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Wibowo DP, Chalid MT, Rasyak MR, El Khobar KE, Turyadi, Sjahril R, Wahyuni R, Setiady Y, Muljono DH. Characteristics of hepatitis B virus surface protein and occult hepatitis B infection in infants with immunoprophylaxis failure from Indonesia. Vaccine 2025; 56:127130. [PMID: 40305978 DOI: 10.1016/j.vaccine.2025.127130] [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: 07/15/2024] [Revised: 03/21/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025]
Abstract
Perinatal hepatitis B virus (HBV) infection carries a significant risk of chronicity and complications while making infected people reservoirs for further transmission. Hepatitis B immunization in infants, with or without hepatitis B immune globulin (HBIG), has proven effective in preventing mother-to-child transmission. Nevertheless, some newborns of mothers with high viremia testing positive for hepatitis B e antigen (HBeAg) may not benefit from HBV immunoprophylaxis. Nineteen (10.2 %) of 186 infants born to HBV-infected mothers were HBV DNA-positive. HBV genotypes, serotypes, and hepatitis B surface antigen (HBsAg) sequences were comparable in most mother-cord blood-infant sample pairings, indicating that the infants' HBV strains originated from their mothers. Three (15.3 %) infants had overt HBV infection, whereas 16 (84.2 %) had occult HBV infection (OBI). The HBV isolates from infants exhibited 26 mutations: 38.5 % in the 'a' determinant and 61.5 % in the rest of HBsAg. Mutations were identified in B-cell and T-cell epitopes, impairing humoral and cellular responses to detect or neutralize the virus. This rendered immunoprophylaxis and diagnostics ineffective while inducing tolerance to the infection. HBV strains with these mutations can persist and cause complications, but they can be transmitted undetected by HBsAg tests commonly used in community healthcare. This study reveals the risk of HBV transmission from HBsAg mutant-infected mothers to newborns despite having received the birth dose with HBIG and complete hepatitis B vaccination.
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Affiliation(s)
- Dhita Prabasari Wibowo
- Post Graduate School, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia; Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency, Bogor, West Java, Indonesia
| | - Maisuri T Chalid
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Muhammad Rezki Rasyak
- Post Graduate School, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia; Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency, Bogor, West Java, Indonesia
| | - Korri E El Khobar
- Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency, Bogor, West Java, Indonesia
| | - Turyadi
- Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency, Bogor, West Java, Indonesia
| | - Rizalinda Sjahril
- Department of Microbiology, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Ridha Wahyuni
- Department of Microbiology, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | | | - David H Muljono
- Department of Internal Medicine, Faculty of Medicine, Universitas Hasanuddin, Makassar, South Sulawesi, Indonesia; Indonesian Academy of Sciences (AIPI), Jakarta, Indonesia; Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.
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2
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He J, Cui H, Jiang G, Fang L, Hao J. Knowledge mapping of trained immunity/innate immune memory: Insights from two decades of studies. Hum Vaccin Immunother 2024; 20:2415823. [PMID: 39434217 PMCID: PMC11497974 DOI: 10.1080/21645515.2024.2415823] [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: 07/14/2024] [Revised: 09/24/2024] [Accepted: 10/09/2024] [Indexed: 10/23/2024] Open
Abstract
This study employs knowledge mapping and bibliometric techniques to analyze the research landscape of trained immunity over the past 20 years and to identify current research hotspots and future development directions. The literature related to trained immunity was searched from the Web of Science Core Collection database, spanning 2004 to 2023. VOSViewer, CiteSpace and Bibliometrix were used for the knowledge mapping analysis. The foremost research institutions are Radboud University Nijmegen, University of Bonn, and Harvard University. Professor Netea MG of Radboud University Nijmegen has published the greatest number of articles. The current research focus encompasses immune memory, nonspecific effects, epigenetics, metabolic reprogramming, BCG vaccine, and the development of trained immunity-based vaccines. It is likely that research on trained immunity-based vaccines will become a major focus in the development of new vaccines in the future. It would be advantageous to observe a greater number of prospective clinical studies with robust evidence.
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Affiliation(s)
- Jiacheng He
- College of Environment and Chemistry Engineering, Yanshan University, Qinhuangdao, Hebei, P.R China
- The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, P.R. China
| | - Hongxia Cui
- College of Environment and Chemistry Engineering, Yanshan University, Qinhuangdao, Hebei, P.R China
| | - Guoqian Jiang
- College of Electrical Engineering, Yanshan University, Qinhuangdao, Hebei, P.R China
| | - Lijun Fang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, China
| | - Jianlei Hao
- The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, P.R. China
- Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, P.R. China
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3
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Hoffmann C, Krasemann S, Wurr S, Hartmann K, Adam E, Bockholt S, Müller J, Günther S, Oestereich L. Lassa virus persistence with high viral titers following experimental infection in its natural reservoir host, Mastomys natalensis. Nat Commun 2024; 15:9319. [PMID: 39472431 PMCID: PMC11522386 DOI: 10.1038/s41467-024-53616-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 10/16/2024] [Indexed: 11/02/2024] Open
Abstract
Lassa virus (LASV) outbreaks in West Africa pose a significant public health threat. We investigated the infection phenotype and transmission (horizontal and vertical) of LASV strain Ba366 in its natural host, Mastomys natalensis. Here we analyze viral RNA levels in body fluids, virus titers in organs and antibody presence in blood. In adults and 2-week-old animals, LASV causes transient infections with subsequent seroconversion. However, mice younger than two weeks exhibit persistent infections lasting up to 16 months despite antibody presence. LASV can be detected in various body fluids, organs, and cell types, primarily in lung, kidney, and gonadal epithelial cells. Despite the systemic virus presence, no pathological alterations in organs are observed. Infected animals efficiently transmit the virus throughout their lives. Our findings underscore the crucial role of persistently infected individuals, particularly infected females and their progeny, in LASV dissemination within the host population.
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Affiliation(s)
- Chris Hoffmann
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Susanne Krasemann
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stephanie Wurr
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Kristin Hartmann
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Elisa Adam
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- German Center for Infectious Diseases (DZIF), Partner Site Hamburg, Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Sabrina Bockholt
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- German Center for Infectious Diseases (DZIF), Partner Site Hamburg, Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Jonas Müller
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Stephan Günther
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- German Center for Infectious Diseases (DZIF), Partner Site Hamburg, Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Lisa Oestereich
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
- German Center for Infectious Diseases (DZIF), Partner Site Hamburg, Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.
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4
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Borghesi A. Life-threatening infections in human newborns: Reconciling age-specific vulnerability and interindividual variability. Cell Immunol 2024; 397-398:104807. [PMID: 38232634 DOI: 10.1016/j.cellimm.2024.104807] [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: 10/29/2023] [Revised: 01/05/2024] [Accepted: 01/10/2024] [Indexed: 01/19/2024]
Abstract
In humans, the interindividual variability of clinical outcome following exposure to a microorganism is immense, ranging from silent infection to life-threatening disease. Age-specific immune responses partially account for the high incidence of infection during the first 28 days of life and the related high mortality at population level. However, the occurrence of life-threatening disease in individual newborns remains unexplained. By contrast, inborn errors of immunity and their immune phenocopies are increasingly being discovered in children and adults with life-threatening viral, bacterial, mycobacterial and fungal infections. There is a need for convergence between the fields of neonatal immunology, with its in-depth population-wide characterization of newborn-specific immune responses, and clinical immunology, with its investigations of infections in patients at the cellular and molecular levels, to facilitate identification of the mechanisms of susceptibility to infection in individual newborns and the design of novel preventive and therapeutic strategies.
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Affiliation(s)
- Alessandro Borghesi
- Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia, EU, Italy; School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland.
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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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6
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Pondé RADA. Unusual serological profile in hepatitis B virus (HBV) infection associated with a probable clinical case of acute exacerbation of pre-existing chronic HBV infection. Mol Biol Rep 2023; 50:6435-6443. [PMID: 37326752 DOI: 10.1007/s11033-023-08546-7] [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: 03/28/2023] [Accepted: 05/22/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Acute or chronic HBV infection in an individual can be laboratory characterized according to the serological profile of the viral markers in the bloodstream, and the dynamics monitoring of these markers is necessary to assess the disorder course and the infection outcome. However, under certain circumstances unusual or atypical serological profiles may be observed in both acute and chronic HBV infection. They are considered as such because they do not properly characterize the form or infection clinical phase or because they seem inconsistent, considering the viral markers dynamics in both clinical contexts. This manuscript comprises the analysis of an unusual serological profile in HBV infection. METHODS AND RESULTS This clinical-laboratory study, had as reference a patient who presented clinical profile suggestive of acute HBV infection after recent exposure, whose laboratory data were initially compatible with this clinical presentation. However, the serological profile analysis and its monitoring demonstrated unusual pattern of viral markers expression, which has been observed in several clinical contexts, and is often associated a number of agent- or host-related factors. CONCLUSION The serological profile analyzed here, associated with the biochemical markers serum levels found, is indicative of active chronic infection, consequence of viral reactivation. This finding suggests that in the event of unusual serological profiles in HBV infection, if the influence of agent- or host-related factors is not properly considered and neither the viral markers dynamics properly analyzed, there may be mistake in the infection clinical diagnosis, especially when the patient's clinical and epidemiological history is unknown.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde -SES/Superintendência de Vigilância em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Brazil.
- Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil.
