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de Moraes ATL, Dos Santos ES, Pedroso CM, Gomes RT, Ferrarotto R, Santos-Silva AR. Human oncogenic viruses: a focus on head and neck carcinogenesis: a systematic review and meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol 2025; 139:328-343. [PMID: 39551637 DOI: 10.1016/j.oooo.2024.10.082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 10/10/2024] [Accepted: 10/16/2024] [Indexed: 11/19/2024]
Abstract
OBJECTIVE This systematic review aimed at identifying oncoviruses associated with head and neck malignant neoplasms (HNC). STUDY DESIGN Five databases and grey literature sources were searched following PRISMA guidelines. The risk of bias in individual studies was analyzed using the Joanna Briggs Institute checklist, and the certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation tool. RESULTS One hundred and 19 studies were included in the qualitative synthesis. Gathered results of 57 studies were combined in a meta-analysis revealing a significant link between oncoviruses and the development of head and neck cancer, with the most common viruses identified were human papillomavirus (HPV)-16, HPV-18, and Epstein-Barr virus. More studies are needed to clarify the association of human cytomegalovirus and Merkel Cell Polyomavirus with HNC. CONCLUSIONS Although the role of viruses in cancer onset has been studied for years, our results demonstrated using a meta-analysis that these viruses are associated with HNC.
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Affiliation(s)
- Antonia Taiane Lopes de Moraes
- Department of Oral Diagnosis, Semiology and Oral Pathology Areas, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Erison Santana Dos Santos
- Department of Oral Diagnosis, Semiology and Oral Pathology Areas, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Caíque Mariano Pedroso
- Department of Oral Diagnosis, Semiology and Oral Pathology Areas, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | | | - Renata Ferrarotto
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Alan Roger Santos-Silva
- Department of Oral Diagnosis, Semiology and Oral Pathology Areas, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil.
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2
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Alsaadawe M, Radman BA, Long J, Alsaadawi M, Fang W, Lyu X. Epstein Barr virus: A cellular hijacker in cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189218. [PMID: 39549877 DOI: 10.1016/j.bbcan.2024.189218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/05/2024] [Accepted: 11/10/2024] [Indexed: 11/18/2024]
Abstract
Numerous studies have demonstrated the importance of the Epstein-Barr Virus (EBV), which was initially identified in 1964 while studying Burkitt's lymphoma, in the development of a number of cancers, including nasopharyngeal carcinoma, Hodgkin's lymphoma, Burkitt's lymphoma, and EBV-associated gastric carcinoma. Gammaherpesvirus EBV is extremely common; by adulthood, over 90 % of people worldwide have been infected. Usually, the virus causes a permanent latent infection in B cells, epithelial cells, and NK/T cells. It then contributes to oncogenesis by inhibiting apoptosis and promoting unchecked cell proliferation through its latent proteins, which include EBNA-1, LMP1, and LMP2A. Tumor progression further accelerated by EBV's capacity to transition between latent and lytic phases, especially in cases of nasopharyngeal carcinoma. Although our understanding of the molecular underpinnings of EBV has advanced, there are still difficulties in identifying latent infections and creating targeted therapeutics. To tackle EBV-associated malignancies, current research efforts are concentrated on developing vaccines, developing better diagnostic tools, and developing targeted treatments. In order to improve treatment approaches and lower the incidence of EBV-related cancers worldwide, more research into the relationship between EBV and immune evasion and cancer formation is necessary.
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Affiliation(s)
- Moyed Alsaadawe
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China; Al-Qadisiyah Education Directorate, Ministry of Education, Al-Qadisiyah, Iraq
| | - Bakeel A Radman
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Biology, College of Science and Education, Albaydha University, Albaydha, Yemen
| | - Jingyi Long
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Mohenned Alsaadawi
- Education College of Pure Science, Al-Muthanna University, Al-Muthanna, Iraq
| | - Weiyi Fang
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xiaoming Lyu
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
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3
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Furlano PL, Böhmig GA, Puchhammer-Stöckl E, Vietzen H. Mechanistic Understanding of EBV+Lymphoproliferative Disease Development After Transplantation. Transplantation 2024; 108:1867-1881. [PMID: 39166902 DOI: 10.1097/tp.0000000000004919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) are among the most common malignant complications after transplantation, leading to a drastic reduction in patient survival rates. The majority of PTLDs are tightly linked to Epstein-Barr virus (EBV+PTLDs) and are the result of an uncontrolled proliferation of EBV-infected cells. However, although EBV infections are a common finding in transplant recipients, most patients with high EBV loads will never develop EBV+PTLD. Natural killer cells and EBV-specific CD8+ T lymphocytes are critical for controlling EBV-infected cells, and the impairment of these cytotoxic immune responses facilitates the unfettered proliferation of EBV-infected cells. Recent years have seen a considerable increase in available literature aiming to describe novel risk factors associated with the development of EBV+PTLD, which may critically relate to the strength of EBV-specific natural killer cell and EBV-CD8+ T lymphocyte responses. The accumulation of risk factors and the increased risk of developing EBV+PTLD go hand in hand. On the one hand, most of these risk factors, such as the level of immunosuppression or the EBV donor and recipient serologic mismatch, and distinct genetic risk factors are host related and affect cytotoxic EBV-specific immune responses. On the other hand, there is growing evidence that distinct EBV variants may have an increased malignant potential and are thus more likely to induce EBV+PTLD. Here, we aim to review, from a mechanistic point of view, the risk factors for EBV+PTLD in the host and the infecting EBV variants that may explain why only a minority of transplant recipients develop EBV+PTLD.
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Affiliation(s)
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Hannes Vietzen
- Center for Virology, Medical University of Vienna, Vienna, Austria
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4
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Huss NP, Majeed ST, Wills BM, Tarakanova VL, Brockman KL, Jondle CN. Nontypeable Haemophilus influenzae challenge during gammaherpesvirus infection enhances viral reactivation and latency. Virology 2024; 597:110153. [PMID: 38941745 PMCID: PMC11257779 DOI: 10.1016/j.virol.2024.110153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/12/2024] [Accepted: 06/20/2024] [Indexed: 06/30/2024]
Abstract
Gammaherpesviruses are ubiquitous, lifelong pathogens associated with multiple cancers that infect over 95% of the adult population. Increases in viral reactivation, due to stress and other unknown factors impacting the immune response, frequently precedes lymphomagenesis. One potential stressor that could promote viral reactivation and increase viral latency would be the myriad of infections from bacterial and viral pathogens that we experience throughout our lives. Using murine gammaherpesvirus 68 (MHV68), a mouse model of gammaherpesvirus infection, we examined the impact of bacterial challenge on gammaherpesvirus infection. We challenged MHV68 infected mice during the establishment of latency with nontypeable Haemophilus influenzae (NTHi) to determine the impact of bacterial infection on viral reactivation and latency. Mice infected with MHV68 and then challenged with NTHi, saw increases in viral reactivation and viral latency. These data support the hypothesis that bacterial challenge can promote gammaherpesvirus reactivation and latency establishment, with possible consequences for viral lymphomagenesis.
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Affiliation(s)
- Nicholas P Huss
- Department of Investigative Medicine and Center for Immunobiology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, 49007, USA
| | - Sheikh Tahir Majeed
- Department of Investigative Medicine and Center for Immunobiology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, 49007, USA
| | - Brandon M Wills
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Vera L Tarakanova
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Kenneth L Brockman
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Christopher N Jondle
- Department of Investigative Medicine and Center for Immunobiology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, 49007, USA.
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5
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Xie W, Bruce K, Belz GT, Farrell HE, Stevenson PG. Indirect CD4 + T cell protection against mouse gamma-herpesvirus infection via interferon gamma. J Virol 2024; 98:e0049324. [PMID: 38578092 PMCID: PMC11092340 DOI: 10.1128/jvi.00493-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 04/06/2024] Open
Abstract
CD4+ T cells play a key role in γ-herpesvirus infection control. However, the mechanisms involved are unclear. Murine herpesvirus type 4 (MuHV-4) allows relevant immune pathways to be dissected experimentally in mice. In the lungs, it colonizes myeloid cells, which can express MHC class II (MHCII), and type 1 alveolar epithelial cells (AEC1), which lack it. Nevertheless, CD4+ T cells can control AEC1 infection, and this control depends on MHCII expression in myeloid cells. Interferon-gamma (IFNγ) is a major component of CD4+ T cell-dependent MuHV-4 control. Here, we show that the action of IFNγ is also indirect, as CD4+ T cell-mediated control of AEC1 infection depended on IFNγ receptor (IFNγR1) expression in CD11c+ cells. Indirect control also depended on natural killer (NK) cells. Together, the data suggest that the activation of MHCII+ CD11c+ antigen-presenting cells is key to the CD4+ T cell/NK cell protection axis. By contrast, CD8+ T cell control of AEC1 infection appeared to operate independently. IMPORTANCE CD4+ T cells are critical for the control of gamma-herpesvirus infection; they act indirectly, by recruiting natural killer (NK) cells to attack infected target cells. Here, we report that the CD4+ T cell/NK cell axis of gamma-herpesvirus control requires interferon-γ engagement of CD11c+ dendritic cells. This mechanism of CD4+ T cell control releases the need for the direct engagement of CD4+ T cells with virus-infected cells and may be a common strategy for host control of immune-evasive pathogens.
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Affiliation(s)
- Wanxiaojie Xie
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia
| | - Kimberley Bruce
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia
| | - Gabrielle T. Belz
- The University of Queensland Frazer Institute, Brisbane, Queensland, Australia
| | - Helen E. Farrell
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia
| | - Philip G. Stevenson
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia
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Preiksaitis J, Allen U, Bollard CM, Dharnidharka VR, Dulek DE, Green M, Martinez OM, Metes DM, Michaels MG, Smets F, Chinnock RE, Comoli P, Danziger-Isakov L, Dipchand AI, Esquivel CO, Ferry JA, Gross TG, Hayashi RJ, Höcker B, L'Huillier AG, Marks SD, Mazariegos GV, Squires J, Swerdlow SH, Trappe RU, Visner G, Webber SA, Wilkinson JD, Maecker-Kolhoff B. The IPTA Nashville Consensus Conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: III - Consensus guidelines for Epstein-Barr virus load and other biomarker monitoring. Pediatr Transplant 2024; 28:e14471. [PMID: 37294621 DOI: 10.1111/petr.14471] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/10/2022] [Accepted: 01/02/2023] [Indexed: 06/11/2023]
Abstract
The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.
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Affiliation(s)
- Jutta Preiksaitis
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Upton Allen
- Division of Infectious Diseases and the Transplant and Regenerative Medicine Center, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Catherine M Bollard
- Center for Cancer and Immunology Research, Children's National Hospital, The George Washington University, Washington, District of Columbia, USA
| | - Vikas R Dharnidharka
- Department of Pediatrics, Division of Pediatric Nephrology, Hypertension & Pheresis, Washington University School of Medicine & St. Louis Children's Hospital, St. Louis, Missouri, USA
| | - Daniel E Dulek
- Division of Pediatric Infectious Diseases, Monroe Carell Jr. Children's Hospital at Vanderbilt and Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Michael Green
- Division of Pediatric Infectious Diseases, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Olivia M Martinez
- Department of Surgery and Program in Immunology, Stanford University School of Medicine, Stanford, California, USA
| | - Diana M Metes
- Departments of Surgery and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Marian G Michaels
- Division of Pediatric Infectious Diseases, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Françoise Smets
- Pediatric Gastroenterology and Hepatology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | | | - Patrizia Comoli
- Cell Factory & Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico, Pavia, Italy
| | - Lara Danziger-Isakov
- Division of Infectious Disease, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Anne I Dipchand
- Labatt Family Heart Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | | | - Judith A Ferry
- Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Thomas G Gross
- Center for Cancer and Blood Diseases, Children's Hospital Colorado, Aurora, Colorado, USA
| | - Robert J Hayashi
- Division of Pediatric Hematology/Oncology, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Britta Höcker
- University Children's Hospital, Pediatrics I, Heidelberg, Germany
| | - Arnaud G L'Huillier
- Faculty of Medicine, Pediatric Infectious Diseases Unit and Laboratory of Virology, Geneva University Hospitals, Geneva, Switzerland
| | - Stephen D Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
- NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, Great Ormond Street Institute of Child Health, London, UK
| | - George Vincent Mazariegos
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - James Squires
- Division of Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Steven H Swerdlow
- Division of Hematopathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Ralf U Trappe
- Department of Hematology and Oncology, DIAKO Ev. Diakonie-Krankenhaus Bremen, Bremen, Germany
- Department of Internal Medicine II: Hematology and Oncology, University Medical Centre Schleswig-Holstein, Kiel, Germany
| | - Gary Visner
- Division of Pulmonary Medicine, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Steven A Webber
- Department of Pediatrics, Vanderbilt School of Medicine, Nashville, Tennessee, USA
| | - James D Wilkinson
- Department of Pediatrics, Vanderbilt School of Medicine, Nashville, Tennessee, USA
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Zaffiri L, Chambers ET. Screening and Management of PTLD. Transplantation 2023; 107:2316-2328. [PMID: 36949032 DOI: 10.1097/tp.0000000000004577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Posttransplant lymphoproliferative disorder (PTLD) represents a heterogeneous group of lymphoproliferative diseases occurring in the setting of immunosuppression following hematopoietic stem cells transplant and solid organ transplantation. Despite its overall low incidence, PTLD is a serious complication following transplantation, with a mortality rate as high as 50% in transplant recipients. Therefore, it is important to establish for each transplant recipient a personalized risk evaluation for the development of PTLD based on the determination of Epstein-Barr virus serostatus and viral load following the initiation of immunosuppression. Due to the dynamic progression of PTLD, reflected in the diverse pathological features, different therapeutic approaches have been used to treat this disorder. Moreover, new therapeutic strategies based on the administration of virus-specific cytotoxic T cells have been developed. In this review, we summarize the available data on screening and treatment to suggest a strategy to identify transplant recipients at a higher risk for PTLD development and to review the current therapeutic options for PTLD.
