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Li J, Tan R, Yang B, Du C, Tian J, Yang Z, Tang D. Genetic evidence identifies a causal relationship between EBV infection and multiple myeloma risk. Sci Rep 2025; 15:6357. [PMID: 39984542 PMCID: PMC11845450 DOI: 10.1038/s41598-025-90479-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 02/13/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND Previous observational studies have suggested a potential association between Epstein-Barr virus (EBV) infection and the development of multiple myeloma (MM), but this relationship is not clear. Therefore, we conducted a systematic Mendelian randomization (MR) analysis to investigate the causal relationship between EBV infection and the risk of MM, while exploring the possible mediating role of immune cells in this association. METHODS The study first conducted a two-sample MR analysis using the MM R11 dataset from the FinnGen Consortium to evaluate the causal relationship between five EBV infection-related antibodies (AEB-IgG, EA-D, EBNA-1, VCA-p18, and ZEBRA) and MM, with validation in the MM R10 dataset. A reverse MR analysis was then performed. For significant results, multivariable MR (MVMR) was used to adjust for the effects of confounding risk factors. Next, a two-step MR mediation analysis was applied to investigate the potential mediating role of 731 immune cell types between positive exposure and MM. Multiple sensitivity analyses were conducted to assess the robustness of the findings. RESULTS A two-sample MR study found that EBNA-1 antibodies (OR = 1.36, 95% CI: 1.06-1.73; P = 0.015) were associated with an increased risk of MM, with similar results observed in the FinnGen Consortium R10 replication study. Although the association did not remain statistically significant after false discovery rate (FDR) adjustment (P_fdr = 0.075), further adjustment for relevant confounders using multivariable MR (MVMR) demonstrated that EBNA-1 antibodies (OR = 1.33, 95% CI: 1.01-1.75; P = 0.041) were still significantly associated with an increased risk of MM. Reverse MR analysis indicated no causal effect of MM on EBV-related antibodies. A two-sample MR analysis involving 731 immune cell phenotypes identified 27 potential mediating cell types. Ultimately, two-step MR confirmed that HLA-DR on myeloid dendritic cells (HLA-DR⁺ mDC) serves as a mediating factor, with EBNA-1 antibodies downregulating HLA-DR⁺ mDC, thereby increasing MM risk. Multiple sensitivity analyses supported the robustness of these findings. CONCLUSION The findings of this study suggest that EBNA-1 antibodies may increase the risk of MM by downregulating HLA-DR⁺ mDC. This indicates that chronic EBV infection may contribute to an elevated risk of MM. We hope these results provide new insights for future research on the prevention and treatment of MM.
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Affiliation(s)
- Jian Li
- The First College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, No. 71, Baoshan North Road, Yunyan District, Guiyang, 550001, Guizhou, China
- Guizhou University of Traditional Chinese Medicine, No. 4, Dongqing Road, Huaxi District, Guiyang, 550025, Guizhou, China
| | - Rong Tan
- Department of Pharmaceutics, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Bing Yang
- The First College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, No. 71, Baoshan North Road, Yunyan District, Guiyang, 550001, Guizhou, China
- Student Management Office, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Changpu Du
- The First College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, No. 71, Baoshan North Road, Yunyan District, Guiyang, 550001, Guizhou, China
- Guizhou University of Traditional Chinese Medicine, No. 4, Dongqing Road, Huaxi District, Guiyang, 550025, Guizhou, China
| | - Jie Tian
- The First College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, No. 71, Baoshan North Road, Yunyan District, Guiyang, 550001, Guizhou, China.
- Department of Oncology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China.
- Guizhou University of Traditional Chinese Medicine, No. 4, Dongqing Road, Huaxi District, Guiyang, 550025, Guizhou, China.
| | - Zhu Yang
- Guizhou University of Traditional Chinese Medicine, No. 4, Dongqing Road, Huaxi District, Guiyang, 550025, Guizhou, China.
| | - Dongxin Tang
- Department of Oncology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China.
- Guizhou University of Traditional Chinese Medicine, No. 4, Dongqing Road, Huaxi District, Guiyang, 550025, Guizhou, China.