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Zhang L, Bi X, Chen X, Zhang L, Xiong Q, Cao W, Lin Y, Yang L, Jiang T, Deng W, Wang S, Wu S, Liu R, Gao Y, Shen G, Chang M, Hao H, Xu M, Hu L, Lu Y, Li M, Xie Y. A nomogram based on HBeAg, AST, and age to predict non-minimal liver inflammation in CHB patients with ALT <80 U/L. Front Immunol 2023; 13:1119124. [PMID: 36741383 PMCID: PMC9892180 DOI: 10.3389/fimmu.2022.1119124] [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: 12/08/2022] [Accepted: 12/28/2022] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE Precise assessment of liver inflammation in untreated hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) infection can determine when to initiate antiviral therapy. The aim of this study was to develop and validate a nomogram model for the prediction of non-minimal liver inflammation based on liver pathological injuries combined with age and alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatitis B surface antigen (HBsAg), HBeAg, and HBV DNA quantification. METHODS We retrospectively included 735 HBeAg-positive chronic hepatitis B (CHB) patients with ALT < 80 U/L as the primary cohort and prospectively enrolled 196 patients as the validation cohort. Multivariate logistic regression analysis identified independent impact factors. A nomogram to predict significant liver inflammation was developed and validated. RESULTS Multivariate logistic regression analysis showed that HBeAg, AST, and age were independent risk factors for predicting non-minimal liver inflammation in untreated CHB patients. The final formula for predicting non-minimal liver inflammation was Logit(P) = -1.99 - 0.68 × Log10HBeAg + 0.04 × Age + 0.06 × AST. A nomogram for the prediction of non-minimal liver inflammation was established based on the results from the multivariate analysis. The predicted probability of the model being consistent with the actual probability was validated by the calibration curves, showing the best agreement in both the primary and validation cohorts. The C-index was 0.767 (95%CI = 0.734-0.802) in the primary cohort and 0.749 (95%CI = 0.681-0.817) in the prospective validation cohort. CONCLUSIONS The nomogram based on HBeAg, AST, and age might help predict non-minimal liver inflammation in HBeAg-positive CHB patients with ALT < 80 U/L, which is practical and easy to use for clinicians.
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Affiliation(s)
- Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoxue Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Luxue Zhang
- Infectious Disease Department, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Qiqiu Xiong
- Department of General Surgery, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Weihua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Infectious Diseases, Miyun Teaching Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongxiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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8
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Ward JW, Wanlapakorn N, Poovorawan Y, Shouval D. Hepatitis B Vaccines. PLOTKIN'S VACCINES 2023:389-432.e21. [DOI: 10.1016/b978-0-323-79058-1.00027-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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9
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Chang KC, Chua HH, Chen YH, Tsuei DJ, Lee MH, Chiang CL, Jeng YM, Wu JF, Chen HL, Hsu HY, Ni YH, Chang MH. Hepatitis B virus X gene impacts on the innate immunity and immune-tolerant phase in chronic hepatitis B virus infection. Liver Int 2022; 42:2154-2166. [PMID: 35762289 DOI: 10.1111/liv.15348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 03/09/2022] [Accepted: 06/24/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS The immunologic features involved in the immune-tolerant phase of chronic hepatitis B (CHB) virus (HBV) infection are unclear. The hepatitis B virus X (HBx) protein disrupts IFN-β induction by downregulating MAVS and may destroy subsequent HBV-specific adaptive immunity. We aimed to analyse the impacts of genetic variability of HBx in CHB patients on the immune-tolerant phase during long-term follow-up. METHODS Children with CHB in the immune-tolerant phase were recruited and followed longitudinally. HBx gene sequencing of infecting HBV strains was performed, and the effects of HBx mutations on the immune-tolerant phase were assessed. Restoration of the host immune response to end the immune-tolerant phase was investigated by immunoblotting, immunostaining, ELISA and reporter assays of MAVS/IFN-β signalling in liver cell lines, patient liver tissues and the HBV plasmid replication system. RESULTS A total of 173 children (median age, 6.92 years) were recruited. Patients carrying HBx R87G, I127V and R87G + I127V double mutations exhibited higher cumulative incidences of immune-tolerant phase breakthrough (p = .011, p = .006 and p = .017 respectively). Cells transfected with HBx R87G and I127V mutants and pHBV1.3-B6.3 replicons containing the HBx R87G and I127V mutations exhibited statistically increased levels of IFN-β, especially under poly(I:C) stimulation or Flag-MAVS cotransfection. HA-HBx wild-type interacted with Flag-MAVS and enhanced its ubiquitination, but this ability was diminished in the R87G and I127V mutants. CONCLUSIONS HBx suppresses IFN-β induction. R87G and I127V mutation restored IFN-β production by preventing MAVS degradation, contributing to curtailing the HBV immune-tolerant phase in CHB patients.
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Affiliation(s)
- Kai-Chi Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Huey-Huey Chua
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Ya-Hui Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Daw-Jen Tsuei
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Mei-Hui Lee
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Cheng-Lun Chiang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yung-Ming Jeng
- Department of Pathology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Medical Education and Bioethics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Medical Education and Bioethics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Medical Microbiota Center, College of Medicine, National Taiwan University, Taipei, Taiwan.,Center of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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10
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Bwire G, Ario AR, Eyu P, Ocom F, Wamala JF, Kusi KA, Ndeketa L, Jambo KC, Wanyenze RK, Talisuna AO. The COVID-19 pandemic in the African continent. BMC Med 2022; 20:167. [PMID: 35501853 PMCID: PMC9059455 DOI: 10.1186/s12916-022-02367-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 04/05/2022] [Indexed: 01/13/2023] Open
Abstract
In December 2019, a new coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and associated disease, coronavirus disease 2019 (COVID-19), was identified in China. This virus spread quickly and in March, 2020, it was declared a pandemic. Scientists predicted the worst scenario to occur in Africa since it was the least developed of the continents in terms of human development index, lagged behind others in achievement of the United Nations sustainable development goals (SDGs), has inadequate resources for provision of social services, and has many fragile states. In addition, there were relatively few research reporting findings on COVID-19 in Africa. On the contrary, the more developed countries reported higher disease incidences and mortality rates. However, for Africa, the earlier predictions and modelling into COVID-19 incidence and mortality did not fit into the reality. Therefore, the main objective of this forum is to bring together infectious diseases and public health experts to give an overview of COVID-19 in Africa and share their thoughts and opinions on why Africa behaved the way it did. Furthermore, the experts highlight what needs to be done to support Africa to consolidate the status quo and overcome the negative effects of COVID-19 so as to accelerate attainment of the SDGs.
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Affiliation(s)
- Godfrey Bwire
- Department of Integrated Epidemiology Surveillance and Public Health Emergencies, Ministry of Health, P.O Box 7272, Kampala, Uganda
- School of Public Health, Makerere University, P.O. Box 7072, Kampala, Uganda
| | | | - Patricia Eyu
- Uganda National Institute of Public Health, Kampala, Uganda
| | - Felix Ocom
- Uganda National Institute of Public Health, Kampala, Uganda
| | | | - Kwadwo A. Kusi
- Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Latif Ndeketa
- Malawi-Liverpool-Wellcome Programme (MLW), Blantyre, Malawi
| | - Kondwani C. Jambo
- Malawi-Liverpool-Wellcome Programme (MLW), Blantyre, Malawi
- Liverpool School of Tropical Medicine, Liverpool, UK
| | - Rhoda K. Wanyenze
- School of Public Health, Makerere University, P.O. Box 7072, Kampala, Uganda
| | - Ambrose O. Talisuna
- Epidemic Preparedness and Response Cluster, World Health Organization, Regional Office for Africa, Brazzaville, Congo
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11
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Fang Z, Zhang Y, Zhu Z, Wang C, Hu Y, Peng X, Zhang D, Zhao J, Shi B, Shen Z, Wu M, Xu C, Chen J, Zhou X, Xie Y, Yu H, Zhang X, Li J, Hu Y, Kozlowski M, Bertoletti A, Yuan Z. Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV. J Exp Med 2022; 219:213051. [PMID: 35254403 PMCID: PMC8906470 DOI: 10.1084/jem.20211838] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/02/2021] [Accepted: 01/31/2022] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus exposure in children usually develops into chronic hepatitis B (CHB). Although hepatitis B surface antigen (HBsAg)–specific CD8+ T cells contribute to resolve HBV infection, they are preferentially undetected in CHB patients. Moreover, the mechanism for this rarely detected HBsAg-specific CD8+ T cells remains unexplored. We herein found that the frequency of HBsAg-specific CD8+ T cells was inversely correlated with expansion of monocytic myeloid-derived suppressor cells (mMDSCs) in young rather than in adult CHB patients, and CCR9 was upregulated by HBsAg on mMDSCs via activation of ERK1/2 and IL-6. Sequentially, the interaction between CCL25 and CCR9 mediated thymic homing of mMDSCs, which caused the cross-presentation, transferring of peripheral HBsAg into the thymic medulla, and then promoted death of HBsAg-specific CD8+ thymocytes. In mice, adoptive transfer of mMDSCs selectively obliterated HBsAg-specific CD8+ T cells and facilitated persistence of HBV in a CCR9-dependent manner. Taken together, our results uncovered a novel mechanism for establishing specific CD8+ tolerance to HBsAg in chronic HBV infection.
