA form of the nuclear localization sequence (DNLS) effectively drives cytoplasmic viral DNA nuclear translocation. These nuclear viral DNA mimics potently induce IFN-β and antiviral IFN-stimulated genes in human A549 cells, HEK293T cells, and mouse macrophages. The subcellular location difference of IFI16 isoforms determines their differential functions in recognizing viral DNA and activating type I IFN-dependent antiviral immunity. IFI16-iso1 preferentially colocalizes with cytoplasmic HSV60mer and cytoplasm-replicating vaccinia virus (VACV), whereas IFI16-iso2 mainly colocalizes with nuclear HSV60-DNLS and nucleus-replicating HSV-1. Compared with IFI16-iso2, IFI16-iso1 induces more transcription of IFN-β and IFN-stimulated genes, as well as stronger antiviral immunity upon HSV60mer transfection or VACV infection. IFI16-iso2, with the ability of nuclear-cytoplasmic shuttling, clears both invaded HSV type 1 and VACV significantly. However, IFI16-iso2 induces more type I IFN-dependent antiviral immunity than IFI16-iso1 upon HSV60-DNLS transfection or HSV type 1 infection. Our study has developed potent agonists for nuclear DNA sensors and also has demonstrated that IFI16 isoforms with cytoplasmic and nuclear locations play differential roles in innate immunity against DNA viruses.
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Affiliation(s)
- Dapei Li
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; .,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Lifen Xie
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Zigang Qiao
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Jingfei Zhu
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Haiping Yao
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Yanghua Qin
- Department of Laboratory Diagnosis, Changhai Hospital of the Second Military Medical University, Shanghai, China; and
| | - Yongdong Yan
- Department of Pulmonary Medicine, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Zhengrong Chen
- Department of Pulmonary Medicine, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Feng Ma
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; .,Suzhou Institute of Systems Medicine, Suzhou, China
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35
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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: 12] [Impact Index Per Article: 3.0] [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.
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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
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36
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Suresh M, Li B, Huang X, Korolowicz KE, Murreddu MG, Gudima SO, Menne S. Agonistic Activation of Cytosolic DNA Sensing Receptors in Woodchuck Hepatocyte Cultures and Liver for Inducing Antiviral Effects. Front Immunol 2021; 12:745802. [PMID: 34671360 PMCID: PMC8521114 DOI: 10.3389/fimmu.2021.745802] [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: 07/22/2021] [Accepted: 09/13/2021] [Indexed: 12/11/2022] Open
Abstract
Immune modulation for the treatment of chronic hepatitis B (CHB) has gained more traction in recent years, with an increasing number of compounds designed for targeting different host pattern recognition receptors (PRRs). These agonistic molecules activate the receptor signaling pathway and trigger an innate immune response that will eventually shape the adaptive immunity for control of chronic infection with hepatitis B virus (HBV). While definitive recognition of HBV nucleic acids by PRRs during viral infection still needs to be elucidated, several viral RNA sensing receptors, including toll-like receptors 7/8/9 and retinoic acid inducible gene-I-like receptors, are explored preclinically and clinically as possible anti-HBV targets. The antiviral potential of viral DNA sensing receptors is less investigated. In the present study, treatment of primary woodchuck hepatocytes generated from animals with CHB with HSV-60 or poly(dA:dT) agonists resulted in increased expression of interferon-gamma inducible protein 16 (IFI16) or Z-DNA-binding protein 1 (ZBP1/DAI) and absent in melanoma 2 (AIM2) receptors and their respective adaptor molecules and effector cytokines. Cytosolic DNA sensing receptor pathway activation correlated with a decline in woodchuck hepatitis virus (WHV) replication and secretion in these cells. Combination treatment with HSV-60 and poly(dA:dT) achieved a superior antiviral effect over monotreatment with either agonist that was associated with an increased expression of