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Affiliation(s)
- Lorenzo Zaffiri
- Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
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Chen J, Zhang X, Ma L, Gao Y, Fu Z, Liu M. 18F-FDG PET/CT findings in a patient with blastic plasmacytoid dendritic cell neoplasm and post-transplant lymphoproliferative disorder after hematopoietic stem cell transplantation: a case report. Front Med (Lausanne) 2023; 10:1258310. [PMID: 37663666 PMCID: PMC10469918 DOI: 10.3389/fmed.2023.1258310] [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: 07/13/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023] Open
Abstract
Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare hematopoietic malignancy, which originating from precursors of plasmacytoid dendritic cells. Allogeneic hematopoietic stem cell transplantation (HSCT) is normally considered in the treatment of BPDCN patients to acquire sustained remission. Post-transplant lymphoproliferative disorder (PTLD) is a group of conditions involving abnormal lymphoid cells proliferation in the context of extrinsic immunosuppression after solid organ transplantation (SOT) or HSCT. Herein, we report a patient with BPDCN, who suffered from PTLD after allogeneic HSCT. Case presentation A 66-year-old man was diagnosed with BPDCN, confirmed by pathologic examination after splenectomy. The post-surgery 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (18F-FDG PET/CT) showed multifocal 18F-FDG avidity in the left cheek, lymph nodes and bone marrow. The patient started chemotherapy, followed by allogeneic HSCT and immunosuppressive therapy. Four months after the HSCT, the patient developed intermittent fever and recurrent lymphadenopathy, accompanied with progressively elevated Epstein-Barr virus (EBV)-DNA both in serum and lymphocytes. 18F-FDG PET/CT was performed again and found multiple new enlarged 18F-FDG-avid lymph nodes, while the previous hypermetabolic lesions all disappeared. The pathology of mesenteric lymph node indicated a monomorphic PTLD (diffuse large B-cell lymphoma). Then the immunosuppressive medications were stopped and two cycles of Rituximab were given, and the follow-up CT scan indicated a complete response. Conclusion When patients with BPDCN recurred new enlarged lymph nodes after allogeneic HSCT and immunosuppressive therapy, PTLD should be taken into consideration. 18F-FDG PET/CT may provide additional evidence for supporting or refuting the suspicion of PTLD, and suggest lesions accessible for biopsy.
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Affiliation(s)
| | | | | | | | - Zhanli Fu
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Meng Liu
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
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Delgado AL, Preston-Hurlburt P, Lim N, Sumida TS, Long SA, McNamara J, Serti E, Higdon L, Herold KC. Latent EBV impairs immune cell signaling and enhances the efficacy of anti-CD3 mAb in Type 1 Diabetes. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.07.11.23292344. [PMID: 37502867 PMCID: PMC10370230 DOI: 10.1101/2023.07.11.23292344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Teplizumab has been approved for the delay of the onset of type 1 diabetes and may modulate new onset disease. We found that patients who were EBV positive at baseline had a more robust response to drug in two clinical trials and therefore postulated that latent virus has general effects in modifying immune responses. We compared the phenotypes, transcriptomes, and development of peripheral blood cells before and after teplizumab treatment. Higher number of Tregs and partially exhausted CD8 + T cells were found in EBV seropositive individuals at the baseline in the TN10 trial and AbATE trial. Single cell transcriptomics and functional assays identified downregulation of the T cell receptor and other signaling pathways before treatment. Impairments in function of adaptive immune cells were enhanced by teplizumab treatment in EBV seropositive individuals. Our data indicate that EBV can impair signaling pathways generally in immune cells, that broadly redirect cell differentiation.
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10
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T Cell-Intrinsic Interleukin 17 Receptor A Signaling Supports the Establishment of Chronic Murine Gammaherpesvirus 68 Infection. J Virol 2022; 96:e0063922. [PMID: 35758659 PMCID: PMC9327704 DOI: 10.1128/jvi.00639-22] [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: 12/30/2022] Open
Abstract
Gammaherpesviruses, such as human Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), are species-specific, ubiquitous pathogens that are associated with multiple cancers, including B cell lymphomas. These viruses have a natural tropism for B cells and usurp B cell differentiation to drive a unique and robust polyclonal germinal center response to establish a long-term latent reservoir in memory B cells. The robust polyclonal germinal center response driven by gammaherpesvirus infection increases the risk for B cell transformation. Unsurprisingly, many gammaherpesvirus cancers are derived from germinal center or post-germinal center B cells. The viral and host factors that influence the gammaherpesvirus-driven germinal center response are not clearly defined. We previously showed that host interleukin 17 receptor A (IL-17RA) signaling promotes the establishment of chronic MHV68 infection and the MHV68-driven germinal center response. In this study, we found that T cell-intrinsic IL-17RA signaling recapitulates some proviral aspects of global IL-17RA signaling during MHV68 infection. Specifically, we found that T cell-intrinsic IL-17RA signaling supports the MHV68-driven germinal center response, the establishment of latency in the spleen, and viral reactivation in the spleen and peritoneal cavity. Our study unveils an unexpected finding where the T cell-specific IL-17RA signaling supports the establishment of a latent reservoir of a B cell-tropic gammaherpesvirus. IMPORTANCE Gammaherpesviruses, such as human EBV, establish lifelong infection in >95% of adults and are associated with B cell lymphomas. Gammaherpesviruses usurp the germinal center response to establish latent infection, and the germinal center B cells are thought to be the target of viral transformation. We previously found that global expression of IL-17RA promotes the establishment of chronic MHV68 infection and the MHV68-driven germinal center response. In this study, we showed that T cell-intrinsic IL-17RA signaling is necessary to promote the MHV68-driven germinal center response by supporting CD4+ T follicular helper cell expansion. We also found that T cell-intrinsic IL-17RA signaling contributes to but is not solely responsible for the systemic proviral role of IL-17RA signaling, highlighting the multifaceted function of IL-17RA signaling during MHV68 infection.
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11
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Zhang XY, Teng QB. Recurrence of infectious mononucleosis in adults after remission for 3 years: A case report. World J Clin Cases 2022; 10:3951-3958. [PMID: 35647138 PMCID: PMC9100724 DOI: 10.12998/wjcc.v10.i12.3951] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/04/2022] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Infectious mononucleosis (IM) is a disease caused by Epstein–Barr virus (EBV). EBV infection is common in children; however, it can cause IM in adults. Studies on recurrence of IM in adults after remission are limited.
CASE SUMMARY We report a 28-year-old man who presented with IM-like symptoms with mild liver damage after initial remission of IM for 3 years. He was first diagnosed with IM and treated in 2015. Follow-up tests in 2016 and 2017 did not show any abnormalities. In November 2018, he presented with swelling of the tonsils. He was misdiagnosed with acute suppurative tonsillitis and treated for 5 d. No signs of improvement were observed. He was readmitted with recurrent fever, pharyngalgia, fatigue, and systemic muscle pain. Examinations revealed enlargement of the tonsils and cervical lymph nodes. Blood tests revealed elevated transaminase levels. Anti-EBV test was positive, indicating virus reactivation. IM recurrence was confirmed on the basis of laboratory tests and clinical manifestations. He was treated with antiviral, anti-infective, and hepatoprotective drugs and vitamin supplements. His condition improved and no abnormalities were observed during follow-up.
CONCLUSION Recurrence of IM after remission is possible in adults; therefore, long-term follow-up and monitoring are essential.
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Affiliation(s)
- Xin-Yue Zhang
- Department of Traditional Chinese Medicine, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou 310052, Zhejiang Province, China
| | - Qi-Bei Teng
- Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang Province, China
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12
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Venkataraman T, Valencia C, Mangino M, Morgenlander W, Clipman SJ, Liechti T, Valencia A, Christofidou P, Spector T, Roederer M, Duggal P, Larman HB. Analysis of antibody binding specificities in twin and SNP-genotyped cohorts reveals that antiviral antibody epitope selection is a heritable trait. Immunity 2022; 55:174-184.e5. [PMID: 35021055 PMCID: PMC8852220 DOI: 10.1016/j.immuni.2021.12.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/19/2021] [Accepted: 12/07/2021] [Indexed: 01/13/2023]
Abstract
Human immune responses to viral infections are highly variable, but the genetic factors that contribute to this variability are not well characterized. We used VirScan, a high-throughput epitope scanning technology, to analyze pan-viral antibody reactivity profiles of twins and SNP-genotyped individuals. Using these data, we determined the heritability and genomic loci associated with antibody epitope selection, response breadth, and control of Epstein-Barr virus (EBV) viral load. 107 EBV peptide reactivities were heritable and at least two Epstein-Barr nuclear antigen 2 (EBNA-2) reactivities were associated with variants in the MHC class II locus. We identified an EBV serosignature that predicted viral load in peripheral blood mononuclear cells and was associated with variants in the MHC class I locus. Our study illustrates the utility of epitope profiling to investigate the genetics of pathogen immunity, reports heritable features of the antibody response to viruses, and identifies specific HLA loci important for EBV epitope selection.
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Affiliation(s)
- Thiagarajan Venkataraman
- Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | - Cristian Valencia
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Massimo Mangino
- Department of Twin Research & Genetic Epidemiology, King’s College of London, London, UK,NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust, London SE1 9RT, UK
| | - William Morgenlander
- Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | - Steven J. Clipman
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Thomas Liechti
- ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA
| | - Ana Valencia
- School of Medicine, Universidad Pontificia Bolivariana, Medellín, Colombia
| | - Paraskevi Christofidou
- Department of Twin Research & Genetic Epidemiology, King’s College of London, London, UK
| | - Tim Spector
- Department of Twin Research & Genetic Epidemiology, King’s College of London, London, UK
| | - Mario Roederer
- ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA
| | - Priya Duggal
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA,Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - H. Benjamin Larman
- Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA,Lead contact,Correspondence: (H.B.L)
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13
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Han S, Tay JK, Loh CJL, Chu AJM, Yeong JPS, Lim CM, Toh HC. Epstein–Barr Virus Epithelial Cancers—A Comprehensive Understanding to Drive Novel Therapies. Front Immunol 2021; 12:734293. [PMID: 34956172 PMCID: PMC8702733 DOI: 10.3389/fimmu.2021.734293] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/12/2021] [Indexed: 12/19/2022] Open
Abstract
Epstein–Barr virus (EBV) is a ubiquitous oncovirus associated with specific epithelial and lymphoid cancers. Among the epithelial cancers, nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma (LELC), and EBV-associated gastric cancers (EBVaGC) are the most common. The role of EBV in the pathogenesis of NPC and in the modulation of its tumour immune microenvironment (TIME) has been increasingly well described. Much less is known about the pathogenesis and tumour–microenvironment interactions in other EBV-associated epithelial cancers. Despite the expression of EBV-related viral oncoproteins and a generally immune-inflamed cancer subtype, EBV-associated epithelial cancers have limited systemic therapeutic options beyond conventional chemotherapy. Immune checkpoint inhibitors are effective only in a minority of these patients and even less efficacious with molecular targeting drugs. Here, we examine the key similarities and differences of NPC, LELC, and EBVaGC and comprehensively describe the clinical, pathological, and molecular characteristics of these cancers. A deeper comparative understanding of these EBV-driven cancers can potentially uncover targets in the tumour, TIME, and stroma, which may guide future drug development and cast light on resistance to immunotherapy.