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Floudas CS, Sarkizova S, Ceccarelli M, Zheng W. Leveraging mRNA technology for antigen based immuno-oncology therapies. J Immunother Cancer 2025; 13:e010569. [PMID: 39848687 PMCID: PMC11784169 DOI: 10.1136/jitc-2024-010569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 01/03/2025] [Indexed: 01/25/2025] Open
Abstract
The application of messenger RNA (mRNA) technology in antigen-based immuno-oncology therapies represents a significant advancement in cancer treatment. Cancer vaccines are an effective combinatorial partner to sensitize the host immune system to the tumor and boost the efficacy of immune therapies. Selecting suitable tumor antigens is the key step to devising effective vaccinations and amplifying the immune response. Tumor neoantigens are de novo epitopes derived from somatic mutations, avoiding T-cell central tolerance of self-epitopes and inducing immune responses to tumors. The identification and prioritization of patient-specific tumor neoantigens are based on advanced computational algorithms taking advantage of the profiling with next-generation sequencing considering factors involved in human leukocyte antigen (HLA)-peptide-T-cell receptor (TCR) complex formation, including peptide presentation, HLA-peptide affinity, and TCR recognition. This review discusses the development and clinical application of mRNA vaccines in oncology, with a particular focus on recent clinical trials and the computational workflows and methodologies for identifying both shared and individual antigens. While this review centers on therapeutic mRNA vaccines targeting existing tumors, it does not cover preventative vaccines. Preclinical experimental validations are crucial in cancer vaccine development, but we emphasize the computational approaches that facilitate neoantigen selection and design, highlighting their role in advancing mRNA vaccine development. The versatility and rapid development potential of mRNA make it an ideal platform for personalized neoantigen immunotherapy. We explore various strategies for antigen target identification, including tumor-associated and tumor-specific antigens and the computational tools used to predict epitopes capable of eliciting strong immune responses. We address key design considerations for enhancing the immunogenicity and stability of mRNA vaccines, as well as emerging trends and challenges in the field. This comprehensive overview highlights the therapeutic potential of mRNA-based cancer vaccines and underscores ongoing research efforts aimed at optimizing these therapies for improved clinical outcomes.
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Affiliation(s)
- Charalampos S Floudas
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | | | - Michele Ceccarelli
- Sylvester Comprehensive Cancer Center, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Wei Zheng
- Moderna, Inc, Cambridge, Massachusetts, USA
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3
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Behrens M, Comabella M, Lünemann JD. EBV-specific T-cell immunity: relevance for multiple sclerosis. Front Immunol 2024; 15:1509927. [PMID: 39776919 PMCID: PMC11703957 DOI: 10.3389/fimmu.2024.1509927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
Genetic and environmental factors jointly determine the susceptibility to develop multiple sclerosis (MS). Improvements in the design of epidemiological studies have helped to identify consistent environmental risk associations such as the increased susceptibility for MS following Epstein-Barr virus (EBV) infection, while biological mechanisms that drive the association between EBV and MS remain incompletely understood. An increased and broadened repertoire of antibody and T-cell immune responses to EBV-encoded antigens, especially to the dominant CD4+ T-cell EBV nuclear antigen 1 (EBNA1), is consistently observed in patients with MS, indicating that protective EBV-specific immune responses are deregulated in MS and potentially contribute to disease development. Exploitation of B-cell trajectories by EBV infection might promote survival of autoreactive B-cell species and proinflammatory B:T-cell interactions. In this review article, we illustrate evidence for a causal role of EBV infection in MS, discuss how EBV-targeting adaptive immune responses potentially modulate disease susceptibility and progression, and provide future perspectives on how novel model systems could be utilized to better define the role of EBV and viral pathogens in MS. Insights gained from these studies might facilitate the development of prevention strategies and more effective treatments for MS.
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Affiliation(s)
- Malina Behrens
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Manuel Comabella
- Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Vall d’Hebron University Hospital, Barcelona, Spain
| | - Jan D. Lünemann
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
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4
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Liu X, Zhang M, Yin L, Kang L, Luo Y, Wang X, Ren L, Zhang G, Yao Y, Liu P. PEDV evades MHC-I-related immunity through nsp1-mediated NLRC5 translation inhibition. J Virol 2024; 98:e0142124. [PMID: 39480087 PMCID: PMC11575403 DOI: 10.1128/jvi.01421-24] [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: 08/15/2024] [Accepted: 10/06/2024] [Indexed: 11/02/2024] Open
Abstract
Major histocompatibility complex class I (MHC-I) plays crucial roles against viral infections not only by initiating CD8+ T cell immunity but also by modulating natural killer (NK) cell cytotoxicity. Understanding how viruses precisely regulate MHC-I to optimize their infection is important; however, the manipulation of MHC-I molecules by porcine epidemic diarrhea virus (PEDV) remains unclear. In this study, we demonstrate that PEDV infection promotes the transcription of NLRC5, a key transactivator of MHC-I, in several porcine cell lines and in vivo. Paradoxically, no increase in MHC-I expression is observed after PEDV infection both in vitro and in vivo. Mechanistic studies revealed that PEDV infection inhibits the translation of PEDV-elicited NLRC5 mRNA and the expression of downstream MHC-I proteins, without affecting the expression of physiological NLRC5 and MHC-I proteins. Through viral protein screening, we identified PEDV nonstructural protein 1 (nsp1) as the critical antagonist that inhibits NLRC5-mediated upregulation of MHC-I, and the nsp1's inhibitory effect on MHC-I requires the motif of 15 amino acids at its C-terminus. Notably, our results revealed that the cytotoxic ability of NK cells against PEDV-infected cells is similar to that against healthy cells. Collectively, our findings uncover an immune evasion mechanism by which PEDV-infected cells masquerade as healthy cells to evade NK and T cell immunity. This is achieved by targeting NLRC5, a key MHC-I transcriptional regulator, via nsp1.IMPORTANCEPorcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus that inflicts substantial financial losses on the swine industry. Major histocompatibility complex class I (MHC-I) is a critical factor influencing both CD8+ T cell and natural killer (NK) cell immunity. However, how PEDV manipulates MHC-I expression to optimize its infection process remains largely unknown. In this study, we demonstrate that PEDV's nonstructural protein 1 (nsp1) inhibits virus-mediated induction of MHC-I expression by directly targeting NLRC5, a key MHC-I transactivator. Intriguingly, nsp1 does not reduce physiological NLRC5 and MHC-I expression. This selective inhibition of virus-elicited NLRC5 mRNA translation allows PEDV-infected cells to masquerade as healthy cells, thereby evading CD8+ T cell and NK cell cytotoxicity. Our findings provide unique insights into the mechanisms by which PEDV evades CD8+ T cell and NK cell immunity.