effector cytokines. The antiviral effect, however, could not be enhanced further by providing additional type-I interferons (IFNs) exogenously, indicating a saturated level of effector cytokines produced by these receptors following agonism. In WHV-uninfected woodchucks, a single poly(dA:dT) dose administered via liver-targeted delivery was well-tolerated and induced the intrahepatic expression of ZBP1/DAI and AIM2 receptors and their effector cytokines, IFN-β and interleukins 1β and 18. Receptor agonism also resulted in increased IFN-γ secretion of peripheral blood cells. Altogether, the effect on WHV replication and secretion following in vitro activation of IFI16, ZBP1/DAI, and AIM2 receptor pathways suggested an antiviral benefit of targeting more than one cytosolic DNA receptor. In addition, the in vivo activation of ZBP1/DAI and AIM2 receptor pathways in liver indicated the feasibility of the agonist delivery approach for future evaluation of therapeutic efficacy against HBV in woodchucks with CHB.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Xu Huang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Kyle E Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G Murreddu
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Severin O Gudima
- Department of Microbiology, Molecular Genetics & Immunology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
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37
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Moon IY, Kim JW. Methylation profile of hepatitis B virus is not influenced by interferon α in human liver cancer cells. Mol Med Rep 2021; 24:715. [PMID: 34396432 PMCID: PMC8383030 DOI: 10.3892/mmr.2021.12354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 07/12/2021] [Indexed: 12/17/2022] Open
Abstract
Interferon (IFN) α is used for the treatment of chronic hepatitis B virus (HBV) infection, but the molecular mechanisms underlying its antiviral effect have not been fully elucidated. Epigenetic modifications regulate the transcriptional activity of covalently closed circular DNA (cccDNA) in cells with chronic HBV infection. IFN‑α has been shown to modify cccDNA‑bound histones, but it is not known whether the anti‑HBV effect of IFN‑α involves methylation of cccDNA. The present study aimed to determine whether IFN‑α induced methylation of HBV cccDNA in a cell‑based model in which HepG2 cells were directly infected with wild‑type HBV virions. Methylation status of HBV cccDNA was assessed using global DNA methylation ELISA assay, methylation‑specific PCR and bisulfite sequencing. IFN‑α suppressed HBV DNA and RNA transcripts, but methylation profiles were similar between the control and IFN‑α treated groups. Chromatin immunoprecipitation results revealed binding of DNA methyltransferases (DNMT) 3A and DNMT3B to HBV cccDNA and treatment with IFN‑α suppressed the recruitment of DNMT3B to cccDNA. Taken together, these results suggest that IFN‑α does not induce methylation of HBV cccDNA. Therefore, it was concluded that methylation is unlikely to contribute to the anti‑HBV effect of IFN‑α in HepG2 cells, and that alternative mechanisms need to be sought to enhance cccDNA methylation as a novel therapy against HBV.
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Affiliation(s)
- In Young Moon
- Department of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Jin-Wook Kim
- Department of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
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38
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Ye J, Chen J. Interferon and Hepatitis B: Current and Future Perspectives. Front Immunol 2021; 12:733364. [PMID: 34557195 PMCID: PMC8452902 DOI: 10.3389/fimmu.2021.733364] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major health burden worldwide for which there is still no effective curative treatment. Interferon (IFN) consists of a group of cytokines with antiviral activity and immunoregulatory and antitumor effects, that play crucial roles in both innate and adaptive immune responses. IFN-α and its pegylated form have been used for over thirty years to treat chronic hepatitis B (CHB) with advantages of finite treatment duration and sustained virologic response, however, the efficacy is limited and side effects are common. Here, we summarize the status and unique advantages of IFN therapy against CHB, review the mechanisms of IFN-α action and factors affecting IFN response, and discuss the possible improvement of IFN-based therapy and the rationale of combinations with other antiviral agents in seeking an HBV cure.