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Affiliation(s)
- Shuting Han
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joshua K. Tay
- Department of Otolaryngology—Head & Neck Surgery, National University of Singapore, Singapore, Singapore
| | | | | | - Joe Poh Sheng Yeong
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Chwee Ming Lim
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- *Correspondence: Han Chong Toh,
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14
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Wang Y, Luo Y, Tang G, Ouyang R, Zhang M, Jiang Y, Wang T, Zhang X, Yin B, Huang J, Wei W, Huang M, Wang F, Wu S, Hou H. HLA-DR Expression Level in CD8 + T Cells Correlates With the Severity of Children With Acute Infectious Mononucleosis. Front Immunol 2021; 12:753290. [PMID: 34804038 PMCID: PMC8596082 DOI: 10.3389/fimmu.2021.753290] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/14/2021] [Indexed: 01/04/2023] Open
Abstract
Background This study aimed to assess the host immune signatures associated with EBV infection and its clinical value in indicating the severity of children with acute infectious mononucleosis (IM). Methods Twenty-eight pediatric patients with IM aged 3–8 years were enrolled. The immune phenotypes and cytokine secretion capability of T cells were detected. Results The percentages and absolute numbers of CD3+ and CD8+ T cells were significantly increased in IM patients compared with HCs. The percentages of Naïve CD4+ and CD8+ T cells were decreased but with increased percentages of memory CD4+ and CD8+ T subsets. Our results showed the upregulation of active marker HLA-DR, TCR-αβ, and inhibitory receptors PD-1, TIGIT in CD8+ T cells from IM patients, which suggested that effective cytotoxic T cells were highly against EBV infection. However, EBV exposure impaired the cytokine (IFN-γ, IL-2, and TNF-α) secretion capability of CD4+ and CD8+ T cells after stimulation with PMA/ionomycin in vitro. Multivariate analysis revealed that the percentage of HLA-DR+ CD8+ T cells was an independent prognostic marker for IM. The percentage of HLA-DR+ CD8+ T cells was significantly correlated with high viral load and abnormal liver function results. Conclusion Robust expansion and upregulation of HLA-DR in CD8+ T cells, accompanied with impaired cytokine secretion, were typical characteristics of children with acute IM. The percentage of HLA-DR+ CD8+ T cells might be used as a prominent marker not only for the early diagnosis but also for indicating the severity of IM.
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Affiliation(s)
- Yun Wang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Luo
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guoxing Tang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Renren Ouyang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Minxia Zhang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhuan Jiang
- Department of Clinical Laboratory, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ting Wang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiwen Zhang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Botao Yin
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin Huang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wei
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Huang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Wang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiji Wu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyan Hou
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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15
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Reguraman N, Hassani A, Philip P, Khan G. Uncovering early events in primary Epstein-Barr virus infection using a rabbit model. Sci Rep 2021; 11:21220. [PMID: 34707156 PMCID: PMC8551192 DOI: 10.1038/s41598-021-00668-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/11/2021] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is an oncogenic herpesvirus implicated in the pathogenesis of several malignant and non-malignant conditions. However, a number of fundamental aspects about the biology of EBV and the mechanism(s) by which this virus induces pathology remain unknown. One major obstacle has been the lack of a suitable animal model for EBV infection. In this study, using our recently established rabbit model of EBV infection, we examined the early events following primary EBV infection. We show that, both immunocompetent and immunosuppressed animals were readily susceptible to EBV infection. However, immunosuppressed animals showed marked splenomegaly and widespread infection. Following EBV infection, the virus primarily targeted naïve IgM+, CD20+, CD21+ and CD79a+ B cells. Infected cells expressed varying sets of viral latent/lytic gene products. Notably, co-expression of latent and lytic proteins in the same cell was not observed. Infected cells in type 0/1 latency (EBERs+), were small and proliferating (Ki67+). By contrast, cells in type 2/3 latency (LMP1+), were large, non-proliferating (Ki-67-) and p53+. Although infected B-cells were widely present in splenic follicles, they did not express germinal center marker, BCL-6. Taken together, this study shows for the first time, some of the early events following primary EBV infection.
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Affiliation(s)
- Narendran Reguraman
- Department of Microbiology and Immunology, College of Medicine and Health Sciences, Tawam Hospital Campus, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Asma Hassani
- Department of Microbiology and Immunology, College of Medicine and Health Sciences, Tawam Hospital Campus, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Pretty Philip
- Department of Microbiology and Immunology, College of Medicine and Health Sciences, Tawam Hospital Campus, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Gulfaraz Khan
- Department of Microbiology and Immunology, College of Medicine and Health Sciences, Tawam Hospital Campus, United Arab Emirates University, Al Ain, United Arab Emirates.
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16
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Blazquez-Navarro A, Dang-Heine C, Wehler P, Roch T, Bauer C, Neumann S, Blazquez-Navarro R, Kurchenko A, Wolk K, Sabat R, Westhoff TH, Olek S, Thomusch O, Seitz H, Reinke P, Hugo C, Sawitzki B, Or-Guil M, Babel N. Risk factors for Epstein-Barr virus reactivation after renal transplantation: Results of a large, multi-centre study. Transpl Int 2021; 34:1680-1688. [PMID: 34448272 DOI: 10.1111/tri.13982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/15/2021] [Accepted: 07/15/2021] [Indexed: 01/02/2023]
Abstract
Epstein-Barr virus (EBV) reactivation is a very common and potentially lethal complication of renal transplantation. However, its risk factors and effects on transplant outcome are not well known. Here, we have analysed a large, multi-centre cohort (N = 512) in which 18.4% of the patients experienced EBV reactivation during the first post-transplant year. The patients were characterized pre-transplant and two weeks post-transplant by a multi-level biomarker panel. EBV reactivation was episodic for most patients, only 12 patients showed prolonged viraemia for over four months. Pre-transplant EBV shedding and male sex were associated with significantly increased incidence of post-transplant EBV reactivation. Importantly, we also identified a significant association of post-transplant EBV with acute rejection and with decreased haemoglobin levels. No further severe complications associated with EBV, either episodic or chronic, could be detected. Our data suggest that despite relatively frequent EBV reactivation, it had no association with serious complications during the first post-transplantation year. EBV shedding prior to transplantation could be employed as biomarkers for personalized immunosuppressive therapy. In summary, our results support the employed immunosuppressive regimes as relatively safe with regard to EBV. However, long-term studies are paramount to support these conclusions.
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Affiliation(s)
- Arturo Blazquez-Navarro
- Systems Immunology Lab, Department of Biology, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Center for Translational Medicine, Universitätsklinikum der Ruhr-Universität Bochum, Medizinische Klinik I, Herne, Germany
| | - Chantip Dang-Heine
- Clinical Study Center (CSC), Berlin Institute of Health, and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Patrizia Wehler
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Center for Translational Medicine, Universitätsklinikum der Ruhr-Universität Bochum, Medizinische Klinik I, Herne, Germany
| | - Toralf Roch
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Center for Translational Medicine, Universitätsklinikum der Ruhr-Universität Bochum, Medizinische Klinik I, Herne, Germany
| | | | | | | | - Andriy Kurchenko
- Department of Clinical Immunology and Allergology, Bogolomets National Medical University, Kiev, Ukraine
| | - Kerstin Wolk
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Psoriasis Research and Treatment Center, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Robert Sabat
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Psoriasis Research and Treatment Center, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Timm H Westhoff
- Center for Translational Medicine, Universitätsklinikum der Ruhr-Universität Bochum, Medizinische Klinik I, Herne, Germany
| | - Sven Olek
- Ivana Türbachova Laboratory for Epigenetics, Epiontis GmbH, Precision for Medicine Group, Berlin, Germany
| | - Oliver Thomusch
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg, Freiburg, Germany
| | - Harald Seitz
- Fraunhofer Institute for Cell Therapy and Immunology, Branch Bioanalytics und Bioprocesses, Leipzig, Germany
| | - Petra Reinke
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Christian Hugo
- Universitätsklinikum Carl Gustav Carus, Medizinische Klinik III - Bereich Nephrologie, Dresden, Germany
| | - Birgit Sawitzki
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Michal Or-Guil
- Systems Immunology Lab, Department of Biology, Humboldt-Universität zu Berlin, Berlin, Germany.,Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Nina Babel
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Center for Translational Medicine, Universitätsklinikum der Ruhr-Universität Bochum, Medizinische Klinik I, Herne, Germany
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17
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T cell-intrinsic Interferon Regulatory Factor-1 expression suppresses differentiation of CD4 + T cell populations that support chronic gammaherpesvirus infection. J Virol 2021; 95:e0072621. [PMID: 34346769 DOI: 10.1128/jvi.00726-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Gammaherpesviruses are ubiquitous pathogens that establish life-long infection and are associated with B cell lymphomas. To establish chronic infection, these viruses usurp B cell differentiation and drive a robust germinal center response to expand the latent viral reservoir and gain access to memory B cells. Germinal center B cells, while important for the establishment of latent infection, are also thought to be the target of viral transformation. The host and viral factors that impact the gammaherpesvirus-driven germinal center response are not clearly defined. We showed that global expression of the antiviral and tumor-suppressor interferon regulatory factor 1 (IRF-1) selectively attenuates the murine gammaherpesvirus 68 (MHV68)-driven germinal center response and restricts expansion of the latent viral reservoir. In this study we found that T cell intrinsic IRF-1 expression recapitulates some aspects of antiviral state imposed by IRF-1 during chronic MHV68 infection, including attenuation of the germinal center response and viral latency in the spleen. We also discovered that global and T cell-intrinsic IRF-1 deficiency leads to unhindered rise of IL-17A-expressing and follicular helper T cell populations, two CD4+ T cell subsets that support chronic MHV68 infection. Thus, this study unveils a novel aspect of antiviral activity of IRF-1 by demonstrating IRF-1-mediated suppression of specific CD4+ T cell subsets that support chronic gammaherpesvirus infection. Importance Gammaherpesviruses infect over 95% of the adult population, last the lifetime of the host, and are associated with multiple cancers. These viruses usurp the germinal center response to establish lifelong infection in memory B cells. This manipulation of B cell differentiation by the virus is thought to contribute to lymphomagenesis, though exactly how the virus precipitates malignant transformation in vivo is unclear. IRF-1, a host transcription factor and a known tumor suppressor, restricts the MHV68-driven germinal center response in a B cell-extrinsic manner. We found that T cell intrinsic IRF-1 expression attenuates the MHV68-driven germinal center response by restricting the CD4+ T follicular helper population. Further, our study identified IRF-1 as a novel negative regulator of IL-17-driven immune responses, highlighting the multifaceted role of IRF-1 in gammaherpesvirus infection.
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18
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Ahmed EH, Brooks E, Sloan S, Schlotter S, Jeney F, Hale C, Mao C, Zhang X, McLaughlin E, Shindiapina P, Shire S, Das M, Prouty A, Lozanski G, Mamuye AT, Abebe T, Alinari L, Caligiuri MA, Baiocchi RA. Targeted Delivery of BZLF1 to DEC205 Drives EBV-Protective Immunity in a Spontaneous Model of EBV-Driven Lymphoproliferative Disease. Vaccines (Basel) 2021; 9:555. [PMID: 34073261 PMCID: PMC8228306 DOI: 10.3390/vaccines9060555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/14/2021] [Accepted: 05/20/2021] [Indexed: 12/14/2022] Open
Abstract
Epstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the world's population and is linked to development of cancer. In immune-competent individuals, EBV infection is mitigated by a highly efficient virus-specific memory T-cell response. Risk of EBV-driven cancers increases with immune suppression (IS). EBV-seronegative recipients of solid organ transplants are at high risk of developing post-transplant lymphoproliferative disease (PTLD) due to iatrogenic IS. While reducing the level of IS may improve EBV-specific immunity and regression of PTLD, patients are at high risk for allograft rejection and need for immune-chemotherapy. Strategies to prevent PTLD in this vulnerable patient population represents an unmet need. We have previously shown that BZLF1-specific cytotoxic T-cell (CTL) expansion following reduced IS correlated with immune-mediated PTLD regression and improved patient survival. We have developed a vaccine to bolster EBV-specific immunity to the BZLF1 protein and show that co-culture of dendritic cells (DCs) loaded with a αDEC205-BZLF1 fusion protein with peripheral blood mononuclear cells (PMBCs) leads to expansion and increased cytotoxic activity of central-effector memory CTLs against EBV-transformed B-cells. Human-murine chimeric Hu-PBL-SCID mice were vaccinated with DCs loaded with αDEC205-BZLF1 or control to assess prevention of fatal human EBV lymphoproliferative disease. Despite a profoundly immunosuppressive environment, vaccination with αDEC205-BZLF1 stimulated clonal expansion of antigen-specific T-cells that produced abundant IFNγ and significantly prolonged survival. These results support preclinical and clinical development of vaccine approaches using BZLF1 as an immunogen to harness adaptive cellular responses and prevent PTLD in vulnerable patient populations.