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Affiliation(s)
- Xiang Liu
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Meng Zhang
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Lingdan Yin
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Li Kang
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yi Luo
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Xiaodong Wang
- Beijing Great Wall Danyu Livestock Co. Ltd., Beijing, China
| | - Li Ren
- Beijing Great Wall Danyu Livestock Co. Ltd., Beijing, China
| | - Guozhong Zhang
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yao Yao
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Pinghuang Liu
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
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Chiu YF, Ponlachantra K, Sugden B. How Epstein Barr Virus Causes Lymphomas. Viruses 2024; 16:1744. [PMID: 39599857 PMCID: PMC11599019 DOI: 10.3390/v16111744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 10/30/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Since Epstein-Barr Virus (EBV) was isolated 60 years ago, it has been studied clinically, epidemiologically, immunologically, and molecularly in the ensuing years. These combined studies allow a broad mechanistic understanding of how this ubiquitous human pathogen which infects more than 90% of adults can rarely cause multiple types of lymphomas. We survey these findings to provide a coherent description of its oncogenesis.
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Affiliation(s)
- Ya-Fang Chiu
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan 33302, Taiwan;
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
- Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan 33302, Taiwan
- Division of Infectious Diseases, Department of Medicine, New Taipei Municipal Tucheng Hospital, New Taipei City 236017, Taiwan
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou 33305, Taiwan
| | - Khongpon Ponlachantra
- School of Biomolecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology, Rayong 21210, Thailand;
| | - Bill Sugden
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA
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6
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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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7
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Moore PS, Chang Y. Are There More Human Cancer Viruses Left to Be Found? Annu Rev Virol 2024; 11:239-259. [PMID: 39326883 DOI: 10.1146/annurev-virology-111821-103721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2024]
Abstract
Of the thousands of viruses infecting humans, only seven cause cancer in the general population. Tumor sequencing is now a common cancer medicine procedure, and so it seems likely that more human cancer viruses already would have been found if they exist. Here, we review cancer characteristics that can inform a dedicated search for new cancer viruses, focusing on Kaposi sarcoma herpesvirus and Merkel cell polyomavirus as the most recent examples of successful genomic and transcriptomic searches. We emphasize the importance of epidemiology in determining which cancers to examine and describe approaches to virus discovery. Barriers to virus discovery, such as novel genomes and viral suppression of messenger RNA expression, may exist that prevent virus discovery using existing approaches. Optimally virus hunting should be performed in such a way that if no virus is found, the tumor can be reasonably excluded from having an infectious etiology and new information about the biology of the tumor can be found.
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Affiliation(s)
- Patrick S Moore
- Cancer Virology Program, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; ,
| | - Yuan Chang
- Cancer Virology Program, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; ,
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8
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Zhu B, Ouda R, Kasuga Y, de Figueiredo P, Kobayashi KS. NLRC5/MHC class I transactivator: A key target for immune escape by SARS-CoV-2. Bioessays 2024; 46:e2300109. [PMID: 38461519 DOI: 10.1002/bies.202300109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/11/2023] [Accepted: 02/01/2024] [Indexed: 03/12/2024]
Abstract
Antigen presentation to CD8+ T cells by MHC class I molecules is essential for host defense against viral infections. Various mechanisms have evolved in multiple viruses to escape immune surveillance and defense to support viral proliferation in host cells. Through in vitro SARS-CoV-2 infection studies and analysis of COVID-19 patient samples, we found that SARS-CoV-2 suppresses the induction of the MHC class I pathway by inhibiting the expression and function of NLRC5, a major transcriptional regulator of MHC class I genes. In this review, we discuss the molecular mechanisms for suppression of the MHC class I pathway and clinical implications for COVID-19.