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Affiliation(s)
- Zhong Fang
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Liver Cancer Institute of Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yi Zhang
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Zhaoqin Zhu
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Cong Wang
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Yao Hu
- Department of Infectious Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Xiuhua Peng
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Dandan Zhang
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jun Zhao
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Bisheng Shi
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Zhongliang Shen
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Min Wu
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Chunhua Xu
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xiaohui Zhou
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Youhua Xie
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Hui Yu
- Department of Infectious Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Xiaonan Zhang
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jianhua Li
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Yunwen Hu
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Maya Kozlowski
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | | | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai, China
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12
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Chen CY, Hajinicolaou C, Walabh P, Ingasia LAO, Song E, Kramvis A. Molecular characterization of hepatitis B virus (HBV) isolated from a pediatric case of acute lymphoid leukemia, with a delayed response to antiviral treatment: a case report. BMC Pediatr 2022; 22:168. [PMID: 35361141 PMCID: PMC8969373 DOI: 10.1186/s12887-022-03204-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF) is effectively used as the first-line antiviral for chronic hepatitis B virus (HBV) infection in adults and children older than 12 years. To date, no confirmed case of virologic breakthrough (VBT) in a pediatric case has been reported. CASE PRESENTATION Here we describe a case of a 5-year old, asymptomatically infected with HBV infection two months after chemotherapy for precursor B acute lymphoblastic leukemia (ALL). Although the 5-year old male is South African, his family originated from Guinea. At the end of the one-year follow-up, the infection progressed to chronic HBV infection, with a high viral load. At 36 weeks (8 months) post-treatment with lamivudine (LAM), there was a partial virologic response (PVR) and after 61 weeks (14 months), he was switched to TDF rescue monotherapy. Even with TDF treatment, he still experienced VBT and subsequent PVR. The full-length genome of HBV isolated 78 weeks after the switch to rescue TDF monotherapy was sequenced and belonged to genotype E. In addition to the LAM mutations (rtS256G and rtM267L), missense mutations in B-cell, T-cell, HLA class I and II-restricted epitopes emerged, which were to evade and escape host surveillance, leading to delayed viral clearance, persistence and disease progression. Two further events of VBT occurred between weeks 113 and 141 of TDF rescue-therapy. Viral loads and liver enzymes are normalizing progressively with long-term therapy. CONCLUSION Although the host immune reconstitution may be delayed, prolonged TDF treatment was effective in treating this pediatric case of HBV infection with VBT and PVR.
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Affiliation(s)
- Chien-Yu Chen
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Christina Hajinicolaou
- Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.,Paediatric Gastroenterology, Hepatology and Nutrition Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.,Paediatric Gastroentrology, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Priya Walabh
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa
| | - Luicer Anne Olubayo Ingasia
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Ernest Song
- Department of Internal Medicine, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.
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13
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Tan Q, Chen J, Gao G, Yizhang, Chen X, Yu Y, Zang G, Tang Z. Adenovirus vector encoding TPPII ignites HBV-specific CTL response by activating autophagy in CD8+ T cell. J Viral Hepat 2022; 29:178-188. [PMID: 34902200 DOI: 10.1111/jvh.13638] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 11/01/2021] [Accepted: 11/26/2021] [Indexed: 12/19/2022]
Abstract
Early studies have shown that autophagy and TPPII are associated with HBV infection. In this study, adenovirus vector containing TPPII was constructed to immunize HBV transgenic mice in vivo to explore the potential mechanism of autophagy and HBV infection. Our goal is to provide new ideas for immunotherapy of hepatitis B. First, adenovirus vector containing TPPII was constructed. Then, we used adenovirus to immunize HBV transgenic mice and ATG5 knockout HBV transgenic mice. The autophagy of CD8+ T cells was detected by transmission electron microscopy and immunofluorescence electron microscopy, Western blot was used to detect the expression of autophagy LC3 and BECN1, CTL reaction, HBV DNA and HBsAg in serum, HBsAg and HBcAg in liver tissues by immunohistochemistry, to further examine the possible mechanisms involved in autophagy. Adv-HBcAg-TPPII promotes autophagy of CD8+ T lymphocyte, activates CTL response, inhibits HBV DNA replication and HBsAg expression, and PI3K/ Akt /m TOR signalling pathway may be involved in autophagy. This study demonstrates that autophagy of CD8+ T cells was induced by Adv-HBcAg-TPPII and the molecular mechanism may be related to the PI3K/ Akt /m TOR signalling pathway, providing a possible theoretical basis for immunotherapy of hepatitis B.
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Affiliation(s)
- Quanhui Tan
- Department of infection Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jie Chen
- Department of infection Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Gao Gao
- Department of infection Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yizhang
- Department of infection Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaohua Chen
- Department of infection Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yongsheng Yu
- Department of infection Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Guoqin Zang
- Department of infection Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhenghao Tang
- Department of infection Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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14
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Valdes AZ. Immunological tolerance and autoimmunity. TRANSLATIONAL AUTOIMMUNITY 2022:325-345. [DOI: 10.1016/b978-0-12-822564-6.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Zhang Z, Lu W, Zeng D, Huang D, Lin W, Yan L, Feng Y. Quantitative HBsAg versus HBV DNA in Predicting Significant Hepatitis Activity of HBeAg-Positive Chronic HBV Infection. J Clin Med 2021; 10:jcm10235617. [PMID: 34884319 PMCID: PMC8658350 DOI: 10.3390/jcm10235617] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/12/2021] [Accepted: 11/24/2021] [Indexed: 12/17/2022] Open
Abstract
(1) Background: As specialparameters in predicting significant hepatitis activity of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection, the quantitative standard of HBV DNA has not been agreed and that of hepatitis B surface antigen(HBsAg) has not been formed. Our objective is to evaluate the validity of HBsAg and HBV DNA in predicting the significant hepatitis activity of HBeAg-positive patients. (2) Methods: A population of 516 patients with HBeAg-positive chronic HBV infection was enrolled. Serum ALT was measured using an Abbott Architect c16000 autoanalyzer; diagnoses of liver pathological grade and stage referred to the Scheuer standard. Three levels of significant hepatitis activity were preset, which were successively “ALT ≥ 20 IU/L or Grade > G1 or Stage > S1”, “ALT ≥ 30 IU/L or Grade > G1 or Stage > S1” and “ALT ≥ 40 IU/L or Grade > G1 or Stage > S1”. (3) Results: A subpopulation of 288 patients with possible high HBV replication was selected based on locally weighted scatterplot smoothing regression curves between ALT and HBsAg, HBeAg and HBV DNA. In the subpopulation with possible high HBV replication, areas under receiver operating characteristic curves of HBsAg for predicting the three levels of significant hepatitis activity were successively 0.868, 0.839 and 0.789, which were all significantly greater than those of HBV DNA, as those were successively 0.553, 0.550 and 0.574 (p = 0.0002, p < 0.0001 and p < 0.0001). With the standard of HBsAg ≤ 4.699 log10 IU/mL, the sensitivity and specificity of HBsAg for predicting the three levels of significant hepatitis activity were successively 75.81% and 81.82%, 79.23% and 78.57% and 80.82% and 67.44%. (4) Conclusion: Quantitative HBsAg instead of HBV DNA is valuable in predicting significant hepatitis activity of HBeAg-positive chronic HBV infection.
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Affiliation(s)
- Zhanqing Zhang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center of Fudan University, Shanghai 201508, China; (W.L.); (D.H.); (W.L.); (L.Y.)
- Correspondence: ; Tel.: +86-21-37990333 (ext. 3245)
| | - Wei Lu
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center of Fudan University, Shanghai 201508, China; (W.L.); (D.H.); (W.L.); (L.Y.)
| | - Dong Zeng
- Department of Clinical Pathology, Shanghai Public Health Clinical Center of Fudan University, Shanghai 201508, China; (D.Z.); (Y.F.)
| | - Dan Huang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center of Fudan University, Shanghai 201508, China; (W.L.); (D.H.); (W.L.); (L.Y.)
| | - Weijia Lin
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center of Fudan University, Shanghai 201508, China; (W.L.); (D.H.); (W.L.); (L.Y.)
| | - Li Yan
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center of Fudan University, Shanghai 201508, China; (W.L.); (D.H.); (W.L.); (L.Y.)
| | - Yanling Feng
- Department of Clinical Pathology, Shanghai Public Health Clinical Center of Fudan University, Shanghai 201508, China; (D.Z.); (Y.F.)
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16
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Oduro-Mensah D, Oduro-Mensah E, Quashie P, Awandare G, Okine L. Explaining the unexpected COVID-19 trends and potential impact across Africa. F1000Res 2021; 10:1177. [PMID: 36605410 PMCID: PMC9763772 DOI: 10.12688/f1000research.74363.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/16/2021] [Indexed: 11/03/2023] Open
Abstract
Official COVID-19 case counts and mortality rates across Africa are lower than had been anticipated. Research reports, however, indicate far higher exposure rates than the official counts in some countries. Particularly in Western and Central Africa, where mortality rates are disproportionately lower than the rest of the continent, this occurrence may be due to immune response adaptations resulting from (1) frequent exposure to certain pro-inflammatory pathogens, and (2) a prevalence of low-grade inflammation coupled with peculiar modifications to the immune response based on one's immunobiography. We suggest that the two factors lead to a situation where post infection, there is a rapid ramp-up of innate immune responses, enough to induce effective defense and protection against plethora pathogens. Alongside current efforts at procuring and distributing vaccines, we draw attention to the need for work towards appreciating the impact of the apparently widespread, asymptomatic SARS-CoV-2 infections on Africa's populations vis a vis systemic inflammation status and long-term consequences for public health.
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Affiliation(s)
- Daniel Oduro-Mensah
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
- West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
| | | | - Peter Quashie
- West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
- Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, LG 581, Ghana
| | - Gordon Awandare
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
- West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
| | - Laud Okine
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
- West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
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17
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Oduro-Mensah D, Oduro-Mensah E, Quashie P, Awandare G, Okine L. Explaining the unexpected COVID-19 trends and potential impact across Africa. F1000Res 2021; 10:1177. [PMID: 36605410 PMCID: PMC9763772 DOI: 10.12688/f1000research.74363.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/16/2022] [Indexed: 11/23/2022] Open
Abstract
Official COVID-19 case counts and mortality rates across Africa are lower than had been anticipated. Research reports, however, indicate far higher exposure rates than the official counts in some countries. Particularly in Western and Central Africa, where mortality rates are disproportionately lower than the rest of the continent, this occurrence may be due to immune response adaptations resulting from (1) frequent exposure to certain pro-inflammatory pathogens, and (2) a prevalence of low-grade inflammation coupled with peculiar modifications to the immune response based on one's immunobiography. We suggest that the two factors lead to a situation where post infection, there is a rapid ramp-up of innate immune responses, enough to induce effective defense and protection against plethora pathogens. Alongside current efforts at procuring and distributing vaccines, we draw attention to the need for work towards appreciating the impact of the apparently widespread, asymptomatic SARS-CoV-2 infections on Africa's populations vis a vis systemic inflammation status and long-term consequences for public health.