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Affiliation(s)
- Elshafa Hassan Ahmed
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA; (E.H.A.); (S.S.)
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
| | - Eric Brooks
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
| | - Shelby Sloan
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA; (E.H.A.); (S.S.)
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
| | - Sarah Schlotter
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
| | - Frankie Jeney
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
| | - Claire Hale
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH 43210, USA;
| | - Charlene Mao
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
| | - Xiaoli Zhang
- Department of Biomedical Informatics/Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA; (X.Z.); (E.M.)
| | - Eric McLaughlin
- Department of Biomedical Informatics/Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA; (X.Z.); (E.M.)
| | - Polina Shindiapina
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Salma Shire
- College of Education and Human Ecology, The Ohio State University, Columbus, OH 43210, USA;
| | - Manjusri Das
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
| | - Alexander Prouty
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
| | - Gerard Lozanski
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA;
| | - Admasu T. Mamuye
- Department of Internal Medicine, Black Lion Hospital, Addis Ababa University, Addis Ababa 3614, Ethiopia;
| | - Tamrat Abebe
- Department of Microbiology, Black Lion Hospital, Addis Ababa University, Addis Ababa 3614, Ethiopia;
| | - Lapo Alinari
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | | | - Robert A. Baiocchi
- Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; (E.B.); (S.S.); (F.J.); (C.M.); (P.S.); (M.D.); (A.P.); (L.A.)
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
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19
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Fournier B, Boutboul D, Bruneau J, Miot C, Boulanger C, Malphettes M, Pellier I, Dunogué B, Terrier B, Suarez F, Blanche S, Castelle M, Winter S, Delecluse HJ, Molina T, Picard C, Ehl S, Moshous D, Galicier L, Barlogis V, Fischer A, Neven B, Latour S. Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection. J Exp Med 2021; 217:152032. [PMID: 32812031 PMCID: PMC7596820 DOI: 10.1084/jem.20192262] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 05/29/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.
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Affiliation(s)
- Benjamin Fournier
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, Imagine Institute, Paris, France.,Université de Paris, Paris, France
| | - David Boutboul
- Department of Clinical Immunology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Julie Bruneau
- Université de Paris, Paris, France.,Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Charline Miot
- Department of Pediatric Immunology Hematology and Oncology, University Hospital, Angers, France
| | - Cécile Boulanger
- Institut Roi Albert II, Cancerology and Hematology Departments, University Clinics Saint-Luc Hospital, Brussels, Belgium
| | - Marion Malphettes
- Department of Clinical Immunology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Isabelle Pellier
- Department of Pediatric Immunology Hematology and Oncology, University Hospital, Angers, France
| | - Bertrand Dunogué
- Department of Internal Medicine, Cochin Hospital, National Referral Centre for Systemic and Autoimmune Diseases, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Benjamin Terrier
- Department of Internal Medicine, Cochin Hospital, National Referral Centre for Systemic and Autoimmune Diseases, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Felipe Suarez
- Department of Adult Hematology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Stéphane Blanche
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Martin Castelle
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Sarah Winter
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Henri-Jacques Delecluse
- Unit F100, Institut National de la Santé et de la Recherche Médicale U1074, Deutsches Krebsforschungszentrum, German Cancer Research Center, Heidelberg, Germany
| | - Thierry Molina
- Université de Paris, Paris, France.,Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Capucine Picard
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, Imagine Institute, Paris, France.,Université de Paris, Paris, France.,Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Stephan Ehl
- Institute for Immunodeficiency-Center for Chronic Immunodeficiency, Department of Pediatrics and Adolescent Medicine, Medical Center - Faculty of Medicine, University of Freiburg, Germany
| | - Despina Moshous
- Université de Paris, Paris, France.,Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Lionel Galicier
- Department of Clinical Immunology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Vincent Barlogis
- Department of Pediatric Hematology-Oncology, La Timone Hospital, Marseille, France
| | - Alain Fischer
- Université de Paris, Paris, France.,Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.,Collège de France, Paris, France.,Institut National de la Santé et de la Recherche Médicale UMR 1163, Paris, France
| | - Bénédicte Neven
- Université de Paris, Paris, France.,Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Sylvain Latour
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, Imagine Institute, Paris, France.,Université de Paris, Paris, France
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Assing K, Nielsen C, Jakobsen M, Andersen CB, Skogstrand K, Gaini S, Preiss B, Mortensen SB, Skov MN, Rasmussen LD. Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report. BMC Infect Dis 2020; 20:878. [PMID: 33228556 PMCID: PMC7685648 DOI: 10.1186/s12879-020-05609-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 11/10/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. CASE PRESENTATION We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman's rho: - 0.86, p < 0.001. CONCLUSIONS To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.
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Affiliation(s)
- Kristian Assing
- Department of Clinical Immunology, Odense University Hospital, J.B. Winsloevs Vej 4, 5000, Odense, Denmark.
| | - Christian Nielsen
- Department of Clinical Immunology, Odense University Hospital, J.B. Winsloevs Vej 4, 5000, Odense, Denmark
| | - Marianne Jakobsen
- Department of Clinical Immunology, Odense University Hospital, J.B. Winsloevs Vej 4, 5000, Odense, Denmark
| | | | - Kristin Skogstrand
- Department of Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark
| | - Shahin Gaini
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
| | - Birgitte Preiss
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Sussi Bagge Mortensen
- Department of Clinical Immunology, Odense University Hospital, J.B. Winsloevs Vej 4, 5000, Odense, Denmark
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21
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Bajda S, Blazquez-Navarro A, Samans B, Wehler P, Kaliszczyk S, Amini L, Schmueck-Henneresse M, Witzke O, Dittmer U, Westhoff TH, Viebahn R, Reinke P, Thomusch O, Hugo C, Olek S, Roch T, Babel N. The role of soluble mediators in the clinical course of EBV infection and B cell homeostasis after kidney transplantation. Sci Rep 2020; 10:19594. [PMID: 33177622 PMCID: PMC7658229 DOI: 10.1038/s41598-020-76607-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 09/24/2020] [Indexed: 01/13/2023] Open
Abstract
Epstein-Barr virus (EBV) reactivation can lead to serious complications in kidney transplant patients, including post-transplant lymphoproliferative disorder (PTLD). Here, we have assessed the impact of EBV on B cell homeostasis at cellular and humoral level. In a multicenter study monitoring 540 kidney transplant patients during the first post-transplant year, EBV reactivation was detected in 109 patients. Thirteen soluble factors and B cell counts were analyzed in an EBV+ sub-cohort (N = 54) before, at peak and after EBV clearance and compared to a control group (N = 50). The B cell activating factor (BAFF) was significantly elevated among EBV+ patients. No additional soluble factors were associated with EBV. Importantly, in vitro experiments confirmed the proliferative effect of BAFF on EBV-infected B cells, simultaneously promoting EBV production. In contrast, elevated levels of BAFF in EBV+ patients did not lead to B cell expansion in vivo. Moreover, diminished positive inter-correlations of soluble factors and alterations of the bi-directional interplay between B cell and soluble factors were observed in EBV+ patients at peak and after clearance. Our data suggest that such alterations may counteract the proliferative effect of BAFF, preventing B cell expansion. The role of these alterations in lymphoma development should be analyzed in future studies.
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Affiliation(s)
- Sharon Bajda
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Arturo Blazquez-Navarro
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Systems Immunology Lab, Department of Biology, Humboldt-Universität zu Berlin, Berlin, Germany
- Medical Department I, Center for Translational Medicine, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany
| | - Björn Samans
- Ivana Türbachova Laboratory for Epigenetics, Epiontis GmbH, Precision for Medicine Group, Berlin, Germany
| | - Patrizia Wehler
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Medical Department I, Center for Translational Medicine, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany
| | - Sviatlana Kaliszczyk
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Medical Department I, Center for Translational Medicine, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany
| | - Leila Amini
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Schmueck-Henneresse
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver Witzke
- Department of Infectious Diseases, Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Department of Infectious Diseases, Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Timm H Westhoff
- Medical Department I, Center for Translational Medicine, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany
| | - Richard Viebahn
- Chirurgical University Hospital, University Hospital Knappschaftskrankenhaus Bochum, University Hospital of the Ruhr-University Bochum, Bochum, Germany
| | - Petra Reinke
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver Thomusch
- Department of General Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Christian Hugo
- Medical Clinic 3 - Nephrology Unit, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Sven Olek
- Ivana Türbachova Laboratory for Epigenetics, Epiontis GmbH, Precision for Medicine Group, Berlin, Germany
| | - Toralf Roch
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Medical Department I, Center for Translational Medicine, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany
| | - Nina Babel
- Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité-Universitätsmedizin Berlin, Berlin, Germany.
- Medical Department I, Center for Translational Medicine, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany.
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22
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Epstein-Barr Virus Promotes B Cell Lymphomas by Manipulating the Host Epigenetic Machinery. Cancers (Basel) 2020; 12:cancers12103037. [PMID: 33086505 PMCID: PMC7603164 DOI: 10.3390/cancers12103037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 12/28/2022] Open
Abstract
Simple Summary Epstein-Barr Virus (EBV)-induced lymphomas have a significant global incidence, given the widespread infection to the human population. EBV adopts several mechanisms to replicate and persist in the host, by hijacking its epigenetic machinery. The main topic of this review details the current insights of EBV interactions with the host epigenetic system, and it will be discussed the potential relationship between the EBV-induced chronic inflammation and the dysregulation of epigenetic modifiers that might lead to tumorigenesis. Promising novel therapies against several types of cancer involve the use of epigenetic modifier inhibitors. To design new therapeutical strategies targeting lymphomas, it is crucial to conduct exhaustive reaserch on the regulation of these enzymes. Abstract During the past decade, the rapid development of high-throughput next-generation sequencing technologies has significantly reinforced our understanding of the role of epigenetics in health and disease. Altered functions of epigenetic modifiers lead to the disruption of the host epigenome, ultimately inducing carcinogenesis and disease progression. Epstein–Barr virus (EBV) is an endemic herpesvirus that is associated with several malignant tumours, including B-cell related lymphomas. In EBV-infected cells, the epigenomic landscape is extensively reshaped by viral oncoproteins, which directly interact with epigenetic modifiers and modulate their function. This process is fundamental for the EBV life cycle, particularly for the establishment and maintenance of latency in B cells; however, the alteration of the host epigenetic machinery also contributes to the dysregulated expression of several cellular genes, including tumour suppressor genes, which can drive lymphoma development. This review outlines the molecular mechanisms underlying the epigenetic manipulation induced by EBV that lead to transformed B cells, as well as novel therapeutic interventions to target EBV-associated B-cell lymphomas.
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23
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Jondle CN, Tarakanova VL. Innate immunity and alpha/gammaherpesviruses: first impressions last a lifetime. Curr Opin Virol 2020; 44:81-89. [PMID: 32777757 DOI: 10.1016/j.coviro.2020.07.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 06/25/2020] [Accepted: 07/04/2020] [Indexed: 12/26/2022]
Abstract
Innate immune system is considered the first line of defense during viral invasion, with the wealth of the literature demonstrating innate immune control of diverse viruses during acute infection. What is far less clear is the role of innate immune system during chronic virus infections. This short review focuses on alphaherpesviruses and gammaherpesviruses, two highly prevalent herpesvirus subfamilies that, following a brief, once in a lifetime period of acute lytic infection, establish life-long latent infection that is characterized by sporadic reactivation in an immunocompetent host. In spite of many similarities, these two viral families are characterized by distinct cellular tropism and pathogenesis. Here we focus on the published in vivo studies to review known interactions of these two viral subfamilies with the innate immunity of the intact host, both during acute and, particularly, chronic virus infection.
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Affiliation(s)
- Christopher N Jondle
- Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 W Watertown Plank Road, Milwaukee, WI, 53226, United States
| | - Vera L Tarakanova
- Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 W Watertown Plank Road, Milwaukee, WI, 53226, United States; Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, United States.