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Affiliation(s)
- Baohui Zhu
- Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Ryota Ouda
- Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Yusuke Kasuga
- Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Paul de Figueiredo
- Christopher S Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri, USA
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, USA
| | - Koichi S Kobayashi
- Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
- Institute for Vaccine Research and Development (IVReD), Hokkaido University, Sapporo, Hokkaido, Japan
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, Texas, USA
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Liu J, Nagy N, Ayala-Torres C, Aguilar-Alonso F, Morais-Esteves F, Xu S, Masucci MG. Remodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases. Nat Commun 2023; 14:8315. [PMID: 38097648 PMCID: PMC10721647 DOI: 10.1038/s41467-023-43946-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 11/23/2023] [Indexed: 12/17/2023] Open
Abstract
The strategies adopted by viruses to reprogram the translation and protein quality control machinery and promote infection are poorly understood. Here, we report that the viral ubiquitin deconjugase (vDUB)-encoded in the large tegument protein of Epstein-Barr virus (EBV BPLF1)-regulates the ribosomal quality control (RQC) and integrated stress responses (ISR). The vDUB participates in protein complexes that include the RQC ubiquitin ligases ZNF598 and LTN1. Upon ribosomal stalling, the vDUB counteracts the ubiquitination of the 40 S particle and inhibits the degradation of translation-stalled polypeptides by the proteasome. Impairment of the RQC correlates with the readthrough of stall-inducing mRNAs and with activation of a GCN2-dependent ISR that redirects translation towards upstream open reading frames (uORFs)- and internal ribosome entry sites (IRES)-containing transcripts. Physiological levels of active BPLF1 promote the translation of the EBV Nuclear Antigen (EBNA)1 mRNA in productively infected cells and enhance the release of progeny virus, pointing to a pivotal role of the vDUB in the translation reprogramming that enables efficient virus production.
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Affiliation(s)
- Jiangnan Liu
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Noemi Nagy
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Carlos Ayala-Torres
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Francisco Aguilar-Alonso
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- Unidad de Desarrollo e Investigación en Bioterapéuticos (UDIBI), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Francisco Morais-Esteves
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Shanshan Xu
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Maria G Masucci
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
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10
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Dinh VT, Loaëc N, Quillévéré A, Le Sénéchal R, Keruzoré M, Martins RP, Granzhan A, Blondel M. The hide-and-seek game of the oncogenic Epstein-Barr virus-encoded EBNA1 protein with the immune system: An RNA G-quadruplex tale. Biochimie 2023; 214:57-68. [PMID: 37473831 DOI: 10.1016/j.biochi.2023.07.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/11/2023] [Accepted: 07/13/2023] [Indexed: 07/22/2023]
Abstract
The Epstein-Barr virus (EBV) is the first oncogenic virus described in human. EBV infects more than 90% of the human population worldwide, but most EBV infections are asymptomatic. After the primary infection, the virus persists lifelong in the memory B cells of the infected individuals. Under certain conditions the virus can cause several human cancers, that include lymphoproliferative disorders such as Burkitt and Hodgkin lymphomas and non-lymphoid malignancies such as 100% of nasopharyngeal carcinoma and 10% of gastric cancers. Each year, about 200,000 EBV-related cancers emerge, hence accounting for at least 1% of worldwide cancers. Like all gammaherpesviruses, EBV has evolved a strategy to escape the host immune system. This strategy is mainly based on the tight control of the expression of its Epstein-Barr nuclear antigen-1 (EBNA1) protein, the EBV-encoded genome maintenance protein. Indeed, EBNA1 is essential for viral genome replication and maintenance but, at the same time, is also highly antigenic and T cells raised against EBNA1 exist in infected individuals. For this reason, EBNA1 is considered as the Achilles heel of EBV and the virus has seemingly evolved a strategy that employs the binding of nucleolin, a host cell factor, to RNA G-quadruplex (rG4) within EBNA1 mRNA to limit its expression to the minimal level required for function while minimizing immune recognition. This review recapitulates in a historical way the knowledge accumulated on EBNA1 immune evasion and discusses how this rG4-dependent mechanism can be exploited as an intervention point to unveil EBV-related cancers to the immune system.