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Affiliation(s)
- Jianyu Ye
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.,Research Unit of Cure of Chronic Hepatitis B Virus Infection, Chinese Academy of Medical Sciences, Shanghai, China
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39
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Yuan H, Zhao L, Yuan Y, Yun H, Zheng W, Geng Y, Yang G, Wang Y, Zhao M, Zhang X. HBx represses WDR77 to enhance HBV replication by DDB1-mediated WDR77 degradation in the liver. Am J Cancer Res 2021; 11:8362-8378. [PMID: 34373747 PMCID: PMC8343998 DOI: 10.7150/thno.57531] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 07/06/2021] [Indexed: 12/18/2022] Open
Abstract
Rationale: Hepatitis B x protein (HBx) is required to initiate and maintain the replication of hepatitis B virus (HBV). Protein arginine methyltransferases 5 (PRMT5) negatively regulates HBV transcription. WD repeat domain 77 protein (WDR77) greatly enhances the methyltransferase activity of PRMT5. However, the role of WDR77 in the modulation of cccDNA transcription and HBV replication is poorly understood. In this study, we investigated the mechanism by which HBx modulated HBV replication involving WDR77 in the liver. Methods: A human liver-chimeric mouse model was established. Immunohistochemistry (IHC) staining, Western blot analysis, Southern blot analysis, Northern blot analysis, immunofluorescence assays, ELISA, RT-qPCR, CoIP assays, and ChIP assays were performed in human liver-chimeric mouse model, primary human hepatocytes (PHHs), HepG2-NTCP, dHepaRG and HepG2 cell lines. Results: HBV infection and HBx expression remarkably reduced the protein levels of WDR77 in human liver-chimeric mice and HepG2-NTCP cells. WDR77 restricted cccDNA transcription and HBV replication in PHHs and HepG2-NTCP cells. Mechanically, WDR77 enhanced PRMT5-triggered symmetric dimethylation of arginine 3 on H4 (H4R3me2s) on the cccDNA minichromosome to control cccDNA transcription. HBx drove the cellular DDB1-containing E3 ubiquitin ligase to degrade WDR77 through recruiting WDR77, leading to the disability of methyltransferase activity of PRMT5. Thus, HBx promoted HBV replication by driving a positive feedback loop of HBx-DDB1/WDR77/PRMT5/H4R3me2s/cccDNA/HBV/HBx in the liver. Conclusions: HBx attenuates the WDR77-mediated HBV repression by driving DDB1-induced WDR77 degradation in the liver. Our finding provides new insights into the mechanism by which HBx enhances HBV replication in the liver.
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Suresh M, Li B, Murreddu MG, Gudima SO, Menne S. Involvement of Innate Immune Receptors in the Resolution of Acute Hepatitis B in Woodchucks. Front Immunol 2021; 12:713420. [PMID: 34367179 PMCID: PMC8340647 DOI: 10.3389/fimmu.2021.713420] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 07/05/2021] [Indexed: 12/15/2022] Open
Abstract
The antiviral property of small agonist compounds activating pattern recognition receptors (PRRs), including toll-like and RIG-I receptors, have been preclinically evaluated and are currently tested in clinical trials against chronic hepatitis B (CHB). The involvement of other PRRs in modulating hepatitis B virus infection is less known. Thus, woodchucks with resolving acute hepatitis B (AHB) after infection with woodchuck hepatitis virus (WHV) were characterized as animals with normal or delayed resolution based on their kinetics of viremia and antigenemia, and the presence and expression of various PRRs were determined in both outcomes. While PRR expression was unchanged immediately after infection, most receptors were strongly upregulated during resolution in liver but not in blood. Besides well-known PRRs, including TLR7/8/9 and RIG-I, other less-characterized receptors, such as IFI16, ZBP1/DAI, AIM2, and NLRP3, displayed comparable or even higher expression. Compared to normal resolution, a 3-4-week lag in peak receptor expression and WHV-specific B- and T-cell responses were noted during delayed resolution. This suggested that PRR upregulation in woodchuck liver occurs when the mounting WHV replication reaches a certain level, and that multiple receptors are involved in the subsequent induction of antiviral immune responses. Liver enzyme elevations occurred early during normal resolution, indicating a faster induction of cytolytic mechanisms than in delayed resolution, and correlated with an increased expression of NK-cell and CD8 markers and cytolytic effector molecules. The peak liver enzyme level, however, was lower during delayed resolution, but hepatic inflammation was more pronounced and associated with a higher expression of cytolytic markers. Further comparison of PRR expression revealed that most receptors were significantly reduced in woodchucks with established and progressing CHB, and several RNA sensors more so than DNA sensors. This correlated with a lower expression of receptor adaptor and effector molecules, suggesting that persistent, high-level WHV replication interferes with PRR activation and is associated with a diminished antiviral immunity based on the reduced expression of immune cell markers, and absent WHV-specific B- and T-cell responses. Overall, the differential expression of PRRs during resolution and persistence of WHV infection emphasizes their importance in the ultimate viral control during AHB that is impaired during CHB.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G. Murreddu