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24
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B Cell-Intrinsic Expression of Interferon Regulatory Factor 1 Supports Chronic Murine Gammaherpesvirus 68 Infection. J Virol 2020; 94:JVI.00399-20. [PMID: 32321819 DOI: 10.1128/jvi.00399-20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/10/2020] [Indexed: 02/07/2023] Open
Abstract
Gammaherpesviruses are ubiquitous pathogens that are associated with cancers, including B cell lymphomas. These viruses are unique in that they infect naive B cells and subsequently drive a robust polyclonal germinal center response in order to amplify the latent reservoir and to establish lifelong infection in memory B cells. The gammaherpesvirus-driven germinal center response in combination with robust infection of germinal center B cells is thought to precipitate lymphomagenesis. Importantly, host and viral factors that selectively affect the gammaherpesvirus-driven germinal center response remain poorly understood. Global deficiency of antiviral tumor-suppressive interferon regulatory factor 1 (IRF-1) selectively promotes the murine gammaherpesvirus 68 (MHV68)-driven germinal center response and expansion of the viral latent reservoir. To determine the extent to which antiviral effects of IRF-1 are B cell intrinsic, we generated mice with conditional IRF-1 deficiency. Surprisingly, B cell-specific IRF-1 deficiency attenuated the establishment of chronic infection and the germinal center response, indicating that MHV68 may, in a B cell-intrinsic manner, usurp IRF-1 to promote the germinal center response and expansion of the latent reservoir. Further, we found that B cell-specific IRF-1 deficiency led to reduced levels of active tyrosine phosphatase SHP1, which plays a B cell-intrinsic proviral function during MHV68 infection. Finally, results of this study indicate that the antiviral functions of IRF-1 unveiled in MHV68-infected mice with global IRF-1 deficiency are mediated via IRF-1 expression by non-B cell populations.IMPORTANCE Gammaherpesviruses establish lifelong infection in over 95% of all adults and are associated with B cell lymphomas. The virus's manipulation of the germinal center response and B cell differentiation to establish lifelong infection is thought to also precipitate malignant transformation, through a mechanism that remains poorly understood. The host transcription factor IRF-1, a well-established tumor suppressor, selectively attenuates MHV68-driven germinal center response, a phenotype that we originally hypothesized to occur in a B cell-intrinsic manner. In contrast, in testing, B cell-intrinsic IRF-1 expression promoted the MHV68-driven germinal center response and the establishment of chronic infection. Our report highlights the underappreciated multifaceted role of IRF-1 in MHV68 infection and pathogenesis.
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25
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Germini D, Sall FB, Shmakova A, Wiels J, Dokudovskaya S, Drouet E, Vassetzky Y. Oncogenic Properties of the EBV ZEBRA Protein. Cancers (Basel) 2020; 12:E1479. [PMID: 32517128 PMCID: PMC7352903 DOI: 10.3390/cancers12061479] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/03/2020] [Accepted: 06/04/2020] [Indexed: 12/14/2022] Open
Abstract
Epstein Barr Virus (EBV) is one of the most common human herpesviruses. After primary infection, it can persist in the host throughout their lifetime in a latent form, from which it can reactivate following specific stimuli. EBV reactivation is triggered by transcriptional transactivator proteins ZEBRA (also known as Z, EB-1, Zta or BZLF1) and RTA (also known as BRLF1). Here we discuss the structural and functional features of ZEBRA, its role in oncogenesis and its possible implication as a prognostic or diagnostic marker. Modulation of host gene expression by ZEBRA can deregulate the immune surveillance, allow the immune escape, and favor tumor progression. It also interacts with host proteins, thereby modifying their functions. ZEBRA is released into the bloodstream by infected cells and can potentially penetrate any cell through its cell-penetrating domain; therefore, it can also change the fate of non-infected cells. The features of ZEBRA described in this review outline its importance in EBV-related malignancies.
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Affiliation(s)
- Diego Germini
- CNRS UMR9018, Université Paris-Saclay, Institut Gustave Roussy, 94805 Villejuif, France; (D.G.); (F.B.S.); (A.S.); (J.W.); (S.D.)
| | - Fatimata Bintou Sall
- CNRS UMR9018, Université Paris-Saclay, Institut Gustave Roussy, 94805 Villejuif, France; (D.G.); (F.B.S.); (A.S.); (J.W.); (S.D.)
- Laboratory of Hematology, Aristide Le Dantec Hospital, Cheikh Anta Diop University, Dakar 12900, Senegal
| | - Anna Shmakova
- CNRS UMR9018, Université Paris-Saclay, Institut Gustave Roussy, 94805 Villejuif, France; (D.G.); (F.B.S.); (A.S.); (J.W.); (S.D.)
| | - Joëlle Wiels
- CNRS UMR9018, Université Paris-Saclay, Institut Gustave Roussy, 94805 Villejuif, France; (D.G.); (F.B.S.); (A.S.); (J.W.); (S.D.)
| | - Svetlana Dokudovskaya
- CNRS UMR9018, Université Paris-Saclay, Institut Gustave Roussy, 94805 Villejuif, France; (D.G.); (F.B.S.); (A.S.); (J.W.); (S.D.)
| | - Emmanuel Drouet
- CIBB-IBS UMR 5075 Université Grenoble Alpes, 38044 Grenoble, France;
| | - Yegor Vassetzky
- CNRS UMR9018, Université Paris-Saclay, Institut Gustave Roussy, 94805 Villejuif, France; (D.G.); (F.B.S.); (A.S.); (J.W.); (S.D.)
- Koltzov Institute of Developmental Biology, 117334 Moscow, Russia
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26
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Identification and Cloning of a New Western Epstein-Barr Virus Strain That Efficiently Replicates in Primary B Cells. J Virol 2020; 94:JVI.01918-19. [PMID: 32102884 DOI: 10.1128/jvi.01918-19] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 02/14/2020] [Indexed: 11/20/2022] Open
Abstract
The Epstein-Barr virus (EBV) causes human cancers, and epidemiological studies have shown that lytic replication is a risk factor for some of these tumors. This fits with the observation that EBV M81, which was isolated from a Chinese patient with nasopharyngeal carcinoma, induces potent virus production and increases the risk of genetic instability in infected B cells. To find out whether this property extends to viruses found in other parts of the world, we investigated 22 viruses isolated from Western patients. While one-third of the viruses hardly replicated, the remaining viruses showed variable levels of replication, with three isolates replicating at levels close to that of M81 in B cells. We cloned one strongly replicating virus into a bacterial artificial chromosome (BAC); the resulting recombinant virus (MSHJ) retained the properties of its nonrecombinant counterpart and showed similarities to M81, undergoing lytic replication in vitro and in vivo after 3 weeks of latency. In contrast, B cells infected with the nonreplicating Western B95-8 virus showed early but abortive replication accompanied by cytoplasmic BZLF1 expression. Sequencing confirmed that rMSHJ is a Western virus, being genetically much closer to B95-8 than to M81. Spontaneous replication in rM81- and rMSHJ-infected B cells was dependent on phosphorylated Btk and was inhibited by exposure to ibrutinib, opening the way to clinical intervention in patients with abnormal EBV replication. As rMSHJ contains the complete EBV genome and induces lytic replication in infected B cells, it is ideal to perform genetic analyses of all viral functions in Western strains and their associated diseases.IMPORTANCE The Epstein-Barr virus (EBV) infects the majority of the world population but causes different diseases in different countries. Evidence that lytic replication, the process that leads to new virus progeny, is linked to cancer development is accumulating. Indeed, viruses such as M81 that were isolated from Far Eastern nasopharyngeal carcinomas replicate strongly in B cells. We show here that some viruses isolated from Western patients, including the MSHJ strain, share this property. Moreover, replication of both M81 and of MSHJ was sensitive to ibrutinib, a commonly used drug, thereby opening an opportunity for therapeutic intervention. Sequencing of MSHJ showed that this virus is quite distant from M81 and is much closer to nonreplicating Western viruses. We conclude that Western EBV strains are heterogeneous, with some viruses being able to replicate more strongly and therefore being potentially more pathogenic than others, and that the virus sequence information alone cannot predict this property.
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27
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Yunis J, Redwood AJ, Belz GT, Stevenson PG. Membrane association of a model CD4 + T-cell vaccine antigen confers enhanced yet incomplete protection against murid herpesvirus-4 infection. Immunol Cell Biol 2020; 98:332-343. [PMID: 31997396 DOI: 10.1111/imcb.12319] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/20/2020] [Accepted: 01/27/2020] [Indexed: 12/14/2022]
Abstract
Vaccination against γ-herpesviruses has proved difficult. CD4+ T cells are essential to contain infection, but how best to prime them and whether this can reduce viral loads remain unclear. To address these questions, we used ovalbumin (OVA) as a model antigen, delivering it with murine cytomegalovirus (MCMV) to protect mice against OVA-expressing murine herpesvirus-4 (MuHV-4). Membrane-associated OVA (mOVA) was more effective than soluble OVA, both to prime CD4+ T cells and as an effector target. It was also a better target than an OVA epitope limited to infected cells, suggesting that protective CD4+ T cells recognize infected cell debris rather than infected cells themselves. While MCMV-mOVA protected acutely against MuHV-4-mOVA, long-term protection was incomplete, even when OVA-specific CD8+ T cells and B cells were also primed. Thus, even optimized single-target vaccines may poorly reduce long-term γ-herpesvirus infections.
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Affiliation(s)
- Joseph Yunis
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia
| | - Alec J Redwood
- Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia
| | - Gabrielle T Belz
- Molecular Immunology, Walter and Eliza Hall Institute, Melbourne, VIC, Australia
| | - Philip G Stevenson
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia
- Royal Children's Hospital, Brisbane, QLD, Australia
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Zachova K, Kosztyu P, Zadrazil J, Matousovic K, Vondrak K, Hubacek P, Julian BA, Moldoveanu Z, Novak Z, Kostovcikova K, Raska M, Mestecky J. Role of Epstein-Barr Virus in Pathogenesis and Racial Distribution of IgA Nephropathy. Front Immunol 2020; 11:267. [PMID: 32184780 PMCID: PMC7058636 DOI: 10.3389/fimmu.2020.00267] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/03/2020] [Indexed: 02/04/2023] Open
Abstract
IgA nephropathy (IgAN) is the dominant type of primary glomerulonephritis worldwide. However, IgAN rarely affects African Blacks and is uncommon in African Americans. Polymeric IgA1 with galactose-deficient hinge-region glycans is recognized as auto-antigen by glycan-specific antibodies, leading to formation of circulating immune complexes with nephritogenic consequences. Because human B cells infected in vitro with Epstein-Barr virus (EBV) secrete galactose-deficient IgA1, we examined peripheral blood B cells from adult IgAN patients, and relevant controls, for the presence of EBV and their phenotypic markers. We found that IgAN patients had more lymphoblasts/plasmablasts that were surface-positive for IgA, infected with EBV, and displayed increased expression of homing receptors for targeting the upper respiratory tract. Upon polyclonal stimulation, these cells produced more galactose-deficient IgA1 than did cells from healthy controls. Unexpectedly, in healthy African Americans, EBV was detected preferentially in surface IgM- and IgD-positive cells. Importantly, most African Blacks and African Americans acquire EBV within 2 years of birth. At that time, the IgA system is naturally deficient, manifested as low serum IgA levels and few IgA-producing cells. Consequently, EBV infects cells secreting immunoglobulins other than IgA. Our novel data implicate Epstein-Barr virus infected IgA+ cells as the source of galactose-deficient IgA1 and basis for expression of relevant homing receptors. Moreover, the temporal sequence of racial-specific differences in Epstein-Barr virus infection as related to the naturally delayed maturation of the IgA system explains the racial disparity in the prevalence of IgAN.
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Affiliation(s)
- Katerina Zachova
- Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia
| | - Petr Kosztyu
- Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia
| | - Josef Zadrazil
- Department of Internal Medicine III Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia
| | - Karel Matousovic
- Department of Medicine, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czechia
| | - Karel Vondrak
- Department of Pediatrics, Second Faculty of Medicine, Charles University, Prague, Czechia
| | - Petr Hubacek
- Department of Medical Microbiology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czechia
| | - Bruce A Julian
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Zina Moldoveanu
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Zdenek Novak
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Klara Kostovcikova
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology, Czech Academy of Sciences, Prague, Czechia
| | - Milan Raska
- Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia.,Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jiri Mestecky
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.,Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States.,Laboratory of Cellular and Molecular Immunology, Institute of Microbiology, Czech Academy of Sciences, Prague, Czechia
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29
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Lawler C, Stevenson PG. Limited protection against γ-herpesvirus infection by replication-deficient virus particles. J Gen Virol 2020; 101:420-425. [PMID: 31985394 DOI: 10.1099/jgv.0.001391] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The γ-herpesviruses have proved hard to vaccination against, with no convincing protection against long-term latent infection by recombinant viral subunits. In experimental settings, whole-virus vaccines have proved more effective, even when the vaccine virus itself establishes latent infection poorly. The main alternative is replication-deficient virus particles. Here high-dose, replication-deficient murid herpesvirus-4 only protected mice partially against wild-type infection. By contrast, latency-deficient but replication-competent vaccine protected mice strongly, even when delivered non-invasively to the olfactory epithelium. Thus, this approach seems to provide the best chance of a safe and effective γ-herpesvirus vaccine.