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Affiliation(s)
- Daniel Oduro-Mensah
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
- West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
| | | | - Peter Quashie
- West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
- Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, LG 581, Ghana
| | - Gordon Awandare
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
- West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
| | - Laud Okine
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
- West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
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18
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Sirilert S, Tongsong T, Kumfu S, Chattipakorn SC, Chattipakorn N. Effects of intrauterine exposure to hepatitis B virus in foetuses. J Med Microbiol 2021; 70. [PMID: 34779762 DOI: 10.1099/jmm.0.001455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Foetal response to hepatitis B viral infection is still unknown. The mechanisms of persistent infection that occurs more often in mother-to-child transmission than adult transmission are also unclear. Various aspects of the environmental factors that accelerate or inhibit infection and the cytokine responses are associated with the persistence of infection. Several studies showed that the cytokine poor immune response in immaturity causes the persistence of the infection. However, some reports suggested that a mature immune response was the cause of this persistent infection. This review comprehensively summarized the reports from in vitro, in vivo as well as clinical reports regarding the responses of the foetuses of hepatitis B infected mothers to the micro-organism. The mechanism of more opportunities to be persistently infected via the mother-to-child transmission route is also summarized and discussed. Since there are limited clinical reports at this time, this review will provide evidence for future studies regarding the intrauterine infection mechanism and foetal response to hepatitis B virus to elucidate the mechanisms responsible for mother-to-child transmission. This understanding may lead to effective interventions to control mother-to-child hepatitis B infection in the future.
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Affiliation(s)
- Sirinart Sirilert
- Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Theera Tongsong
- Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Sirinart Kumfu
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
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19
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Ehara H. Detailed Analysis of Immune Tolerance Mechanisms to SARS-CoV-2 in Children Is Needed. Front Pediatr 2021; 9:652838. [PMID: 34796148 PMCID: PMC8594572 DOI: 10.3389/fped.2021.652838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 10/12/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Hiroshi Ehara
- Pediatrics and Primary Care, Ehara Clinic, Tokyo, Japan
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20
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Kusi KA, Frimpong A, Partey FD, Lamptey H, Amoah LE, Ofori MF. High infectious disease burden as a basis for the observed high frequency of asymptomatic SARS-CoV-2 infections in sub-Saharan Africa. AAS Open Res 2021; 4:2. [PMID: 34729457 PMCID: PMC8524298 DOI: 10.12688/aasopenres.13196.3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2021] [Indexed: 12/19/2022] Open
Abstract
Following the coronavirus outbreaks described as severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome (MERS) in 2012, the world has again been challenged by yet another corona virus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infections were first detected in a Chinese Province in December 2019 and then declared a pandemic by the World Health Organization in March 2020. An infection caused by SARS-CoV-2 may result in asymptomatic, uncomplicated or fatal coronavirus disease 2019 (COVID-19). Fatal disease has been linked with the uncontrolled "cytokine storm" manifesting with complications mostly in people with underlying cardiovascular and pulmonary disease conditions. The severity of COVID-19 disease and the associated mortality has been disproportionately lower in terms of number of cases and deaths in Africa and also Asia in comparison to Europe and North America. Also, persons of colour residing in Europe and North America have been identified as a highly susceptible population due to a combination of several socioeconomic factors and poor access to quality healthcare. Interestingly, this has not been the case in sub-Saharan Africa where majority of the population are even more deprived of the aforementioned factors. On the contrary, sub-Saharan Africa has recorded the lowest levels of mortality and morbidity associated with the disease, and an overwhelming proportion of infections are asymptomatic. Whilst it can be argued that these lower number of cases in Africa may be due to challenges associated with the diagnosis of the disease such as lack of trained personnel and infrastructure, the number of persons who get infected and develop symptoms is proportionally lower than those who are asymptomatic, including asymptomatic cases that are never diagnosed. This review discusses the most probable reasons for the significantly fewer cases of severe COVID-19 disease and deaths in sub-Saharan Africa.
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Affiliation(s)
- Kwadwo Asamoah Kusi
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Augustina Frimpong
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Frederica Dedo Partey
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Helena Lamptey
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Linda Eva Amoah
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Michael Fokuo Ofori
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
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21
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Analysis of chronic inflammatory lesions of the colon for BMMF Rep antigen expression and CD68 macrophage interactions. Proc Natl Acad Sci U S A 2021; 118:2025830118. [PMID: 33723077 PMCID: PMC8000208 DOI: 10.1073/pnas.2025830118] [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] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Bovine meat and milk factors (BMMF) are routinely found in bovine sera and dairy products, predominantly of Eurasian dairy cattle. BMMF DNA and proteins are demonstrated in tissues of colon cancer patients, specifically interstitial macrophages of peritumor tissues. BMMF represent plasmid-like, zoonotic infectious agents with an indirect role in cancer formation by inducing chronic inflammation leading to oxidative stress and DNA mutation in nearby replicating cells, which may develop into polyps as progenitors for colon cancer. Detection of BMMF during long latency periods prior to symptoms developing allows for specific preventive and early therapeutic measures. Detection of BMMF might offer a prognostic tool for prediction of patient survival, preventive approaches, and therapy success. Consumption of Eurasian bovine meat and milk has been associated with cancer development, in particular with colorectal cancer (CRC). In addition, zoonotic infectious agents from bovine products were proposed to cause colon cancer (zur Hausen et al., 2009). Bovine meat and milk factors (BMMF) are small episomal DNA molecules frequently isolated from bovine sera and milk products, and recently, also from colon cancer (de Villiers et al., 2019). BMMF are bioactive in human cells and were proposed to induce chronic inflammation in precancerous tissue leading to increased radical formation: for example, reactive oxygen and reactive nitrogen species and elevated levels of DNA mutations in replicating cells, such as cancer progenitor cells (zur Hausen et al., 2018). Mouse monoclonal antibodies against the replication (Rep) protein of H1MSB.1 (BMMF1) were used to analyze BMMF presence in different cohorts of CRC peritumor and tumor tissues and cancer-free individuals by immunohistochemistry and Western blot. BMMF DNA was isolated by laser microdissection from immunohistochemistry-positive tissue regions. We found BMMF Rep protein present specifically in close vicinity of CD68+ macrophages in the interstitial lamina propria adjacent to CRC tissues, suggesting the presence of local chronic inflammation. BMMF1 (modified H1MSB.1) DNA was isolated from the same tissue regions. Rep and CD68+ detection increased significantly in peritumor cancer tissues when compared to tissues of cancer-free individuals. This strengthens previous postulations that BMMF function as indirect carcinogens by inducing chronic inflammation and DNA damage in replicating cells, which represent progress to progenitor cells for adenoma (polyps) formation and cancer.
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22
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Clemens EA, Alexander-Miller MA. Understanding Antibody Responses in Early Life: Baby Steps towards Developing an Effective Influenza Vaccine. Viruses 2021; 13:v13071392. [PMID: 34372597 PMCID: PMC8310046 DOI: 10.3390/v13071392] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/13/2021] [Indexed: 01/01/2023] Open
Abstract
The immune system of young infants is both quantitatively and qualitatively distinct from that of adults, with diminished responsiveness leaving these individuals vulnerable to infection. Because of this, young infants suffer increased morbidity and mortality from respiratory pathogens such as influenza viruses. The impaired generation of robust and persistent antibody responses in these individuals makes overcoming this increased vulnerability through vaccination challenging. Because of this, an effective vaccine against influenza viruses in infants under 6 months is not available. Furthermore, vaccination against influenza viruses is challenging even in adults due to the high antigenic variability across viral strains, allowing immune evasion even after induction of robust immune responses. This has led to substantial interest in understanding how specific antibody responses are formed to variable and conserved components of influenza viruses, as immune responses tend to strongly favor recognition of variable epitopes. Elicitation of broadly protective antibody in young infants, therefore, requires that both the unique characteristics of young infant immunity as well as the antibody immunodominance present among epitopes be effectively addressed. Here, we review our current understanding of the antibody response in newborns and young infants and discuss recent developments in vaccination strategies that can modulate both magnitude and epitope specificity of IAV-specific antibody.