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Affiliation(s)
- Van-Trang Dinh
- Univ Brest; Inserm UMR1078; Etablissement Français Du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 22 Avenue Camille Desmoulins, F-29200 Brest, France.
| | - Nadège Loaëc
- Univ Brest; Inserm UMR1078; Etablissement Français Du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 22 Avenue Camille Desmoulins, F-29200 Brest, France
| | - Alicia Quillévéré
- Univ Brest; Inserm UMR1078; Etablissement Français Du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 22 Avenue Camille Desmoulins, F-29200 Brest, France
| | - Ronan Le Sénéchal
- Univ Brest; Inserm UMR1078; Etablissement Français Du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 22 Avenue Camille Desmoulins, F-29200 Brest, France
| | - Marc Keruzoré
- Univ Brest; Inserm UMR1078; Etablissement Français Du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 22 Avenue Camille Desmoulins, F-29200 Brest, France
| | | | - Anton Granzhan
- Chemistry and Modelling for the Biology of Cancer (CMBC), CNRS UMR9187, Inserm U1196, Institut Curie, Université Paris Saclay, F-91405 Orsay, France
| | - Marc Blondel
- Univ Brest; Inserm UMR1078; Etablissement Français Du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 22 Avenue Camille Desmoulins, F-29200 Brest, France.
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11
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Zhang Q, Xu M. EBV-induced T-cell responses in EBV-specific and nonspecific cancers. Front Immunol 2023; 14:1250946. [PMID: 37841280 PMCID: PMC10576448 DOI: 10.3389/fimmu.2023.1250946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/12/2023] [Indexed: 10/17/2023] Open
Abstract
Epstein-Barr virus (EBV) is a ubiquitous human tumor virus associated with various malignancies, including B-lymphoma, NK and T-lymphoma, and epithelial carcinoma. It infects B lymphocytes and epithelial cells within the oropharynx and establishes persistent infection in memory B cells. With a balanced virus-host interaction, most individuals carry EBV asymptomatically because of the lifelong surveillance by T cell immunity against EBV. A stable anti-EBV T cell repertoire is maintained in memory at high frequency in the blood throughout persistent EBV infection. Patients with impaired T cell immunity are more likely to develop life-threatening lymphoproliferative disorders, highlighting the critical role of T cells in achieving the EBV-host balance. Recent studies reveal that the EBV protein, LMP1, triggers robust T-cell responses against multiple tumor-associated antigens (TAAs) in B cells. Additionally, EBV-specific T cells have been identified in EBV-unrelated cancers, raising questions about their role in antitumor immunity. Herein, we summarize T-cell responses in EBV-related cancers, considering latency patterns, host immune status, and factors like human leukocyte antigen (HLA) susceptibility, which may affect immune outcomes. We discuss EBV-induced TAA-specific T cell responses and explore the potential roles of EBV-specific T cell subsets in tumor microenvironments. We also describe T-cell immunotherapy strategies that harness EBV antigens, ranging from EBV-specific T cells to T cell receptor-engineered T cells. Lastly, we discuss the involvement of γδ T-cells in EBV infection and associated diseases, aiming to elucidate the comprehensive interplay between EBV and T-cell immunity.
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Affiliation(s)
| | - Miao Xu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, Guangdong, China
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12
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Bialek W, Collawn JF, Bartoszewski R. Ubiquitin-Dependent and Independent Proteasomal Degradation in Host-Pathogen Interactions. Molecules 2023; 28:6740. [PMID: 37764516 PMCID: PMC10536765 DOI: 10.3390/molecules28186740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/18/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
Ubiquitin, a small protein, is well known for tagging target proteins through a cascade of enzymatic reactions that lead to protein degradation. The ubiquitin tag, apart from its signaling role, is paramount in destabilizing the modified protein. Here, we explore the complex role of ubiquitin-mediated protein destabilization in the intricate proteolysis process by the 26S proteasome. In addition, the significance of the so-called ubiquitin-independent pathway and the role of the 20S proteasome are considered. Next, we discuss the ubiquitin-proteasome system's interplay with pathogenic microorganisms and how the microorganisms manipulate this system to establish infection by a range of elaborate pathways to evade or counteract host responses. Finally, we focus on the mechanisms that rely either on (i) hijacking the host and on delivering pathogenic E3 ligases and deubiquitinases that promote the degradation of host proteins, or (ii) counteracting host responses through the stabilization of pathogenic effector proteins.