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Severin O. Gudima
- Department of Microbiology, Molecular Genetics & Immunology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
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Song Y, Li M, Wang Y, Zhang H, Wei L, Xu W. E3 ubiquitin ligase TRIM21 restricts hepatitis B virus replication by targeting HBx for proteasomal degradation. Antiviral Res 2021; 192:105107. [PMID: 34097931 DOI: 10.1016/j.antiviral.2021.105107] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 04/29/2021] [Accepted: 05/31/2021] [Indexed: 12/13/2022]
Abstract
As a cytosol ubiquitin ligase and antibody receptor, Tripartite motif-containing 21 (TRIM21) has been reported to mediate the restriction of hepatitis B virus (HBV) through an HBx-antibody-dependent intracellular neutralization (ADIN) mechanism. However, whether TRIM21 limits HBV replication by targeting viral proteins remains unclarified. In this study, we demonstrate that TRIM21 inhibits HBV gene transcription and replication in HBV plasmid transfected and HBV-infected hepatoma cells. RING and PRY-SPRY domains are involved in this activity. TRIM21 interacts with HBx protein and targets HBx for ubiquitination and proteasomal degradation, leading to impaired HBx-mediated degradation of structural maintenance of chromosomes 6 (Smc6) and suppression of HBV replication. TRIM21 fails to restrict the replication of an HBx-deficient HBV. And knock-down of Smc6 largely impairs the anti-HBV activity of TRIM21 in HepG2 cells. In a hydrodynamic injection (HDI)-based HBV mouse model, we confirm an in vivo anti-HBV and anti-HBx therapeutic effect of TRIM21 by over-expression or knocking-out strategy. Our findings reveal a novel mechanism that TRIM21 restricts HBV replication through targeting HBx-Smc5/6 pathway, which may have an implication in the future TRIM21-based therapeutic application.
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Affiliation(s)
- Yahui Song
- 199 RengAi Road, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, P.R. China
| | - Min Li
- 199 RengAi Road, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, P.R. China
| | - Yanqi Wang
- 199 RengAi Road, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, P.R. China
| | - Hongkai Zhang
- 199 RengAi Road, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, P.R. China
| | - Lin Wei
- 199 RengAi Road, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, P.R. China
| | - Wei Xu
- 199 RengAi Road, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, P.R. China.
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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.
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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
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Novotny LA, Evans JG, Su L, Guo H, Meissner EG. Review of Lambda Interferons in Hepatitis B Virus Infection: Outcomes and Therapeutic Strategies. Viruses 2021; 13:1090. [PMID: 34207487 PMCID: PMC8230240 DOI: 10.3390/v13061090] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/27/2022] Open
Abstract
Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of patients achieve seroclearance after treatment with type-I interferons, defined as sustained absence of detectable HBV DNA and surface antigen (HBsAg) antigenemia. However, type-I interferons cause significant side effects, are costly, must be administered for months, and most patients have viral rebound or non-response. Nucleos(t)ide reverse transcriptase inhibitors reduce HBV viral load and improve liver-related outcomes, but do not lower HBsAg levels or impart seroclearance. Thus, new therapeutics are urgently needed. Lambda interferons (IFNLs) have been tested as an alternative strategy to stimulate host antiviral pathways to treat HBV infection. IFNLs comprise an evolutionarily conserved innate immune pathway and have cell-type specific activity on hepatocytes, other epithelial cells found at mucosal surfaces, and some immune cells due to restricted cellular expression of the IFNL receptor. This article will review work that examined expression of IFNLs during acute and chronic HBV infection, the impact of IFNLs on HBV replication in vitro and in vivo, the association of polymorphisms in IFNL genes with clinical outcomes, and the therapeutic evaluation of IFNLs for the treatment of chronic HBV infection.