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23
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Kusi KA, Frimpong A, Partey FD, Lamptey H, Amoah LE, Ofori MF. High infectious disease burden as a basis for the observed high frequency of asymptomatic SARS-CoV-2 infections in sub-Saharan Africa. AAS Open Res 2021; 4:2. [PMID: 34729457 PMCID: PMC8524298 DOI: 10.12688/aasopenres.13196.2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2021] [Indexed: 11/03/2023] Open
Abstract
Following the coronavirus outbreaks described as severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome (MERS) in 2012, the world has again been challenged by yet another corona virus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infections were first detected in a Chinese Province in December 2019 and then declared a pandemic by the World Health Organization in March 2020. An infection caused by SARS-CoV-2 may result in asymptomatic, uncomplicated or fatal coronavirus disease 2019 (COVID-19). Fatal disease has been linked with the uncontrolled "cytokine storm" manifesting with complications mostly in people with underlying cardiovascular and pulmonary disease conditions. The severity of COVID-19 disease and the associated mortality has been disproportionately lower in terms of number of cases and deaths in Africa and also Asia in comparison to Europe and North America. Also, persons of colour residing in Europe and North America have been identified as a highly susceptible population due to a combination of several socioeconomic factors and poor access to quality healthcare. Interestingly, this has not been the case in sub-Saharan Africa where majority of the population are even more deprived of the aforementioned factors. On the contrary, sub-Saharan Africa has recorded the lowest levels of mortality and morbidity associated with the disease, and an overwhelming proportion of infections are asymptomatic. Whilst it can be argued that these lower number of cases in Africa may be due to challenges associated with the diagnosis of the disease such as lack of trained personnel and infrastructure, the number of persons who get infected and develop symptoms is proportionally lower than those who are asymptomatic, including asymptomatic cases that are never diagnosed. This review discusses the most probable reasons for the significantly fewer cases of severe COVID-19 disease and deaths in sub-Saharan Africa.
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Affiliation(s)
- Kwadwo Asamoah Kusi
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Augustina Frimpong
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Frederica Dedo Partey
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Helena Lamptey
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Linda Eva Amoah
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Michael Fokuo Ofori
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
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24
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Zhang YT, Liu J, Pan XB, Gao YD, Hu YF, Lin L, Cheng HJ, Chen GY. Successful treatment of infantile hepatitis B with lamivudine: A case report. World J Clin Cases 2021; 9:3442-3448. [PMID: 34002156 PMCID: PMC8107904 DOI: 10.12998/wjcc.v9.i14.3442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 02/08/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND How to treat infantile hepatitis B virus (HBV) infection remains a controversial issue. The nucleoside analogue lamivudine (LAM) has been approved to treat children (2 to 17 years old) with chronic hepatitis B. Here, we aimed to investigate the benefit of LAM treatment in infantile hepatitis B.
CASE SUMMARY A 4-mo-old infant born to a hepatitis B surface antigen (HBsAg)-positive woman was found to be infected by HBV during a health checkup. Liver chemistry and HBV seromarker tests showed alanine aminotransferase of 106 U/L, HBsAg of 685.2 cut-off index, hepatitis B “e” antigen of 1454.0 cut-off index, and HBV DNA of > 1.0 × 109 IU/mL. LAM treatment (20 mg/d) was initiated, and after 19 mo, serum HBsAg was entirely cleared and hepatitis B surface antibody was present. The patient received LAM treatment for 2 years in total and has been followed for 3 years. During this period, serum hepatitis B surface antibody has been persistently positive, and serum HBV DNA was undetectable.
CONCLUSION Early treatment of infantile hepatitis B with LAM could be safe and effective.
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Affiliation(s)
- Yu-Ting Zhang
- Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Jing Liu
- Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
| | - Xiao-Ben Pan
- Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
- Department of Basic Medical Sciences, School of Medicine, Hangzhou Normal University, Hangzhou 310036, Zhejiang Province, China
| | - Yi-Dan Gao
- Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
| | - Yin-Fei Hu
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Li Lin
- The Clinical Medical College, Hangzhou Normal University, Hangzhou 310036, Zhejiang Province, China
| | - Hua-Jun Cheng
- Department of Gastroenterology, Yiwu Chouzhou Hospital, Jinhua 322000, Zhejiang Province, China
| | - Gong-Ying Chen
- Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
- The Clinical Medical College, Hangzhou Normal University, Hangzhou 310036, Zhejiang Province, China
- Department of Gastroenterology, Yiwu Chouzhou Hospital, Jinhua 322000, Zhejiang Province, China
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25
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Liu Y, Maya S, Ploss A. Animal Models of Hepatitis B Virus Infection-Success, Challenges, and Future Directions. Viruses 2021; 13:v13050777. [PMID: 33924793 PMCID: PMC8146732 DOI: 10.3390/v13050777] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/23/2021] [Accepted: 04/24/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects more than 250 million people worldwide, which greatly increases the risk for terminal liver diseases, such as liver cirrhosis and hepatocellular carcinoma (HCC). Even though current approved antiviral therapies, including pegylated type I interferon (IFN) and nucleos(t)ide analogs, can effectively suppress viremia, HBV infection is rarely cured. Since HBV exhibits a narrow species tropism and robustly infects only humans and higher primates, progress in HBV research and preclinical testing of antiviral drugs has been hampered by the scarcity of suitable animal models. Fortunately, a series of surrogate animal models have been developed for the study of HBV. An increased understanding of the barriers towards interspecies transmission has aided in the development of human chimeric mice and has greatly paved the way for HBV research in vivo, and for evaluating potential therapies of chronic hepatitis B. In this review, we summarize the currently available animal models for research of HBV and HBV-related hepadnaviruses, and we discuss challenges and future directions for improvement.
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26
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Traum D, Wang YJ, Schwarz KB, Schug J, Wong DK, Janssen HLA, Terrault NA, Khalili M, Wahed AS, Murray KF, Rosenthal P, Ling SC, Rodriguez-Baez N, Sterling RK, Lau DT, Block TM, Feldman MD, Furth EE, Lee WM, Kleiner DE, Lok AS, Kaestner KH, Chang KM. Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver. JCI Insight 2021; 6:146883. [PMID: 33621209 PMCID: PMC8119221 DOI: 10.1172/jci.insight.146883] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral, and structural markers in liver biopsies from patients with hepatitis B e antigen+ (HBeAg+) chronic hepatitis B, we provide potentially novel comprehensive visualization, quantitation, and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis, and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.
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Affiliation(s)
- Daniel Traum
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Medical Research, The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Yue J Wang
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Biomedical Sciences, College of Medicine, Florida State University, Tallahasee, Florida, USA
| | | | - Jonathan Schug
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - David Kh Wong
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - Harry LA Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - Norah A Terrault
- Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Mandana Khalili
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Abdus S Wahed
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Karen F Murray
- Cleveland Clinic Pediatric Institute, Cleveland, Ohio, USA
| | | | - Simon C Ling
- The Hospital for Sick Children and Department of Paediatrics and University of Toronto, Toronto, Canada
| | - Norberto Rodriguez-Baez
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Richard K Sterling
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Daryl Ty Lau
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | | | - Michael D Feldman
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Elizabeth E Furth
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - William M Lee
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
| | - Anna S Lok
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Kyong-Mi Chang
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Medical Research, The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
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27
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Park JJ, Thi EP, Carpio VH, Bi Y, Cole AG, Dorsey BD, Fan K, Harasym T, Iott CL, Kadhim S, Kim JH, Lee ACH, Nguyen D, Paratala BS, Qiu R, White A, Lakshminarasimhan D, Leo C, Suto RK, Rijnbrand R, Tang S, Sofia MJ, Moore CB. Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1. Nat Commun 2021; 12:1222. [PMID: 33619272 PMCID: PMC7900207 DOI: 10.1038/s41467-021-21410-1] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 01/26/2021] [Indexed: 12/19/2022] Open
Abstract
Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.
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Affiliation(s)
| | | | | | - Yingzhi Bi
- Arbutus Biopharma Inc, Warminster, PA, USA
| | | | | | - Kristi Fan
- Arbutus Biopharma Inc, Warminster, PA, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Sunny Tang
- Arbutus Biopharma Inc, Warminster, PA, USA
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28
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El-Mesery M, El-Mowafy M, Youssef LF, El-Mesery A, Abed SY, Elgaml A. Serum Soluble Fibrinogen-Like Protein 2 Represents a Novel Biomarker for Differentiation Between Acute and Chronic Egyptian Hepatitis B Virus-Infected Patients. J Interferon Cytokine Res 2021; 41:52-59. [DOI: 10.1089/jir.2020.0118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Mohamed El-Mesery
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohammed El-Mowafy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Laila F. Youssef
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Ahmed El-Mesery
- Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Sally Yussef Abed
- Department of Respiratory Care, College of Applied Medical Science in Jubail, Imam Abdulrahman Bin Faisal University, Jubail, Saudi Arabia
| | - Abdelaziz Elgaml
- Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Horus University, New Damietta, Egypt
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29
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Khera T, Du Y, Todt D, Deterding K, Strunz B, Hardtke S, Aregay A, Port K, Hardtke-Wolenski M, Steinmann E, Björkström NK, Manns MP, Hengst J, Cornberg M, Wedemeyer H. Long-lasting Imprint in the Soluble Inflammatory Milieu despite Early Treatment of Acute Symptomatic Hepatitis C. J Infect Dis 2021; 226:441-452. [PMID: 33517457 PMCID: PMC9417126 DOI: 10.1093/infdis/jiab048] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 01/28/2021] [Indexed: 11/13/2022] Open
Abstract
Background Treatment with direct-acting antivirals (DAAs) in patients with chronic hepatitis C infection leads to partial restoration of soluble inflammatory mediators (SIMs). In contrast, we hypothesized that early DAA treatment of acute hepatitis C virus (HCV) with DAAs may normalize most SIMs. Methods In this study, we made use of a unique cohort of acute symptomatic hepatitis C patients who cleared HCV with a 6-week course of ledipasvir/sofosbuvir. Plasma samples were used for proximity extension assay measuring 92 proteins. Results Profound SIM alterations were observed in acute HCV patients, with marked upregulation of interleukin (IL)-6 and CXCL-10, whereas certain mediators were downregulated (eg, monocyte chemoattractant protein-4, IL-7). During treatment and follow-up, the majority of SIMs decreased but not all normalized (eg, CDCP1, IL-18). Of note, SIMs that were downregulated before DAA treatment remained suppressed, whereas others that were initially unchanged declined to lower values during treatment and follow-up (eg, CD244). Conclusions Acute hepatitis C was associated with marked changes in the soluble inflammatory milieu compared with both chronic hepatitis patients and healthy controls. Whereas early DAA treatment partly normalized this altered signature, long-lasting imprints of HCV remained.