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Affiliation(s)
- Clara Lawler
- Present address: School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.,School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia
| | - Philip G Stevenson
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.,Child Health Research Center, University of Queensland, South Brisbane, Australia
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30
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Kedi W, Dongjiang X, Zhi L, Yan G, Kun J, Jianrong S. The rational specimen for the quantitative detection of Epstein-Barr virus DNA load. Clin Chem Lab Med 2019; 57:759-765. [PMID: 30267627 DOI: 10.1515/cclm-2018-0733] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 08/28/2018] [Indexed: 12/15/2022]
Abstract
Background Epstein-Barr virus (EBV) DNA load monitoring in blood is essential for the diagnosis of EBV-associated diseases. However, the best-suited blood compartment for detection is still under discussion. The aim of this study was to evaluate the diagnostic value of EBV-DNA load in peripheral blood mononuclear cells (PBMC), plasma and whole blood (WB) samples. Methods A total of 156 patients, including 45 patients with infectious mononucleosis (IM), 57 patients with EBV-associated hemophagocytic lymphohistiocytosis (HLH) and 54 patients with post-transplant lymphoproliferative disorders (PTLD), were enrolled in this study. The EBV-DNA load in PBMC, plasma and WB samples were measured with real-time quantitative polymerase chain reaction (PCR). Results EBV-DNA load of patients with HLH showed no statistical difference in PBMC, plasma and WB samples, while patients with IM and PTLD showed a higher viral load in PBMC samples. The strongest correlation of EBV-DNA level was found between PBMC and WB samples among patients with IM, HLH and PTLD. The follow-up of EBV-DNA showed that the viral load became negative along with the recovery from the disease, while that in WB and PBMC would remain positive for a long time. Conclusions For the diagnosis and monitoring of EBV-DNA, the type of specimen should be chosen reasonably according to the disease. As for IM and HLH, plasma is recommended to quantify the EBV-DNA load, while PBMC and plasma are preferred in PTLD.
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Affiliation(s)
- Wang Kedi
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China
| | - Xu Dongjiang
- Clinical Laboratory, Beijing Jishuitan Hospital, Peking University, Beijing, P.R. China
| | - Lv Zhi
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China
| | - Gao Yan
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China
| | - Jia Kun
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China
| | - Su Jianrong
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
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31
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Lawler C, Simas JP, Stevenson PG. Vaccine protection against murid herpesvirus-4 is maintained when the priming virus lacks known latency genes. Immunol Cell Biol 2019; 98:67-78. [PMID: 31630452 DOI: 10.1111/imcb.12299] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 10/13/2019] [Accepted: 10/16/2019] [Indexed: 11/30/2022]
Abstract
γ-Herpesviruses establish latent infections of lymphocytes and drive their proliferation, causing cancers and motivating a search for vaccines. Effective vaccination against murid herpesvirus-4 (MuHV-4)-driven lymphoproliferation by latency-impaired mutant viruses suggests that lytic access to the latency reservoir is a viable target for control. However, the vaccines retained the immunogenic MuHV-4 M2 latency gene. Here, a strong reduction in challenge virus load was maintained when the challenge virus lacked the main latency-associated CD8+ T-cell epitope of M2, or when the vaccine virus lacked M2 entirely. This protection was maintained also when the vaccine virus lacked both episome maintenance and the genomic region encompassing M1, M2, M3, M4 and ORF4. Therefore, protection did not require immunity to known MuHV-4 latency genes. As the remaining vaccine virus genes have clear homologs in human γ-herpesviruses, this approach of deleting viral latency genes could also be applied to them, to generate safe and effective vaccines against human disease.
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Affiliation(s)
- Clara Lawler
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia
| | - João Pedro Simas
- Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal
| | - Philip G Stevenson
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia.,Royal Children's Hospital, Brisbane, QLD, Australia
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32
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Münz C. Latency and lytic replication in Epstein-Barr virus-associated oncogenesis. Nat Rev Microbiol 2019; 17:691-700. [PMID: 31477887 DOI: 10.1038/s41579-019-0249-7] [Citation(s) in RCA: 285] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2019] [Indexed: 12/19/2022]
Abstract
Epstein-Barr virus (EBV) was the first tumour virus identified in humans. The virus is primarily associated with lymphomas and epithelial cell cancers. These tumours express latent EBV antigens and the oncogenic potential of individual latent EBV proteins has been extensively explored. Nevertheless, it was presumed that the pro-proliferative and anti-apoptotic functions of these oncogenes allow the virus to persist in humans; however, recent evidence suggests that cellular transformation is not required for virus maintenance. Vice versa, lytic EBV replication was assumed to destroy latently infected cells and thereby inhibit tumorigenesis, but at least the initiation of the lytic cycle has now been shown to support EBV-driven malignancies. In addition to these changes in the roles of latent and lytic EBV proteins during tumorigenesis, the function of non-coding RNAs has become clearer, suggesting that they might mainly mediate immune escape rather than cellular transformation. In this Review, these recent findings will be discussed with respect to the role of EBV-encoded oncogenes in viral persistence and the contributions of lytic replication as well as non-coding RNAs in virus-driven tumour formation. Accordingly, early lytic EBV antigens and attenuated viruses without oncogenes and microRNAs could be harnessed for immunotherapies and vaccination.
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Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
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33
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Shannon-Lowe C, Rickinson A. The Global Landscape of EBV-Associated Tumors. Front Oncol 2019; 9:713. [PMID: 31448229 PMCID: PMC6691157 DOI: 10.3389/fonc.2019.00713] [Citation(s) in RCA: 288] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 07/18/2019] [Indexed: 12/12/2022] Open
Abstract
Epstein-Barr virus (EBV), a gamma-1 herpesvirus, is carried as a life-long asymptomatic infection by the great majority of individuals in all human populations. Yet this seemingly innocent virus is aetiologically linked to two pre-malignant lymphoproliferative diseases (LPDs) and up to nine distinct human tumors; collectively these have a huge global impact, being responsible for some 200,000 new cases of cancer arising worldwide each year. EBV replicates in oral epithelium but persists as a latent infection within the B cell system and several of its diseases are indeed of B cell origin; these include B-LPD of the immunocompromised, Hodgkin Lymphoma (HL), Burkitt Lymphoma (BL), Diffuse Large B cell Lymphoma (DLBCL) and two rarer tumors associated with profound immune impairment, plasmablastic lymphoma (PBL) and primary effusion lymphoma (PEL). Surprisingly, the virus is also linked to tumors arising in other cellular niches which, rather than being essential reservoirs of virus persistence in vivo, appear to represent rare cul-de-sacs of latent infection. These non-B cell tumors include LPDs and malignant lymphomas of T or NK cells, nasopharyngeal carcinoma (NPC) and gastric carcinoma of epithelial origin, and leiomyosarcoma, a rare smooth muscle cell tumor of the immunocompromised. Here we describe the main characteristics of these tumors, their distinct epidemiologies, histological features and degrees of EBV association, then consider how their different patterns of EBV latency may reflect the alternative latency programmes through which the virus first colonizes and then persists in immunocompetent host. For each tumor, we discuss current understanding of EBV's role in the oncogenic process, the identity (where known) of host genetic and environmental factors predisposing tumor development, and the recent evidence from cancer genomics identifying somatic changes that either complement or in some cases replace the contribution of the virus. Thereafter we look for possible connections between the pathogenesis of these apparently different malignancies and point to new research areas where insights may be gained.
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Affiliation(s)
- Claire Shannon-Lowe
- Institute for Immunology and Immunotherapy, The University of Birmingham, Birmingham, United Kingdom
| | - Alan Rickinson
- Institute for Immunology and Immunotherapy, The University of Birmingham, Birmingham, United Kingdom
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34
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Abstract
Vaccination against γ-herpesviruses has been hampered by our limited understanding of their normal control. Epstein–Barr virus (EBV)-transformed B cells are killed by viral latency antigen-specific CD8+ T cells in vitro, but attempts to block B cell infection with antibody or to prime anti-viral CD8+ T cells have protected poorly in vivo. The Doherty laboratory used Murid Herpesvirus-4 (MuHV-4) to analyze γ-herpesvirus control in mice and found CD4+ T cell dependence, with viral evasion limiting CD8+ T cell function. MuHV-4 colonizes germinal center (GC) B cells via lytic transfer from myeloid cells, and CD4+ T cells control myeloid infection. GC colonization and protective, lytic antigen-specific CD4+ T cells are now evident also for EBV. Subunit vaccines have protected only transiently against MuHV-4, but whole virus vaccines give long-term protection, via CD4+ T cells and antibody. They block infection transfer to B cells, and need include no known viral latency gene, nor any MuHV-4-specific gene. Thus, the Doherty approach of in vivo murine analysis has led to a plausible vaccine strategy for EBV and, perhaps, some insight into what CD8+ T cells really do.
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Affiliation(s)
- Philip G Stevenson
- School of Chemistry and Molecular Biosciences, University of Queensland and Brisbane, Australia.,Child Health Research Center, Brisbane, Australia
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35
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Conserved Gammaherpesvirus Protein Kinase Selectively Promotes Irrelevant B Cell Responses. J Virol 2019; 93:JVI.01760-18. [PMID: 30728267 DOI: 10.1128/jvi.01760-18] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 01/06/2019] [Indexed: 12/21/2022] Open
Abstract
Gammaherpesviruses are ubiquitous pathogens that are associated with B cell lymphomas. In the early stages of chronic infection, these viruses infect naive B cells and subsequently usurp the B cell differentiation process through the germinal center response to ensure latent infection of long-lived memory B cells. A unique feature of early gammaherpesvirus chronic infection is a robust differentiation of irrelevant, virus-nonspecific B cells with reactivities against self-antigens and antigens of other species. In contrast, protective, virus-specific humoral responses do not reach peak levels until a much later time. While several host factors are known to either promote or selectively restrict gammaherpesvirus-driven germinal center response, viral mechanisms that contribute to the irrelevant B cell response have not been defined. In this report we show that the expression and the enzymatic activity of the gammaherpesvirus-encoded conserved protein kinase selectively facilitates the irrelevant, but not virus-specific, B cell responses. Further, we show that lack of interleukin-1 (IL-1) receptor attenuates gammaherpesvirus-driven B cell differentiation and viral reactivation. Because germinal center B cells are thought to be the target of malignant transformation during gammaherpesvirus-driven lymphomagenesis, identification of host and viral factors that promote germinal center responses during gammaherpesvirus infection may offer an insight into the mechanism of gammaherpesvirus pathogenesis.IMPORTANCE Gammaherpesviruses are ubiquitous cancer-associated pathogens that usurp the B cell differentiation process to establish life-long latent infection in memory B cells. A unique feature of early gammaherpesvirus infection is the robust increase in differentiation of B cells that are not specific for viral antigens and instead encode antibodies that react with self-antigens and antigens of other species. Viral mechanisms that are involved in driving such irrelevant B cell differentiation are not known. Here, we show that gammaherpesvirus-encoded conserved protein kinase and host IL-1 signaling promote irrelevant B cell responses and gammaherpesvirus-driven germinal center responses, with the latter thought to be the target of viral transformation.
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36
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Glauser DL, Milho R, Lawler C, Stevenson PG. Antibody arrests γ-herpesvirus olfactory super-infection independently of neutralization. J Gen Virol 2018; 100:246-258. [PMID: 30526737 DOI: 10.1099/jgv.0.001183] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Protecting against persistent viruses is an unsolved challenge. The clearest example for a gamma-herpesvirus is resistance to super-infection by Murid herpesvirus-4 (MuHV-4). Most experimental infections have delivered MuHV-4 into the lungs. A more likely natural entry site is the olfactory epithelium. Its protection remains unexplored. Here, prior exposure to olfactory MuHV-4 gave good protection against super-infection. The protection was upstream of B cell infection, which occurs in lymph nodes, and showed redundancy between antibody and T cells. Adding antibody to virions that blocked heparan binding strongly reduced olfactory host entry - unlike in the lungs, opsonized virions did not reach IgG Fc receptor+ myeloid cells. However, the nasal antibody response to primary infection was too low to reduce host entry. Instead, the antibody acted downstream, reducing viral replication in the olfactory epithelium. This depended on IgG Fc receptor engagement rather than virion neutralization. Thus antibody can protect against natural γ-herpesvirus infection before it reaches B cells and independently of neutralization.