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Affiliation(s)
- Laura A. Novotny
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
| | - John Grayson Evans
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
| | - Lishan Su
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology, Microbiology, and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Haitao Guo
- Department of Microbiology and Molecular Genetics, Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;
| | - Eric G. Meissner
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
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Goh ZY, Ren EC, Ko HL. Intracellular interferon signalling pathways as potential regulators of covalently closed circular DNA in the treatment of chronic hepatitis B. World J Gastroenterol 2021; 27:1369-1391. [PMID: 33911462 PMCID: PMC8047536 DOI: 10.3748/wjg.v27.i14.1369] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/23/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Infection with the hepatitis B virus (HBV) is still a major global health threat as 250 million people worldwide continue to be chronically infected with the virus. While patients may be treated with nucleoside/nucleotide analogues, this only suppresses HBV titre to sub-detection levels without eliminating the persistent HBV covalently closed circular DNA (cccDNA) genome. As a result, HBV infection cannot be cured, and the virus reactivates when conditions are favorable. Interferons (IFNs) are cytokines known to induce powerful antiviral mechanisms that clear viruses from infected cells. They have been shown to induce cccDNA clearance, but their use in the treatment of HBV infection is limited as HBV-targeting immune cells are exhausted and HBV has evolved multiple mechanisms to evade and suppress IFN signalling. Thus, to fully utilize IFN-mediated intracellular mechanisms to effectively eliminate HBV, instead of direct IFN administration, novel strategies to sustain IFN-mediated anti-cccDNA and antiviral mechanisms need to be developed. This review will consolidate what is known about how IFNs act to achieve its intracellular antiviral effects and highlight the critical interferon-stimulated gene targets and effector mechanisms with potent anti-cccDNA functions. These include cccDNA degradation by APOBECs and cccDNA silencing and transcription repression by epigenetic modifications. In addition, the mechanisms that HBV employs to disrupt IFN signalling will be discussed. Drugs that have been developed or are in the pipeline for components of the IFN signalling pathway and HBV targets that detract IFN signalling mechanisms will also be identified and discussed for utility in the treatment of HBV infections. Together, these will provide useful insights into design strategies that specifically target cccDNA for the eradication of HBV.
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Affiliation(s)
- Zhi Yi Goh
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore 119077, Singapore
| | - Ee Chee Ren
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore
| | - Hui Ling Ko
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
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Wang G, Guan J, Khan NU, Li G, Shao J, Zhou Q, Xu L, Huang C, Deng J, Zhu H, Chen Z. Potential capacity of interferon-α to eliminate covalently closed circular DNA (cccDNA) in hepatocytes infected with hepatitis B virus. Gut Pathog 2021; 13:22. [PMID: 33845868 PMCID: PMC8040234 DOI: 10.1186/s13099-021-00421-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/01/2021] [Indexed: 12/14/2022] Open
Abstract
Interferon-alpha (IFN-α) and nucleot(s)ide analogs (NAs) are first-line drugs for the treatment of chronic hepatitis B virus (HBV) infections. Generally, NAs target the reverse transcription of HBV pregenomic RNA, but they cannot eliminate covalently-closed-circular DNA (cccDNA). Although effective treatment with NAs can dramatically decrease HBV proteins and DNA loads, and even promote serological conversion, cccDNA persists in the nucleus of hepatocytes due to the lack of effective anti-cccDNA drugs. Of the medications currently available, only IFN-α can potentially target cccDNA. However, the clinical effects of eradicating cccDNA using IFN-α in the hepatocytes of patients with HBV are not proficient as well as expected and are not well understood. Herein, we review the anti-HBV mechanisms of IFN-α involving cccDNA modification as the most promising approaches to cure HBV infection. We expect to find indications of promising areas of research that require further study to eliminate cccDNA of HBV in patients.
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Affiliation(s)
- Gang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Nazif U Khan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Guojun Li
- Institute for Hepatology, Shenzhen Third People's Hospital, National Clinical Research Center for Infectious Disease, Shenzhen, 518112, Guangdong, China.,The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, 518112, Shenzhen, China
| | - Junwei Shao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Qihui Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Lichen Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Chunhong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jingwen Deng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
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Xu F, Zeng Z, Yan B, Fu Y, Sun Y, Yang G, Tu L, Watanabe S, Jabbour SK, Bravaccini S, Fanini F, Zhou J, Shen Y. Safety and efficacy of anti-PD-1 inhibitors in Chinese patients with advanced lung cancer and hepatitis B virus infection: a retrospective single-center study. Transl Lung Cancer Res 2021; 10:1819-1828. [PMID: 34012795 PMCID: PMC8107742 DOI: 10.21037/tlcr-21-79] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 04/22/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Programmed death protein (ligand) 1 [PD-(L)1] inhibitors have provided new therapeutic options for advanced lung cancer. However, patients with hepatitis B virus (HBV) infection have been traditionally excluded from most registered trials of this form of treatment. METHODS We performed a retrospective analysis of patients with HBV and advanced lung cancer who received anti-PD-1 immunotherapy from September 2018 to May 2020 in our department. Treatment-related hepatotoxicity was evaluated and recorded. Overall response rate and progression free survival were also assessed in the patients using iRECIST. RESULTS Seventeen patients were evaluated in this analysis. Of these, six (35.3%) experienced hepatic transaminase elevation during immunotherapy. Three of these patients developed Grade 3 hepatic immune-related adverse events and received systemic corticosteroids, following which aminotransferase levels recovered to normal in all patients and no adverse events were observed in subsequent treatment. No patient experienced HBV reactivation or flare. One patient developed active pulmonary tuberculosis (TB). Other adverse events were mild, well tolerated and short term. The objective response rate (ORR) of the cohort was 62.5%, and the median progression-free survival (PFS) was 3 months. CONCLUSIONS Lung cancer patients can be treated safely with anti-PD-1 inhibitors in the context of HBV infection. Close monitoring for hepatotoxicity and prophylactic antiviral therapy is advised. Further studies on the use of anti-PD-1 inhibitors in HBV-infected patients are needed.