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Affiliation(s)
- Tanvi Khera
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany
| | - Yanqin Du
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.,European Virus Bioinformatics Center (EVBC), Jena, Germany
| | - Katja Deterding
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany
| | - Benedikt Strunz
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Svenja Hardtke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany
| | - Amare Aregay
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Niklas K Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany.,German Center for Infection Research (DZIF), partner site Braunschweig, Germany
| | - Julia Hengst
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany.,German Center for Infection Research (DZIF), partner site Braunschweig, Germany.,Center for individualized infection medicine (CIIM), Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, HepNet Study-House, German Liver Foundation, Hannover, Germany.,German Center for Infection Research (DZIF), partner site Braunschweig, Germany
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30
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Mastrodomenico M, Muselli M, Provvidenti L, Scatigna M, Bianchi S, Fabiani L. Long-term immune protection against HBV: associated factors and determinants. Hum Vaccin Immunother 2021; 17:2268-2272. [PMID: 33522392 PMCID: PMC8189074 DOI: 10.1080/21645515.2020.1852869] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
In Italy, vaccination against hepatitis B became compulsory for all the newborns and 12-years-old adolescents in 1991. The main purpose of this study was to evaluate the persistence of long-term protection against HBV in medical students of the University of L’Aquila and in postgraduates Medical Doctors (HCWs) working in San Salvatore Hospital. The second aim was to study the variables associated with a protective anti-HBs antibody level, such as age at vaccination, gender, time elapsed from the last dose of vaccination. Three hundred and forty-two subjects were enrolled from January 2017 to January 2019 and a blood sample was collected to evaluate the levels of serum HBsAg, anti-HBs and anti-HBc. Statistical analysis calculated a multivariable logistic regression model to examine predictors of a protective anti-HBs titer. The larger part (239, 70%) of the students had an anti-HBs titer >10 mIU/mL, those were statistically significant older (26.7 vs 24.5 years, p < .001), vaccinated at age 12 years (83.5% vs 59.9% among vaccinate at infancy, p < .001) and more frequently attending postgraduate medical school (80.8% vs 57.5% among healthcare profession school, p < .001). The multivariable logistic regression model showed that HBV vaccination at age of 12 was significantly and independently associated with protective titers (OR = 10.27, p = .019). The results agreed with literature on HBV vaccination, confirming the efficacy of vaccination after 20 years. In particular, our results suggest that adolescent administration is the main predictor of a protective title, regardless of gender, course and years since vaccinations.
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Affiliation(s)
- Marianna Mastrodomenico
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Mario Muselli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Luca Provvidenti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Maria Scatigna
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Serena Bianchi
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Leila Fabiani
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
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31
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Komatsu H, Inui A, Yoshio S, Fujisawa T. Pharmacotherapy options for managing hepatitis B in children. Expert Opin Pharmacother 2021; 22:449-467. [PMID: 33090882 DOI: 10.1080/14656566.2020.1841165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION To eliminate viral hepatitis by 2030, the World Health Organization (WHO) launched the first global health sector strategy on viral hepatitis, with particular focus given to hepatitis B and C in 2016. To achieve the reduction of mortality in children, it is indispensable to know which children should be treated and how to treat them. AREA COVERED In this article, the authors review the antiviral treatment of children with chronic hepatitis B virus (HBV) infection including antivirals available for children with chronic HBV infection. EXPERT OPINION The approvals of nucleos(t)ide analogues (NAs) and pegylated interferon (PEG-IFN) for children have lowered a hurdle to the initiation of antiviral treatment in children. The international guidelines use nearly the same criteria of antiviral treatment for children with chronic HBV infection, but the WHO guidelines provide a cautious stance on the antiviral treatment of children. Not only PEG-IFN but also NAs with a high genetic barrier to drug resistance should be the first-line treatment for children. In settings with limited medical resources, NAs can be the first-line treatment for children. Although the concept of an 'immune-tolerant phase' is challenged, evidence is not sufficient to recommend the treatment of HBeAg-positive immune-tolerant children.
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Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, Toho University, Sakura Medical Center, Chiba, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Sachiyo Yoshio
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
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Kusi KA, Frimpong A, Partey FD, Lamptey H, Amoah LE, Ofori MF. High infectious disease burden as a basis for the observed high frequency of asymptomatic SARS-CoV-2 infections in sub-Saharan Africa. AAS Open Res 2021; 4:2. [PMID: 34729457 PMCID: PMC8524298 DOI: 10.12688/aasopenres.13196.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2021] [Indexed: 11/03/2023] Open
Abstract
Following the coronavirus outbreaks described as severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome (MERS) in 2012, the world has again been challenged by yet another corona virus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infections were first detected in a Chinese Province in December 2019 and then declared a pandemic by the World Health Organization in March 2020. An infection caused by SARS-CoV-2 may result in asymptomatic, uncomplicated or fatal coronavirus disease 2019 (COVID-19). Fatal disease has been linked with the uncontrolled "cytokine storm" manifesting with complications mostly in people with underlying cardiovascular and pulmonary disease conditions. The severity of COVID-19 disease and the associated mortality has been disproportionately lower in Africa and Asia in comparison to Europe and North America in terms of number of cases and deaths. While persons of colour who live in Europe and North America have been identified as a highly susceptible population due to a combination of several socioeconomic factors and poor access to quality healthcare, this has not been the case in sub-Saharan Africa where inhabitants are even more deprived concerning the said factors. On the contrary, sub-Saharan Africa has recorded the lowest levels of mortality and morbidity associated with the disease, and an overwhelming proportion of infections are asymptomatic. This review discusses the most probable reasons for the significantly fewer cases of severe COVID-19 disease and deaths in sub-Saharan Africa.
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Affiliation(s)
- Kwadwo Asamoah Kusi
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Augustina Frimpong
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Frederica Dedo Partey
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Helena Lamptey
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Linda Eva Amoah
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Michael Fokuo Ofori
- Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
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Wang CR, Tsai HW. Human hepatitis viruses-associated cutaneous and systemic vasculitis. World J Gastroenterol 2021; 27:19-36. [PMID: 33505148 PMCID: PMC7789062 DOI: 10.3748/wjg.v27.i1.19] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 12/19/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023] Open
Abstract
Human hepatitis viruses (HHVs) include hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus, and hepatitis E virus and can cause liver inflammation in their common human host. Usually, HHV is rapidly cleared by the immune system, following acute HHV invasion. The morbidities associated with hepatitis A virus and hepatitis E virus infection occur shortly after their intrusion, in the acute stage. Nevertheless, the viral infectious process can persist for a long period of time, especially in HBV and HCV infection, leading to chronic hepatitis and further progressing to hepatic cirrhosis and liver cancer. HHV infection brings about complications in other organs, and both acute and chronic hepatitis have been associated with clinical presentations outside the liver. Vascular involvement with cutaneous and systemic vasculitis is a well-known extrahepatic presentation; moreover, there is growing evidence for a possible causal relationship between viral pathogens and vasculitis. Except for hepatitis delta virus, other HHVs have participated in the etiopathogenesis of cutaneous and systemic vasculitis via different mechanisms, including direct viral invasion of vascular endothelial cells, immune complex-mediated vessel wall damage, and autoimmune responses with stimulation of autoreactive B-cells and impaired regulatory T-cells. Cryoglobulinemic vasculitis and polyarteritis nodosa are recognized for their association with chronic HHV infection. Although therapeutic guidelines for HHV-associated vasculitis have not yet been established, antiviral therapy should be initiated in HBV and HCV-related systemic vasculitis in addition to the use of corticosteroids. Plasma exchange and/or combined cyclophosphamide and corticosteroid therapy can be considered in patients with severe life-threatening vasculitis manifestations.
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Affiliation(s)
- Chrong-Reen Wang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
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IMMUNOHISTOCHEMICAL PARAMETERS OF TGAB AND FOX–1 EXPRESSION IN THE THYROID GLAND OF RATS AFTER PRENATAL ANTIGEN EXPOSURE. WORLD OF MEDICINE AND BIOLOGY 2021. [DOI: 10.26724/2079-8334-2021-2-76-252-257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Wedemeyer H, Khera T, Strunz B, Björkström NK. Reversal of Immunity After Clearance of Chronic HCV Infection-All Reset? Front Immunol 2020; 11:571166. [PMID: 33133084 PMCID: PMC7578424 DOI: 10.3389/fimmu.2020.571166] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic viral infections cause deterioration of our immune system. However, since persistent infections rarely can be eliminated, the reinvigoration capacity of an exhausted immune system has remained largely elusive. Chronic hepatitis C virus (HCV) infection can since some years be effectively cured with novel direct acting antiviral agents. Thus, it is now possible to study reversal of immunity in patients that are cured from a long-lasting chronic infection. We here highlight recent developments in the analysis of various immune cell populations during and after clearance of HCV infection. Surprisingly, whereas reinvigoration of certain immune traits clearly can be seen, many features of immune exhaustion persist over time after viral elimination. Thus, a long-term chronic insult might result in irreversible damage to our immune system. This will be important to consider in therapeutic vaccination efforts against chronic infection and in the development of immunotherapy based strategies against cancer.
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Affiliation(s)
- Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Tanvi Khera
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Benedikt Strunz
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Meng Z, Chen Y, Lu M. Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection. Front Immunol 2020; 10:3127. [PMID: 32117201 PMCID: PMC7018702 DOI: 10.3389/fimmu.2019.03127] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 12/23/2019] [Indexed: 12/12/2022] Open
Abstract
“Functional cure” is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. “Functional cure” can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.