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Affiliation(s)
- Wojciech Bialek
- Department of Biophysics, Faculty of Biotechnology, University of Wrocław, 50-383 Wrocław, Poland
| | - James F. Collawn
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
| | - Rafal Bartoszewski
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
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13
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Oswald J, Constantine M, Adegbuyi A, Omorogbe E, Dellomo AJ, Ehrlich ES. E3 Ubiquitin Ligases in Gammaherpesviruses and HIV: A Review of Virus Adaptation and Exploitation. Viruses 2023; 15:1935. [PMID: 37766341 PMCID: PMC10535929 DOI: 10.3390/v15091935] [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: 08/21/2023] [Revised: 09/10/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
For productive infection and replication to occur, viruses must control cellular machinery and counteract restriction factors and antiviral proteins. Viruses can accomplish this, in part, via the regulation of cellular gene expression and post-transcriptional and post-translational control. Many viruses co-opt and counteract cellular processes via modulation of the host post-translational modification machinery and encoding or hijacking kinases, SUMO ligases, deubiquitinases, and ubiquitin ligases, in addition to other modifiers. In this review, we focus on three oncoviruses, Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), and human immunodeficiency virus (HIV) and their interactions with the ubiquitin-proteasome system via viral-encoded or cellular E3 ubiquitin ligase activity.
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Affiliation(s)
| | | | | | | | | | - Elana S. Ehrlich
- Department of Biological Sciences, Towson University, Towson, MD 21252, USA
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14
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Andersen O, Ernberg I, Hedström AK. Treatment Options for Epstein-Barr Virus-Related Disorders of the Central Nervous System. Infect Drug Resist 2023; 16:4599-4620. [PMID: 37465179 PMCID: PMC10351589 DOI: 10.2147/idr.s375624] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 06/28/2023] [Indexed: 07/20/2023] Open
Abstract
Epstein-Barr virus (EBV), a causative agent for several types of lymphomas and mucosal cancers, is a human lymphotropic herpesvirus with the capacity to establish lifelong latent infection. More than 90% of the human population worldwide is infected. The primary infection is usually asymptomatic in childhood, whereas infectious mononucleosis (IM) is common when the infection occurs in adolescence. Primary EBV infection, with or without IM, or reactivation of latent infection in immunocompromised individuals have been associated with a wide range of neurologic conditions, such as encephalitis, meningitis, acute disseminated encephalomyelitis, and cerebellitis. EBV is also involved in malignant lymphomas in the brain. An increasing number of reports on EBV-related disorders of the central nervous system (CNS) including the convincing association with multiple sclerosis (MS) have put in focus EBV-related conditions beyond its established link to malignancies. In this review, we present the clinical manifestations of EBV-related CNS-disorders, put them in the context of known EBV biology and focus on available treatment options and future therapeutic approaches.
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Affiliation(s)
- Oluf Andersen
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ingemar Ernberg
- Department of Microbiology, Tumor and Cell Biology, Biomedicum Q8C, Karolinska Institutet, Stockholm, 171 77, Sweden
| | - Anna Karin Hedström
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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15
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Zhu B, Ouda R, de Figueiredo P, Kobayashi KS. ORF6, a repressor of the MHC class I pathway: new molecular target for SARS-CoV-2 drug discovery? Expert Opin Ther Targets 2023; 27:639-644. [PMID: 37602463 DOI: 10.1080/14728222.2023.2248377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 07/19/2023] [Accepted: 08/10/2023] [Indexed: 08/22/2023]
Affiliation(s)
- Baohui Zhu
- Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Ryota Ouda
- Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Paul de Figueiredo
- Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology and Immunology, and Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA
| | - Koichi S Kobayashi
- Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Hokkaido University, Institute for Vaccine Research and Development (HU-IVReD), Sapporo, Japan
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX, USA
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16
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Parisi F, Fonti N, Millanta F, Freer G, Pistello M, Poli A. Exploring the link between viruses and cancer in companion animals: a comprehensive and comparative analysis. Infect Agent Cancer 2023; 18:40. [PMID: 37386451 DOI: 10.1186/s13027-023-00518-7] [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: 05/12/2023] [Accepted: 06/16/2023] [Indexed: 07/01/2023] Open
Abstract
Currently, it is estimated that 15% of human neoplasms globally are caused by infectious agents, with new evidence emerging continuously. Multiple agents have been implicated in various forms of neoplasia, with viruses as the most frequent. In recent years, investigation on viral mechanisms underlying tumoral transformation in cancer development and progression are in the spotlight, both in human and veterinary oncology. Oncogenic viruses in veterinary medicine are of primary importance not only as original pathogens of pets, but also in the view of pets as models of human malignancies. Hence, this work will provide an overview of the main oncogenic viruses of companion animals, with brief notes of comparative medicine.