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Affiliation(s)
- Fei Xu
- Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhu Zeng
- Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China
| | - Bing Yan
- Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China
| | - Yiqi Fu
- Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China
| | - Yilan Sun
- Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China
| | - Guangdie Yang
- Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China
| | - Lingfang Tu
- Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China
| | - Satoshi Watanabe
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Salma K. Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Sara Bravaccini
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Francesca Fanini
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Jianying Zhou
- Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China
| | - Yihong Shen
- Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China
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Roca Suarez AA, Testoni B, Baumert TF, Lupberger J. Nucleic Acid-Induced Signaling in Chronic Viral Liver Disease. Front Immunol 2021; 11:624034. [PMID: 33613561 PMCID: PMC7892431 DOI: 10.3389/fimmu.2020.624034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
A hallmark for the development and progression of chronic liver diseases is the persistent dysregulation of signaling pathways related to inflammatory responses, which eventually promotes the development of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The two major etiological agents associated with these complications in immunocompetent patients are hepatitis B virus (HBV) and hepatitis C virus (HCV), accounting for almost 1.4 million liver disease-associated deaths worldwide. Although both differ significantly from the point of their genomes and viral life cycles, they exert not only individual but also common strategies to divert innate antiviral defenses. Multiple virus-modulated pathways implicated in stress and inflammation illustrate how chronic viral hepatitis persistently tweaks host signaling processes with important consequences for liver pathogenesis. The following review aims to summarize the molecular events implicated in the sensing of viral nucleic acids, the mechanisms employed by HBV and HCV to counter these measures and how the dysregulation of these cellular pathways drives the development of chronic liver disease and the progression toward HCC.
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MESH Headings
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- DNA, Viral/immunology
- Hepacivirus/immunology
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/mortality
- Hepatitis B, Chronic/pathology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/mortality
- Hepatitis C, Chronic/pathology
- Humans
- Liver Neoplasms/immunology
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- RNA, Viral/immunology
- Signal Transduction/immunology
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Affiliation(s)
- Armando Andres Roca Suarez
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Thomas F. Baumert
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
- Institut Universitaire de France (IUF), Paris, France
| | - Joachim Lupberger
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
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Zhang F, Yuan Y, Ma F. Function and Regulation of Nuclear DNA Sensors During Viral Infection and Tumorigenesis. Front Immunol 2021; 11:624556. [PMID: 33505405 PMCID: PMC7829187 DOI: 10.3389/fimmu.2020.624556] [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: 10/31/2020] [Accepted: 11/25/2020] [Indexed: 12/13/2022] Open
Abstract
IFI16, hnRNPA2B1, and nuclear cGAS are nuclear-located DNA sensors that play important roles in initiating host antiviral immunity and modulating tumorigenesis. IFI16 triggers innate antiviral immunity, inflammasome, and suppresses tumorigenesis by recognizing double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), damaged nuclear DNA, or cooperatively interacting with multiple tumor suppressors such as p53 and BRCA1. hnRNPA2B1 initiates interferon (IFN)-α/β production and enhances STING-dependent cytosolic antiviral signaling by directly binding viral dsDNA from invaded viruses and facilitating N6 -methyladenosine (m6A) modification of cGAS, IFI16, and STING mRNAs. Nuclear cGAS is recruited to double-stranded breaks (DSBs), suppresses DNA repair, and promotes tumorigenesis. This review briefly describes the nuclear functions of IFI16, hnRNPA2B1, and cGAS, and summarizes the transcriptional, post-transcriptional, and post-translational regulation of these nuclear DNA sensors.