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Affiliation(s)
- Zhongji Meng
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yuanyuan Chen
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, Essen, Germany
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Lu C, Xie H, Li H, Geng Q, Chen H, Mo X, Tang W. Feasibility and efficacy of home rectal irrigation in neonates and early infancy with Hirschsprung disease. Pediatr Surg Int 2019; 35:1245-1253. [PMID: 31535199 DOI: 10.1007/s00383-019-04552-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/09/2019] [Indexed: 11/24/2022]
Abstract
PURPOSE A single-stage pull-through (SSPT) is the most commonly performed procedure for Hirschsprung disease (HSCR) and has been shown to be better than multi-stage procedures. However, performing a SSPT in the neonatal period or early in infancy is a risk factor for an inaccurate diagnosis, post-operative enterocolitis, and a protracted post-operative recovery. The present study was primarily designed to evaluate the feasibility and efficacy of home rectal irrigation in the neonatal period and early in infancy, followed by a delayed and planned SSPT in a prospective cohort with HSCR. METHODS Between January 2014 and December 2016, a total of 147 neonates diagnosed with HSCR were enrolled in the study. Six patients were excluded as a result of ganglion cells found in second rectal biopsies after the neonatal period. One hundred twenty-two patients successfully underwent 2-4 months of home rectal irrigation during the neonatal period, followed by a SSPT procedure after the neonatal period (group A, n = 122). Nineteen patients were not candidates for home rectal irrigation, and thus, colostomies were performed during the neonatal period followed by multi-stage procedures after the neonatal period (group B, n = 19). One hundred twenty-two healthy children, age- and gender-matched to group A were enrolled as the healthy control group for assessment of nutrition status (group C, n = 122). The birth weight, gender ratio, aganglionic segment, age, and Hirschsprung-associated enterocolitis (HAEC) score at the time of HSCR diagnosis were measured to evaluate the feasibility of home rectal irrigation in neonates and early in infancy. The nutritional indices, including weight, body length, serum albumin, serum prealbumin, serum retinol-binding protein, and incidence of HAEC after 2-4 successful home rectal irrigation, were used to assess the efficacy of home rectal irrigation. Anastomotic strictures or leakage, perianal excoriation, frequency of defecation, and morbidity of post-operative HAEC were recorded to evaluate the beneficial effects to pull through (PT), which were facilitated by home rectal irrigation. RESULTS Higher HAEC scores and older age at the time of diagnosis of HSCR were associated with group B, compared to group A (4.34 ± 1.25 vs. 11.0 ± 2.56 [t = 18.20, p < 0.05] and 2.8 ± 1.46 days vs. 12.1 ± 5.3 days [t = 16.10, p < 0.05], respectively). The ratio of rectosigmoid HSCR to non-rectosigmoid HSCR was higher in group A than group B (104/18 vs. 4/15 [χ2 = 34.29, p < 0.05]). There were no differences in birth weight, weight at the time of diagnosis of HSCR, and gender ratio between groups A and B. There were no differences in birth weight, birth length, post-home rectal irrigation age, post-home rectal irrigation weight, post-home rectal irrigation length, and post-home rectal irrigation serum albumin between groups A and C (3.47 ± 0.42 kg vs. 3.48 ± 0.40 kg [t = 0.10, p > 0.05], 50.02 ± 0.49 cm vs. 50.05 ± 0.46 cm [t = 0.61, p > 0.05], 98.59 ± 13.34 days vs. 97.83 ± 13.58 days [t = 0.44, p > 0.05], 6.77 ± 0.66 kg vs. 6.97 ± 0.87 kg [t = 1.95, p > 0.05], 61.55 ± 2.14 cm vs. 61.70 ± 2.07 cm [t = 0.59, p > 0.05], and 41.78 ± 2.42 g/L vs. 41.85 ± 2.37 g/L [t = 0.22, p > 0.05], respectively). The rate of HAEC in the period of home rectal irrigation in group A was low; however, the post-home rectal irrigation serum prealbumin level and retinol-binding protein were significantly lower in group A than group C (0.15 ± 0.04 g/L vs. 0.17 ± 0.05 g/L [t = 3.50, p < 0.05] and 22.51 ± 7.53 g/L vs. 30.57 ± 9.26 g/L [t = 7.46, p < 0.05], respectively). There were no anastomotic strictures or leakage after definitive PT performed in group A. The frequency of defecation ranged from 2-6 times per day, 10 patients had perianal excoriation 3 months after PT, and 11 patients had post-operative HAEC during 6 months of follow-up after PT. CONCLUSION Home rectal irrigation in neonates and early in infancy, followed by a delayed and planned SSPT is feasible and effective in patients with HSCR, and could be beneficial to definitive PT. However, for patients with an extended aganglionic segment, older age, or high HAEC score at the time of diagnosis of HSCR, rectal irrigation maybe not suitable. TRIAL REGISTRATION This was a prospective comparative study designed to evaluate the effects of home rectal irrigation for facilitating and enhancing recovery after PT, and was registered at Clinical Trials.gov as NCT02776176.
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Affiliation(s)
- Changgui Lu
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Hua Xie
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Hongxing Li
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Qiming Geng
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Huan Chen
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Xuming Mo
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
| | - Weibing Tang
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
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Zhang Z, Wang C, Liu Z, Zou G, Li J, Lu M. Host Genetic Determinants of Hepatitis B Virus Infection. Front Genet 2019; 10:696. [PMID: 31475028 PMCID: PMC6702792 DOI: 10.3389/fgene.2019.00696] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 07/03/2019] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is still a major health problem worldwide. Recently, a great number of genetic studies based on single nucleotide polymorphisms (SNPs) and genome-wide association studies have been performed to search for host determinants of the development of chronic HBV infection, clinical outcomes, therapeutic efficacy, and responses to hepatitis B vaccines, with a focus on human leukocyte antigens (HLA), cytokine genes, and toll-like receptors. In addition to SNPs, gene insertions/deletions and copy number variants are associated with infection. However, conflicting results have been obtained. In the present review, we summarize the current state of research on host genetic factors and chronic HBV infection, its clinical type, therapies, and hepatitis B vaccine responses and classify published results according to their reliability. The potential roles of host genetic determinants of chronic HBV infection identified in these studies and their clinical significance are discussed. In particular, HLAs were relevant for HBV infection and pathogenesis. Finally, we highlight the need for additional studies with large sample sizes, well-matched study designs, appropriate statistical methods, and validation in multiple populations to improve the treatment of HBV infection.
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Affiliation(s)
- Zhenhua Zhang
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Changtai Wang
- Department of Infectious Diseases, the Affiliated Anqing Hospital of Anhui Medical University, Anqing, China
| | - Zhongping Liu
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guizhou Zou
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jun Li
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Duisburg-Essen, Essen, Germany
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Sung PS, Park DJ, Kim JH, Han JW, Lee EB, Lee GW, Nam HC, Jang JW, Bae SH, Choi JY, Shin EC, Park SH, Yoon SK. Ex vivo Detection and Characterization of Hepatitis B Virus-Specific CD8 + T Cells in Patients Considered Immune Tolerant. Front Immunol 2019; 10:1319. [PMID: 31244857 PMCID: PMC6563765 DOI: 10.3389/fimmu.2019.01319] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 05/23/2019] [Indexed: 12/21/2022] Open
Abstract
In this study, we aimed to detect and characterize ex vivo virus-specific CD8+ T cells in patients with immune-tolerant hepatitis B virus (HBV) infection. We investigated a Korean chronic hepatitis B cohort composed of 15 patients in the immune-tolerant phase, 17 in the immune-active phase, and 13 under antiviral treatment. We performed enzyme-linked immunospot (ELISpot) assays ex vivo and intracellular cytokine staining after in vitro culture. We also performed ex vivo multimer staining assays and examined the expression of programmed death-1 (PD-1) and CD127 in pentamer-positive cells. Ex vivo ELISpot revealed that HBV-specific T cell function was weaker in immune-tolerant patients than in those under antiviral treatment. In vitro culture of peripheral blood mononuclear cells for 10 days revealed that HBV-specific CD8+ T cells produced interferon-γ in some immune-tolerant patients. We detected HBV-specific CD8+ T cells ex vivo (using the HBV core18-27 pentamer) in patients from all three groups. The PD-1+ subset of pentamer+ CD8+ T cells was smaller ex vivo in the immune-tolerant phase than in the immune-active phase or under antiviral treatment. Interestingly, the proportion of PD-1+ CD8+ T cells in HBV-specific CD8+ T cells correlated with patient age when all enrolled patients were analyzed. Overall, HBV-specific CD8+ T cells are present in patients considered as immune-tolerant, although their ex vivo functionality is significantly weaker than that in patients under antiviral treatment (P < 0.05). Despite the high viral load, the proportion of PD-1 expression in HBV-specific CD8+ T cells is lower in the immune-tolerant phase than in other phases. Our results indicate appropriate stimulation may enhance the effector function of HBV-specific CD8+ T cells in patients considered as being in the immune-tolerant phase.