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Affiliation(s)
- Daniel L Glauser
- 1Division of Virology, University of Cambridge, UK
- ‡Present address: Suisselab AG, Bern, Switzerland
| | - Ricardo Milho
- 1Division of Virology, University of Cambridge, UK
- §Present address: Costello Medical, Cambridge, UK
| | - Clara Lawler
- 2School of Chemistry and Molecular Biosciences, University of Queensland, Australia
| | - Philip G Stevenson
- 3Royal Children's Hospital, Brisbane, Australia
- 1Division of Virology, University of Cambridge, UK
- 2School of Chemistry and Molecular Biosciences, University of Queensland, Australia
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37
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Jiang L, Xie C, Lung HL, Lo KW, Law GL, Mak NK, Wong KL. EBNA1-targeted inhibitors: Novel approaches for the treatment of Epstein-Barr virus-associated cancers. Am J Cancer Res 2018; 8:5307-5319. [PMID: 30555548 PMCID: PMC6276081 DOI: 10.7150/thno.26823] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 08/14/2018] [Indexed: 12/11/2022] Open
Abstract
Epstein-Barr virus (EBV) infects more than 90% of humans worldwide and establishes lifelong latent infection in the hosts. It is closely associated with endemic forms of a wide range of human cancers and directly contributes to the formation of some. Despite its critical role in cancer development, no EBV- or EBV latent protein-targeted therapy is available. The EBV-encoded latent protein, Epstein-Barr nuclear antigen 1 (EBNA1), is expressed in all EBV-associated tumors and acts as the only latent protein in some of these tumors. This versatile protein functions in the maintenance, replication, and segregation of the EBV genome and can therefore serve as an attractive therapeutic target to treat EBV-associated cancers. In the last decades, efforts have been made for designing specific EBNA1 inhibitors to decrease EBNA1 expression or interfere with EBNA1-dependent functions. In this review, we will briefly introduce the salient features of EBNA1, summarize its functional domains, and focus on the recent developments in the identification and design of EBNA1 inhibitors related to various EBNA1 domains as well as discuss their comparative merits.
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Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma. mSphere 2018; 3:3/4/e00378-18. [PMID: 30135222 PMCID: PMC6106053 DOI: 10.1128/mspheredirect.00378-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The novel SYK and FLT3 inhibitor TAK-659 prevents the enlargement of spleen and tumor development in a mouse model of EBV-associated lymphoma by counteracting the activation of cellular kinase SYK through the viral LMP2A gene by inducing cell death in tumor cells but not in nontumor cells. These findings indicate that TAK-659 may be a very effective nontoxic therapeutic molecule especially for EBV-positive hematologic malignancies. Epstein-Barr virus (EBV) is associated with several B and epithelial cell cancers. EBV-encoded latent membrane protein 2A (LMP2A) contributes to cellular transformation by mimicking B cell receptor signaling. LMP2A/MYC double transgenic mice develop splenomegaly and B cell lymphoma much faster than MYC transgenic mice do. In this study, we explored the potential therapeutic efficacy of a novel spleen tyrosine kinase (SYK) and FLT3 inhibitor TAK-659 for development of a treatment option for EBV-associated malignancies. In our transgenic model, TAK-659 treatment totally abrogated splenomegaly and tumor development in LMP2A/MYC mice in both pretumor and tumor cell transfer experiments. TAK-659 treatment killed tumor cells, but not host cells within the spleen and tumors. Furthermore, TAK-659 treatment abrogated metastasis of tumor cells into bone marrow. Our data also show that TAK-659 inhibits SYK phosphorylation and induces apoptosis in LMP2A/MYC tumor cells at low nanomolar concentrations. Therefore, TAK-659 may provide an effective therapeutic option for treatment of LMP2A-positive EBV-associated malignancies and should be explored further in clinical trials. IMPORTANCE The novel SYK and FLT3 inhibitor TAK-659 prevents the enlargement of spleen and tumor development in a mouse model of EBV-associated lymphoma by counteracting the activation of cellular kinase SYK through the viral LMP2A gene by inducing cell death in tumor cells but not in nontumor cells. These findings indicate that TAK-659 may be a very effective nontoxic therapeutic molecule especially for EBV-positive hematologic malignancies.
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39
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Kearns PKA, Casey HA, Leach JP. Hypothesis: Multiple sclerosis is caused by three-hits, strictly in order, in genetically susceptible persons. Mult Scler Relat Disord 2018; 24:157-174. [PMID: 30015080 DOI: 10.1016/j.msard.2018.06.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/25/2018] [Accepted: 06/18/2018] [Indexed: 12/15/2022]
Abstract
Multiple Sclerosis is a chronic, progressive and debilitating neurological disease which, despite extensive study for over 100 years, remains of enigmatic aetiology. Drawn from the epidemiological evidence, there exists a consensus that there are environmental (possibly infectious) factors that contribute to disease pathogenesis that have not yet been fully elucidated. Here we propose a three-tiered hypothesis: 1) a clinic-epidemiological model of multiple sclerosis as a rare late complication of two sequential infections (with the temporal sequence of infections being important); 2) a proposal that the first event is helminthic infection with Enterobius Vermicularis, and the second is Epstein Barr Virus infection; and 3) a proposal for a testable biological mechanism, involving T-Cell exhaustion for Epstein-Barr Virus protein LMP2A. We believe that this model satisfies some of the as-yet unexplained features of multiple sclerosis epidemiology, is consistent with the clinical and neuropathological features of the disease and is potentially testable by experiment. This model may be generalizable to other autoimmune diseases.
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40
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Bilger A, Plowshay J, Ma S, Nawandar D, Barlow EA, Romero-Masters JC, Bristol JA, Li Z, Tsai MH, Delecluse HJ, Kenney SC. Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication. Oncotarget 2018; 8:44266-44280. [PMID: 28574826 PMCID: PMC5546479 DOI: 10.18632/oncotarget.17863] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 04/27/2017] [Indexed: 12/25/2022] Open
Abstract
EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both "on target" and "off target" mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.
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Affiliation(s)
- Andrea Bilger
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Julie Plowshay
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.,Rocky Mountain Infectious Disease Specialists, Aurora, Colorado, USA
| | - Shidong Ma
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.,Sanofi Pharmaceuticals, Cambridge, Massachusetts, USA
| | - Dhananjay Nawandar
- Department Cellular and Molecular Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, USA.,Department of Cancer Biology and Immunology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Cambridge, Massachusetts, USA
| | - Elizabeth A Barlow
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - James C Romero-Masters
- Department of Cellular and Molecular Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Jillian A Bristol
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Zhe Li
- Joint DKFZ Inserm Unit U1074, German Cancer Center (DKFZ), Heidelberg, Germany
| | - Ming-Han Tsai
- Joint DKFZ Inserm Unit U1074, German Cancer Center (DKFZ), Heidelberg, Germany
| | | | - Shannon C Kenney
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.,Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
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41
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Epstein-Barr Virus (EBV) Latent Protein EBNA3A Directly Targets and Silences the STK39 Gene in B Cells Infected by EBV. J Virol 2018; 92:JVI.01918-17. [PMID: 29367247 PMCID: PMC5972881 DOI: 10.1128/jvi.01918-17] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/16/2018] [Indexed: 01/10/2023] Open
Abstract
Epstein-Barr virus (EBV) establishes latent infection in human B cells and is associated with a wide range of cancers. The EBV nuclear antigen 3 (EBNA3) family proteins are critical for B cell transformation and function as transcriptional regulators. It is well established that EBNA3A and EBNA3C cooperate in the regulation of cellular genes. Here, we demonstrate that the gene STK39 is repressed only by EBNA3A. This is the first example of a gene regulated only by EBNA3A in EBV-transformed lymphoblastoid cell lines (LCLs) without the help of EBNA3C. This was demonstrated using a variety of LCLs carrying either knockout, revertant, or conditional EBNA3 recombinants. Investigating the kinetics of EBNA3A-mediated changes in STK39 expression showed that STK39 becomes derepressed quickly after EBNA3A inactivation. This derepression is reversible as EBNA3A reactivation represses STK39 in the same cells expressing a conditional EBNA3A. STK39 is silenced shortly after primary B cell infection by EBV, and no STK39-encoded protein (SPAK) is detected 3 weeks postinfection. Chromatin immunoprecipitation (ChIP) analysis indicates that EBNA3A directly binds to a regulatory region downstream of the STK39 transcription start site. For the first time, we demonstrated that the polycomb repressive complex 2 with the deposition of the repressive mark H3K27me3 is not only important for the maintenance of an EBNA3A target gene (STK39) but is also essential for the initial establishment of its silencing. Finally, we showed that DNA methyltransferases are involved in the EBNA3A-mediated repression of STK39. IMPORTANCE EBV is well known for its ability to transform B lymphocytes to continuously proliferating lymphoblastoid cell lines. This is achieved in part by the reprogramming of cellular gene transcription by EBV transcription factors, including the EBNA3 proteins that play a crucial role in this process. In the present study, we found that EBNA3A epigenetically silences STK39. This is the first gene where EBNA3A has been found to exert its repressive role by itself, without needing its coregulators EBNA3B and EBNA3C. Furthermore, we demonstrated that the polycomb repressor complex is essential for EBNA3A-mediated repression of STK39. Findings in this study provide new insights into the regulation of cellular genes by the transcription factor EBNA3A.
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Mukohyama J, Iwakiri D, Zen Y, Mukohara T, Minami H, Kakeji Y, Shimono Y. Evaluation of the risk of lymphomagenesis in xenografts by the PCR-based detection of EBV BamHI W region in patient cancer specimens. Oncotarget 2018; 7:50150-50160. [PMID: 27367028 PMCID: PMC5226574 DOI: 10.18632/oncotarget.10322] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 06/13/2016] [Indexed: 01/27/2023] Open
Abstract
Establishment of patient-derived tumor xenografts (PDXs) is hampered by lymphomagenesis mostly caused by the latently-infected Epstein-Barr virus (EBV) contained in patient cancer tissues. However, the character of patient tissues that result in lymphomagenesis after xenotransplantation is not elucidated. In this study, we analyzed the patient colorectal cancer (CRC) tissues and the PDXs established by their xenotransplantation. We found that 2 of 9 (22%) PDX tumors were EBV-associated human diffuse large B cell lymphoma which was formed by clonal proliferation of human B-cell lymphocytes, were strongly positive for EBER-ISH, and were classified as type III latency. Expression of EBV genes and RNAs, such as EBNAs, LMP1, EBER and EBV-associated microRNAs in patient CRC tissues were unlikely to be associated with lymphomagenesis in PDXs. In contrast, the positive PCR-based amplification of BamHI W region, a major internal repeat in EBV genome, in the patient CRC tissues was correlated with lymphomagenesis in PDXs. These results suggest that the detection of the EBV BamHI W region in the patient surgical specimens will be an effective way to predict the risk of lymphomagenesis in PDXs before xenotransplantation.
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Affiliation(s)
- Junko Mukohyama
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.,Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Dai Iwakiri
- Division of Clinical Virology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoh Zen
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Toru Mukohara
- Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.,Cancer Center, Kobe University Hospital, Kobe, Japan
| | - Hironobu Minami
- Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.,Cancer Center, Kobe University Hospital, Kobe, Japan
| | - Yoshihiro Kakeji
- Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yohei Shimono
- Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.,Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
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Münz C. Epstein-Barr Virus-Specific Immune Control by Innate Lymphocytes. Front Immunol 2017; 8:1658. [PMID: 29225606 PMCID: PMC5705607 DOI: 10.3389/fimmu.2017.01658] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 11/13/2017] [Indexed: 01/24/2023] Open
Abstract
Epstein–Barr virus (EBV) is a potent B cell transforming pathogen in humans. In most persistently EBV-infected individuals, potent cytotoxic lymphocyte responses prevent EBV-associated pathologies. In addition to comprehensive adaptive T cell responses, several innate lymphocyte populations seem to target different stages of EBV infection and are compromised in primary immunodeficiencies that render individuals susceptible to symptomatic EBV infection. In this mini-review, I will highlight the functions of natural killer, γδ T cells, and natural killer T cells during innate immune responses to EBV. These innate lymphocyte populations seem to restrict both lytic replication and transforming latent EBV antigen expression. The mechanisms underlying the recognition of these different EBV infection programs by the respective innate lymphocytes are just starting to become unraveled, but will provide immunotherapeutic strategies to target pathologies that are associated with the different EBV infection programs.