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Affiliation(s)
- Francesca Parisi
- Dipartimento di Scienze Veterinarie, Università di Pisa, Viale delle Piagge, 2, 56124, Pisa, Italy.
| | - Niccolò Fonti
- Dipartimento di Scienze Veterinarie, Università di Pisa, Viale delle Piagge, 2, 56124, Pisa, Italy
| | - Francesca Millanta
- Dipartimento di Scienze Veterinarie, Università di Pisa, Viale delle Piagge, 2, 56124, Pisa, Italy
| | - Giulia Freer
- Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, Via Risorgimento, 36, 56126, Pisa, Italy
| | - Mauro Pistello
- Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, Via Risorgimento, 36, 56126, Pisa, Italy
| | - Alessandro Poli
- Dipartimento di Scienze Veterinarie, Università di Pisa, Viale delle Piagge, 2, 56124, Pisa, Italy
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17
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Gomes AC, Baraniak IA, McIntosh MR, Sodi I, Langstone T, Siddiqui S, Atkinson C, McLean GR, Griffiths PD, Reeves MB. A temperature-dependent virus-binding assay reveals the presence of neutralizing antibodies in human cytomegalovirus gB vaccine recipients' sera. J Gen Virol 2023; 104:001860. [PMID: 37310000 PMCID: PMC10661908 DOI: 10.1099/jgv.0.001860] [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: 03/22/2023] [Accepted: 05/15/2023] [Indexed: 06/14/2023] Open
Abstract
Human cytomegalovirus (HCMV) remains an important cause of mortality in immune-compromised transplant patients and following congenital infection. Such is the burden, an effective vaccine strategy is considered to be of the highest priority. The most successful vaccines to date have focused on generating immune responses against glycoprotein B (gB) - a protein essential for HCMV fusion and entry. We have previously reported that an important component of the humoral immune response elicited by gB/MF59 vaccination of patients awaiting transplant is the induction of non-neutralizing antibodies that target cell-associated virus with little evidence of concomitant classical neutralizing antibodies. Here we report that a modified neutralization assay that promotes prolonged binding of HCMV to the cell surface reveals the presence of neutralizing antibodies in sera taken from gB-vaccinated patients that cannot be detected using standard assays. We go on to show that this is not a general feature of gB-neutralizing antibodies, suggesting that specific antibody responses induced by vaccination could be important. Although we can find no evidence that these neutralizing antibody responses are a correlate of protection in vivo in transplant recipients their identification demonstrates the utility of the approach in identifying these responses. We hypothesize that further characterization has the potential to aid the identification of functions within gB that are important during the entry process and could potentially improve future vaccine strategies directed against gB if they prove to be effective against HCMV at higher concentrations.
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Affiliation(s)
- Ariane C. Gomes
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, Royal Free Campus, London, NW3 2PP, UK
| | - Ilona A. Baraniak
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, Royal Free Campus, London, NW3 2PP, UK
| | - Megan R. McIntosh
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, Royal Free Campus, London, NW3 2PP, UK
| | - Isabella Sodi
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, Royal Free Campus, London, NW3 2PP, UK
| | - Toby Langstone
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, Royal Free Campus, London, NW3 2PP, UK
| | - Saima Siddiqui
- London Metropolitan University, School of Human Sciences, London, N7 8DB, UK
| | - Claire Atkinson
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, Royal Free Campus, London, NW3 2PP, UK
| | - Gary R. McLean
- London Metropolitan University, School of Human Sciences, London, N7 8DB, UK
- Imperial College London, National Heart and Lung Institute, London, W2 1PG, UK
| | - Paul D. Griffiths
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, Royal Free Campus, London, NW3 2PP, UK
| | - Matthew B. Reeves
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, Royal Free Campus, London, NW3 2PP, UK
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18
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Abstract
The critical role of conventional dendritic cells in physiological cross-priming of immune responses to tumors and pathogens is widely documented and beyond doubt. However, there is ample evidence that a wide range of other cell types can also acquire the capacity to cross-present. These include not only other myeloid cells such as plasmacytoid dendritic cells, macrophages and neutrophils, but also lymphoid populations, endothelial and epithelial cells and stromal cells including fibroblasts. The aim of this review is to provide an overview of the relevant literature that analyzes each report cited for the antigens and readouts used, mechanistic insight and in vivo experimentation addressing physiological relevance. As this analysis shows, many reports rely on the exceptionally sensitive recognition of an ovalbumin peptide by a transgenic T cell receptor, with results that therefore cannot always be extrapolated to physiological settings. Mechanistic studies remain basic in most cases but reveal that the cytosolic pathway is dominant across many cell types, while vacuolar processing is most encountered in macrophages. Studies addressing physiological relevance rigorously remain exceptional but suggest that cross-presentation by non-dendritic cells may have significant impact in anti-tumor immunity and autoimmunity.
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Affiliation(s)
- François-Xavier Mauvais
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France; Service de Physiologie - Explorations Fonctionnelles Pédiatriques, AP-HP, Hôpital Universitaire Robert Debré, F-75019 Paris, France.
| | - Peter van Endert
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France; Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, F-75015 Paris, France.