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Affiliation(s)
- Pil Soo Sung
- Department of Internal Medicine, College of Medicine, Eunpyeong St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Dong Jun Park
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jung-Hee Kim
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ji Won Han
- Graduate School of Medical Science and Engineering, KAIST, Daejeon, South Korea
| | - Eun Byul Lee
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Gil Won Lee
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hee Chul Nam
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
- Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Jeong Won Jang
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
- Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, Eunpyeong St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jong Young Choi
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
- Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, KAIST, Daejeon, South Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, KAIST, Daejeon, South Korea
| | - Seung Kew Yoon
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
- Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
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Endogenously Expressed Antigens Bind Mammalian RNA via Cationic Domains that Enhance Priming of Effector CD8 T Cells by DNA Vaccination. Mol Ther 2019; 27:661-672. [PMID: 30713086 PMCID: PMC6403493 DOI: 10.1016/j.ymthe.2019.01.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 01/08/2019] [Accepted: 01/11/2019] [Indexed: 01/11/2023] Open
Abstract
Hepatitis B virus (HBV) core (HBV-C) antigens with homologous or heterologous HIV-tat48-57-like (HBV-C149tat) cationic domains non-specifically bind cellular RNA in vector-transfected cells. Here, we investigated whether RNA-binding to cationic domains influences the immunogenicity of endogenously expressed antigens delivered by DNA vaccination. We initially evaluated induction of HBV-C (Kb/C93)-specific CD8+ T cell responses in C57BL/6J (B6) and 1.4HBV-Smut transgenic (tg) mice that harbor a replicating HBV genome in hepatocytes by DNA immunization. RNA-binding HBV-C and HBV-C149tat antigens moderately enhanced Kb/C93-specific CD8+ T cells in B6 mice as compared with RNA-free HBV-C149 antigen (lacking cationic domains). However, only the RNA-binding antigens elicited Kb/C93-specific CD8+ T cells that inhibited HBV replication in 1.4HBV-Smut tg mice. Moreover, RNA-binding to designer antigens, which express a Kb/p15E epitope from an endogenous murine leukemia virus-derived tumor-specific gp70 protein, was crucial to prime tumor-rejecting effector CD8+ T cells in B6 mice. Antigen-bound endogenous RNAs function as a Toll-like receptor 7 (TLR-7) ligand and stimulated priming of Kb/p15E-specific CD8+ T cells in B6, but not TLR-7−/−, mice. Antigen-bound cellular RNAs thus function as an endogenous natural adjuvant in in vivo vector-transfected cells, and thus are an attractive tool to induce and/or enhance effector CD8+ T cell responses directed against chronic viral infections or tumor self-antigens by DNA vaccination.
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He S, Zheng G, Zhou D, Li G, Zhu M, Du X, Zhou J, Cheng Z. Clonal anergy of CD117 +chB6 + B cell progenitors induced by avian leukosis virus subgroup J is associated with immunological tolerance. Retrovirology 2019; 16:1. [PMID: 30602379 PMCID: PMC6317241 DOI: 10.1186/s12977-018-0463-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 12/24/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The pathogenesis of immunological tolerance caused by avian leukosis virus subgroup J (ALV-J), an oncogenic retrovirus, is largely unknown. RESULTS In this study, the development, differentiation, and immunological capability of B cells and their progenitors infected with ALV-J were studied both morphologically and functionally by using a model of ALV-J congenital infection. Compared with posthatch infection, congenital infection of ALV-J resulted in severe immunological tolerance, which was identified as the absence of detectable specific antivirus antibodies. In congenitally infected chickens, immune organs, particularly the bursa of Fabricius, were poorly developed. Moreover, IgM-and IgG-positive cells and total immunoglobulin levels were significantly decreased in these chickens. Large numbers of bursa follicles with no differentiation into cortex and medulla indicated that B cell development was arrested at the early stage. Flow cytometry analysis further confirmed that ALV-J blocked the differentiation of CD117+chB6+ B cell progenitors in the bursa of Fabricius. Furthermore, both the humoral immunity and the immunological capability of B cells and their progenitors were significantly suppressed, as assessed by (a) the antibody titres against sheep red blood cells and the Marek's disease virus attenuated serotype 1 vaccine; (b) the proliferative response of B cells against thymus-independent antigen lipopolysaccharide (LPS) in the spleen germinal centres; and (c) the capacities for proliferation, differentiation and immunoglobulin gene class-switch recombination of B cell progenitors in response to LPS and interleukin-4(IL-4) in vitro. CONCLUSIONS These findings suggested that the anergy of B cells in congenitally infected chickens is caused by the developmental arrest and dysfunction of B cell progenitors, which is an important factor for the immunological tolerance induced by ALV-J.
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Affiliation(s)
- Shuhai He
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, 271018 China
- College of Husbandry and Veterinary, Xinyang Agriculture and Forestry University, Xinyang, 464000 China
| | - Gaoying Zheng
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, 271018 China
| | - Defang Zhou
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, 271018 China
| | - Gen Li
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, 271018 China
| | - Mingjun Zhu
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, 271018 China
| | - Xusheng Du
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, 271018 China
| | - Jing Zhou
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, 271018 China
| | - Ziqiang Cheng
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, 271018 China
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Han Q, Hou Z, Yin C, Zhang C, Zhang J. 5'-triphosphate siRNA targeting HBx elicits a potent anti-HBV immune response in pAAV-HBV transfected mice. Antiviral Res 2018; 161:36-45. [PMID: 30448255 DOI: 10.1016/j.antiviral.2018.11.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 10/02/2018] [Accepted: 11/14/2018] [Indexed: 12/19/2022]
Abstract
RNA with 5'-triphosphate (3p-RNA) is recognized by RNA sensor RIG-I (retinoic acid-inducible gene I protein). Previously, we reported that small interfering RNA targeting HBx (3p-siHBx) could confer potent anti-hepatitis B virus (HBV) efficacy via HBx silencing and RIG-I activation. However, the characteristics of innate and adaptive immunity especially exhaustion profiles in the liver microenvironment in response to 3p-siHBx therapy have not been fully elucidated. Here, we observed that 3p-siHBx more significantly inhibited HBV replication in vivo. 3p-siHBx enhanced natural killer (NK) cell activation with KLRG1 and CD69 upregulation and interferon (IFN)-γ secretion. 3p-siHBx significantly reversed the exhaustion phenotype of CD8+ T cells, and augmented CD8+ T cell activation and function. Importantly, 3p-siHBx disrupted the differentiation of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), accompanied by the reduction of the immunosuppressive cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β. 3p-siHBx also enhanced dendritic cell maturation. Further investigation showed that RIG-I was involved in 3p-siHBx-induced IFN-α, IFN-β, and IFN-λ production. Moreover, RIG-I activation in HBV+ hepatocytes would improve the recruitment of CD8+ T cells and NK cells. These results reveal that 3p-siHBx therapy can improve the immune microenvironment in HBV-carrier liver and inhibit HBV replication, indicating the potential utility of RIG-I ligands as molecular adjuvants for viral vaccines or candidate drugs.
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Affiliation(s)
- Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China
| | - Zhaohua Hou
- Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), 19 Keyuan Road, Jinan 250014, China
| | - Chunlai Yin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China
| | - Cai Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China.
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Osiowy C. From infancy and beyond… ensuring a lifetime of hepatitis B virus (HBV) vaccine-induced immunity. Hum Vaccin Immunother 2018; 14:2093-2097. [PMID: 29641290 PMCID: PMC6150009 DOI: 10.1080/21645515.2018.1462428] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Despite the long-term efficacy and immune persistence observed following HBV vaccination of infants, the need for a booster dose following infant immunization continues to be deliberated. Evidence from HBV booster dose response studies and long-term immunization program reviews are the basis for the recommendation that a vaccine booster is not necessary. However, further studies continue to emerge and highlight the need for standardization among observational studies in order to appropriately compare outcomes. There is an assumption that neonatal and infant (within 12 months of age) vaccine immune responses are equivalent; however, evidence exists for distinct vaccine responses within the first year of life. HBV vaccine programs have evolved over time, particularly regarding the type and dosage of vaccine used. Several universal neonatal immunization programs initially incorporated a 2.5 μg dosage (Recombivax-HB, Merck). This dosage has been shown in multiple long-term studies and meta-analyses to be associated with a lower primary response, decreased antibody persistence over time, and a reduced booster response 10 to 20 years following immunization. Ongoing surveillance of this and other HBV neonatally-vaccinated populations, particularly in low endemic regions, is necessary to understand the impact on long-term protection in order to ensure lifelong protection against hepatitis B infection.
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Affiliation(s)
- Carla Osiowy
- a National Microbiology Laboratory , Public Health Agency of Canada , Winnipeg , Manitoba , Canada
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44
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Infectious Agents as Stimuli of Trained Innate Immunity. Int J Mol Sci 2018; 19:ijms19020456. [PMID: 29401667 PMCID: PMC5855678 DOI: 10.3390/ijms19020456] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 01/26/2018] [Accepted: 02/02/2018] [Indexed: 12/13/2022] Open
Abstract
The discoveries made over the past few years have modified the current immunological paradigm. It turns out that innate immunity cells can mount some kind of immunological memory, similar to that observed in the acquired immunity and corresponding to the defense mechanisms of lower organisms, which increases their resistance to reinfection. This phenomenon is termed trained innate immunity. It is based on epigenetic changes in innate immune cells (monocytes/macrophages, NK cells) after their stimulation with various infectious or non-infectious agents. Many infectious stimuli, including bacterial or fungal cells and their components (LPS, β-glucan, chitin) as well as viruses or even parasites are considered potent inducers of innate immune memory. Epigenetic cell reprogramming occurring at the heart of the phenomenon may provide a useful basis for designing novel prophylactic and therapeutic strategies to prevent and protect against multiple diseases. In this article, we present the current state of art on trained innate immunity occurring as a result of infectious agent induction. Additionally, we discuss the mechanisms of cell reprogramming and the implications for immune response stimulation/manipulation.
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45
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Kollmann TR, Marchant A. Immunity and immunopathology in early human life. Semin Immunopathol 2017; 39:575-576. [PMID: 29170801 DOI: 10.1007/s00281-017-0657-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 10/09/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Tobias R Kollmann
- Division of Infectious Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
| | - Arnaud Marchant
- Institute for Medical Immunology, Université libre de Bruxelles, Charleroi, Belgium
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