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Affiliation(s)
- Fan Zhang
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Yi Yuan
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China.,Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine of Tongji University, Shanghai, China
| | - Feng Ma
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
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Emerging Role of PYHIN Proteins as Antiviral Restriction Factors. Viruses 2020; 12:v12121464. [PMID: 33353088 PMCID: PMC7767131 DOI: 10.3390/v12121464] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/11/2022] Open
Abstract
Innate immune sensors and restriction factors are cellular proteins that synergize to build an effective first line of defense against viral infections. Innate sensors are usually constitutively expressed and capable of detecting pathogen-associated molecular patterns (PAMPs) via specific pattern recognition receptors (PRRs) to stimulate the immune response. Restriction factors are frequently upregulated by interferons (IFNs) and may inhibit viral pathogens at essentially any stage of their replication cycle. Members of the Pyrin and hematopoietic interferon-inducible nuclear (HIN) domain (PYHIN) family have initially been recognized as important sensors of foreign nucleic acids and activators of the inflammasome and the IFN response. Accumulating evidence shows, however, that at least three of the four members of the human PYHIN family restrict viral pathogens independently of viral sensing and innate immune activation. In this review, we provide an overview on the role of human PYHIN proteins in the innate antiviral immune defense and on viral countermeasures.
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Chen H, He G, Chen Y, Zhang X. Hepatitis B Virus Might Be Sensed by STING-Dependent DNA Sensors and Attenuates the Response of STING-Dependent DNA Sensing Pathway in Humans with Acute and Chronic Hepatitis B Virus Infection. Viral Immunol 2020; 33:642-651. [PMID: 33170089 DOI: 10.1089/vim.2020.0096] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
DNA-dependent activator of interferon regulatory factors (DAIs), interferon gamma inducible protein 16 (IFI16), DEAD-box polypeptide 41 (DDX41), DNA-dependent protein kinase (DNA-PK), meiotic recombination 11 homolog A (MRE11), and cyclic GMP-AMP synthase (cGAS) have been identified as intracellular STING-dependent DNA sensors in recent years. Studies have shown that the DNA sensor-STING-interferon (IFN)-β pathway plays an important role in the defense against intracellular invasion of many DNA viruses. However, the intracellular recognition of hepatitis B virus (HBV) DNA by DNA sensors is still largely unclear. In this study, we aimed to determine whether the DNA sensor-STING pathway in peripheral blood mononuclear cells (PBMCs) can be activated by acute and chronic HBV infections in humans. We first evaluated the expression of these DNA sensors in PBMCs of acute and chronic HBV-infected patients by quantitative real-time polymerase chain reaction. We next compared the expression of the upregulated DNA sensor between monocytes and nonmonocytes to find its cellular source. Finally, by in vitro stimulation, we analyzed the IFN-β response of the DNA sensor-STING pathway in PBMCs and monocytes from chronic HBV-infected patients. The results showed that IFI16, DDX41, MRE11, and the adaptor STING were upregulated in chronic HBV-infected patients, whereas only IFI16 was upregulated in acute HBV-infected patients. However, IFN-β expression was not changed in PBMCs from acute and chronic HBV-infected patients. We next found IFI16 was mainly expressed in monocytes of acute and chronic hepatitis B patients. Finally, by stimulation of monocytes with VACV ds 70mer, a ligand for IFI16, we confirmed the attenuated response of the IFI16-STING pathway. Taken together, our results suggest that HBV might be sensed by DNA sensors in PBMCs of acute and chronic HBV-infected patients, and meanwhile HBV infection attenuates the response of the DNA sensor-STING pathway in PBMCs and monocytes, which may facilitate the persistence of HBV infection.
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Affiliation(s)
- Hongtao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Infectious Diseases, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China.,Key Laboratory of Pathogenic Microorganisms of Shenzhen, Shenzhen Institute of Respiratory Diseases, Shenzhen, China
| | - Guirong He
- Department of Clinical Laboratory, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China
| | - Yue Chen
- Department of Clinical Laboratory, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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