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Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
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Abbott RJ, Pachnio A, Pedroza-Pacheco I, Leese AM, Begum J, Long HM, Croom-Carter D, Stacey A, Moss PAH, Hislop AD, Borrow P, Rickinson AB, Bell AI. Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases. J Virol 2017; 91:e00382-17. [PMID: 28835490 PMCID: PMC5640854 DOI: 10.1128/jvi.00382-17] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 07/28/2017] [Indexed: 02/07/2023] Open
Abstract
Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. In contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterized by anti-EBV IgM antibody positivity, high loads of circulating latently infected B cells, and a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8+ T cells plus a milder expansion of CD56dim NKG2A+ KIR- natural killer (NK) cells. How the two situations compare is unclear due to the paucity of studies on clinically silent infection. Here we describe five prospectively studied patients with asymptomatic infections identified in a seroepidemiologic survey of university entrants. In each case, the key blood sample had high cell-associated viral loads without a marked CD8 lymphocytosis or NK cell disturbance like those seen in patients during the acute phase of IM. Two of the cases with the highest viral loads showed a coincident expansion of activated EBV-specific CD8+ T cells, but overall CD8+ T cell numbers were either unaffected or only mildly increased. Two cases with slightly lower loads, in whom serology suggests the infection may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another case with a higher viral load, in which T and NK cell responses were undetectable in the primary blood sample in which infection was detected, EBV-specific T cell responses did not appear until several months later, by which time the viral loads in the blood had already fallen. Thus, some patients with asymptomatic primary infections have very high circulating viral loads similar to those in patients during the acute phase of IM and a cell-mediated immune response that is qualitatively similar to that in IM patients but of a lower magnitude. However, other patients may have quite different immune responses that ultimately could reveal novel mechanisms of host control.IMPORTANCE Epstein-Barr virus (EBV) is transmitted orally, replicates in the throat, and then invades the B lymphocyte pool through a growth-transforming latent infection. While primary infection in childhood is usually asymptomatic, delayed infection is associated with infectious mononucleosis (IM), a febrile illness in which patients have high circulating viral loads and an exaggerated virus-induced immune response involving both CD8+ T cells and natural killer (NK) cells. Here we show that in five cases of asymptomatic infection, viral loads in the blood were as high as those in patients during the acute phase of IM, whereas the cell-mediated responses, even when they resembled those in patients during the acute phase of IM in timing and quality, were never as exaggerated. We infer that IM symptoms arise as a consequence not of the virus infection per se but of the hyperactivated immune response. Interestingly, there were idiosyncratic differences among asymptomatic cases in the relationship between the viral load and the response kinetics, emphasizing how much there is still to learn about primary EBV infection.
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Affiliation(s)
- Rachel J Abbott
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Annette Pachnio
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | | | - Alison M Leese
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Jusnara Begum
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Heather M Long
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Debbie Croom-Carter
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Andrea Stacey
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
| | - Paul A H Moss
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Andrew D Hislop
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Persephone Borrow
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
| | - Alan B Rickinson
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Andrew I Bell
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
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Lytic EBV infection investigated by detection of Soluble Epstein-Barr virus ZEBRA in the serum of patients with PTLD. Sci Rep 2017; 7:10479. [PMID: 28874674 PMCID: PMC5585268 DOI: 10.1038/s41598-017-09798-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 07/28/2017] [Indexed: 12/14/2022] Open
Abstract
The ZEBRA protein (encoded by the BZLF1 gene), is the major transcription factor of EBV, expressed upon EBV lytic cycle activation. Several studies highlighted the critical role of EBV lytic infection as a risk factor for lymphoproliferative disorders like post-transplant lymphoproliferative disease (PTLD). Here, we use an antigen-capture ELISA assay specifically designed to detecting the circulating soluble ZEBRA (sZEBRA) in serum samples (threshold value determined at 40ng/mL). We retrospectively investigated a population of 66 transplanted patients comprising 35 PTLD. All the samples from a control population (30 EBV-seronegative subjects and 25 immunocompetent individuals with EBV serological reactivation), classified as sZEBRA < 40ng/mL were assigned as negative. At PTLD diagnosis, EBV genome (quantified by qPCR with EBV DNA>200 copies/mL) and sZEBRA were detectable in 51% and 60% of cases, respectively. In the patients who developed a pathologically-confirmed PTLD, the mean sZEBRA value in cases, was 399 ng/mL +/− 141 versus 53ng/mL +/− 7 in patients who did not (p < 0,001). This is the first report relating to the detection of the circulating ZEBRA in serum specimens, as well as the first analysis dealing with the lytic cycle of EBV in PTLD patients with this new biomarker.
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Absalon MJ, Khoury RA, Phillips CL. Post-transplant lymphoproliferative disorder after solid-organ transplant in children. Semin Pediatr Surg 2017; 26:257-266. [PMID: 28964482 DOI: 10.1053/j.sempedsurg.2017.07.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The post-transplant lymphoproliferative disorders (PTLD) are a diverse group of potentially life-threatening conditions affecting organ transplant recipients. PTLD arises in the setting of an attenuated host immunologic system that is manipulated to allow a foreign graft but then fails to provide adequate immune surveillance of transformed malignant or premalignant lymphocytes. The diversity of biological behavior and clinical presentation makes for a challenging clinical situation for those involved in the care of children with PTLD occurring after solid-organ transplantation. This review details a large transplant center's multidisciplinary approach to monitoring for PTLD and systematic approach to intervention, which has been essential for early recognition and successful treatment.
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Affiliation(s)
- Michael J Absalon
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 7018, Cincinnati, Ohio 45229.
| | - Ruby A Khoury
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 7018, Cincinnati, Ohio 45229
| | - Christine L Phillips
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 7018, Cincinnati, Ohio 45229
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Tan CSE, Lawler C, Stevenson PG. CD8+ T cell evasion mandates CD4+ T cell control of chronic gamma-herpesvirus infection. PLoS Pathog 2017; 13:e1006311. [PMID: 28394921 PMCID: PMC5398720 DOI: 10.1371/journal.ppat.1006311] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Revised: 04/20/2017] [Accepted: 03/23/2017] [Indexed: 12/15/2022] Open
Abstract
Gamma-herpesvirus infections are regulated by both CD4+ and CD8+ T cells. However clinical disease occurs mainly in CD4+ T cell-deficient hosts. In CD4+ T cell-deficient mice, CD8+ T cells control acute but not chronic lung infection by Murid Herpesvirus-4 (MuHV-4). We show that acute and chronic lung infections differ in distribution: most acute infection was epithelial, whereas most chronic infection was in myeloid cells. CD8+ T cells controlled epithelial infection, but CD4+ T cells and IFNγ were required to control myeloid cell infection. Disrupting the MuHV-4 K3, which degrades MHC class I heavy chains, increased viral epitope presentation by infected lung alveolar macrophages and allowed CD8+ T cells to prevent disease. Thus, viral CD8+ T cell evasion led to niche-specific immune control, and an essential role for CD4+ T cells in limiting chronic infection. Gamma-herpesviruses chronically infect most people. While infection is usually asymptomatic, disease occurs if the immune system is weakened. Understanding how immune control normally works should provide a basis for preventing disease. In mice, CD8+ T cells can control acute gamma-herpesvirus infection but not chronic infection. We show that acute and chronic infections involve different cell types. CD8+ T cells controlled epithelial cell infection, which predominated acutely, but they could not control chronic macrophage infection unless viral immune evasion was disabled. Instead CD4+ T cells were required. Thus, viral evasion made host defence cell type-specific: CD8+ T cells controlled epithelial cell infection; CD4+ T cells controlled macrophage infection; and comprehensive control required both T cell subsets.
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Affiliation(s)
- Cindy S. E. Tan
- School of Chemistry and Molecular Biosciences, University of Queensland and Royal Children’s Hospital, Brisbane, Australia
| | - Clara Lawler
- School of Chemistry and Molecular Biosciences, University of Queensland and Royal Children’s Hospital, Brisbane, Australia
| | - Philip G. Stevenson
- School of Chemistry and Molecular Biosciences, University of Queensland and Royal Children’s Hospital, Brisbane, Australia
- * E-mail:
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48
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Singh S, Jha HC. Status of Epstein-Barr Virus Coinfection with Helicobacter pylori in Gastric Cancer. JOURNAL OF ONCOLOGY 2017; 2017:3456264. [PMID: 28421114 PMCID: PMC5379099 DOI: 10.1155/2017/3456264] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 02/14/2017] [Indexed: 12/14/2022]
Abstract
Epstein-Barr virus is a ubiquitous human herpesvirus whose primary infection causes mononucleosis, Burkett's lymphoma, nasopharyngeal carcinoma, autoimmune diseases, and gastric cancer (GC). The persistent infection causes malignancies in lymph and epithelial cells. Helicobacter pylori causes gastritis in human with chronic inflammation. This chronic inflammation is thought to be the cause of genomic instability. About 45%-word population have a probability of having both pathogens, namely, H. pylori and EBV. Approximately 180 per hundred thousand population is developing GC along with many gastric abnormalities. This makes GC the third leading cause of cancer-related death worldwide. Although lots of research are carried out individually for EBV and H. pylori, still there are very few reports available on coinfection of both pathogens. Recent studies suggested that EBV and H. pylori coinfection increases the occurrence of GC as well as the early age of GC detection comparing to individual infection. The aim of this review is to present status on coinfection of both pathogens and their association with GC.
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Affiliation(s)
- Shyam Singh
- Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, India
| | - Hem Chandra Jha
- Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, India
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King RL, Paessler ME, Howard MT, Wertheim GB. Incidental EBV-positivity in paediatric post-transplant specimens demonstrates the need for stringent criteria for diagnosing post-transplant lymphoproliferative disorders. J Clin Pathol 2017; 70:270-273. [PMID: 27852687 DOI: 10.1136/jclinpath-2016-203924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 10/03/2016] [Accepted: 10/26/2016] [Indexed: 12/14/2022]
Abstract
AIMS To examine the need for minimal diagnostic criteria for post-transplant lymphoproliferative disorders (PTLD) in children, we sought to determine the rate of incidental Epstein-Barr virus (EBV)-positivity in tissues from organ transplant recipients (OTR). METHODS EBV in situ hybridisation (ISH) was done retrospectively on tissue from 34 paediatric autopsies of OTR and paediatric tonsillectomy specimens from non-OTR (96) and OTR (6). Patients with a history of PTLD were excluded from both data sets. RESULTS EBV-positivity was found incidentally in 2/34 autopsy cases (5.9%). Median time from transplant to death for all patients was 12.8 months (range 0.1-153 months). Median time between transplant and death in EBV-positive cases was 34 months. EBV was positive in 26/102 tonsils (25%). Among tonsils from OTR, 4/6 (67%) were EBV-positive. CONCLUSIONS These findings reinforce the need for strict morphological and clinical criteria, other than EBV-positivity, when diagnosing PTLD in the paediatric population.
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Affiliation(s)
- Rebecca L King
- Division of Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michele E Paessler
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Matthew T Howard
- Division of Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gerald B Wertheim
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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Abstract
Epstein-Barr virus (EBV) infection is associated with several distinct hematological and epithelial malignancies, e.g., Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and others. The association with several malignant tumors of local and worldwide distribution makes EBV one of the most important tumor viruses. Furthermore, because EBV can cause posttransplant lymphoproliferative disease, transplant medicine has to deal with EBV as a major pathogenic virus second only to cytomegalovirus. In this review, we summarize briefly the natural history of EBV infection and outline some of the recent advances in the pathogenesis of the major EBV-associated neoplasms. We present alternative scenarios and discuss them in the light of most recent experimental data. Emerging research areas including EBV-induced patho-epigenetic alterations in host cells and the putative role of exosome-mediated information transfer in disease development are also within the scope of this review. This book contains an in-depth description of a series of modern methodologies used in EBV research. In this introductory chapter, we thoroughly refer to the applications of these methods and demonstrate how they contributed to the understanding of EBV-host cell interactions. The data gathered using recent technological advancements in molecular biology and immunology as well as the application of sophisticated in vitro and in vivo experimental models certainly provided deep and novel insights into the pathogenetic mechanisms of EBV infection and EBV-associated tumorigenesis. Furthermore, the development of adoptive T cell immunotherapy has provided a novel approach to the therapy of viral disease in transplant medicine and hematology.
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Affiliation(s)
- Janos Minarovits
- Faculty of Dentistry, Department of Oral Biology and Experimental Dental Research, University of Szeged, Tisza Lajos krt. 64, H-6720, Szeged, Hungary.
| | - Hans Helmut Niller
- Institute of Medical Microbiology and Hygiene, University of Regensburg, D-93053, Regensburg, Germany
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