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19
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Yu H, Robertson ES. Epstein-Barr Virus History and Pathogenesis. Viruses 2023; 15:714. [PMID: 36992423 PMCID: PMC10056551 DOI: 10.3390/v15030714] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/04/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Epstein-Barr virus (EBV) is the first identified human oncogenic virus that can establish asymptomatic life-long persistence. It is associated with a large spectrum of diseases, including benign diseases, a number of lymphoid malignancies, and epithelial cancers. EBV can also transform quiescent B lymphocytes into lymphoblastoid cell lines (LCLs) in vitro. Although EBV molecular biology and EBV-related diseases have been continuously investigated for nearly 60 years, the mechanism of viral-mediated transformation, as well as the precise role of EBV in promoting these diseases, remain a major challenge yet to be completely explored. This review will highlight the history of EBV and current advances in EBV-associated diseases, focusing on how this virus provides a paradigm for exploiting the many insights identified through interplay between EBV and its host during oncogenesis, and other related non-malignant disorders.
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Affiliation(s)
- Hui Yu
- Department of Hematology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, The Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Erle S. Robertson
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, The Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
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20
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Chapman J. Immunodeficiency-Associated Epstein-Barr Virus-Positive B-cell Lymphoproliferative Disorders. Surg Pathol Clin 2023; 16:213-231. [PMID: 37149357 DOI: 10.1016/j.path.2023.01.008] [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: 03/12/2023]
Abstract
Sources of immune deficiency and dysregulation (IDD) are being increasingly recognized and defined, as are IDD-related B-cell lymphoproliferative lesions and lymphomas occurring in these patients. In this review, basic biology of Epstein-Barr virus (EBV) as it relates to classification of EBV-positive B-cell lymphoproliferative disorders (LPDs) is reviewed. Also discussed is the new paradigm of classification of IDD-related LPDs adopted by the fifth edition World Health Organization classification. IDD-related EBV-positive B-cell hyperplasias, LPDs, and lymphomas are discussed with particular attention to unifying and unique features that assist with recognition of these IDD-related lesions and their classification scheme.
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Affiliation(s)
- Jennifer Chapman
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Miami Hospital/Sylvester Comprehensive Cancer Center, 1400 Northwest 12th Avenue, Miami, FL 33136, USA.
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21
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The lytic phase of Epstein-Barr virus plays an important role in tumorigenesis. Virus Genes 2023; 59:1-12. [PMID: 36242711 DOI: 10.1007/s11262-022-01940-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 10/02/2022] [Indexed: 01/13/2023]
Abstract
Epstein-Barr virus (EBV) is a recognized oncogenic virus that is related to the occurrence of lymphoma, nasopharyngeal carcinoma (NPC), and approximately 10% of gastric cancer (GC). EBV is a herpesvirus, and like other herpesviruses, EBV has a biphasic infection mode made up of latent and lytic infections. It has been established that latent infection promotes tumorigenesis in previous research, but in recent years, there has been new evidence that suggests that the lytic infection mode could also promote tumorigenesis. In this review, we mainly discuss the contribution of the EBV lytic phase to tumorigenesis, and graphically illustrate their relationship in detail. In addition, we described the relationship between the lytic cycle of EBV and autophagy. Finally, we also preliminarily explored the influence of the tumorigenesis effect of the EBV lytic phase on the future treatment of EBV-associated tumors.
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22
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Abstract
Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus with a well-established causal role in several cancers. Recent studies have provided compelling epidemiological and mechanistic evidence for a causal role of EBV in multiple sclerosis (MS). MS is the most prevalent chronic inflammatory and neurodegenerative disease of the central nervous system and is thought to be triggered in genetically predisposed individuals by an infectious agent, with EBV as the lead candidate. How a ubiquitous virus that typically leads to benign latent infections can promote cancer and autoimmune disease in at-risk populations is not fully understood. Here we review the evidence that EBV is a causal agent for MS and how various risk factors may affect EBV infection and immune control. We focus on EBV contributing to MS through reprogramming of latently infected B lymphocytes and the chronic presentation of viral antigens as a potential source of autoreactivity through molecular mimicry. We consider how knowledge of EBV-associated cancers may be instructive for understanding the role of EBV in MS and discuss the potential for therapies that target EBV to treat MS.
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Affiliation(s)
- Samantha S. Soldan
- grid.251075.40000 0001 1956 6678The Wistar Institute, Philadelphia, PA USA
| | - Paul M. Lieberman
- grid.251075.40000 0001 1956 6678The Wistar Institute, Philadelphia, PA USA
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23
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Huang J, Harris E, Lorch J. Vaccination as a therapeutic strategy for Nasopharyngeal carcinoma. Oral Oncol 2022; 135:106083. [DOI: 10.1016/j.oraloncology.2022.106083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/01/2022] [Accepted: 08/10/2022] [Indexed: 11/06/2022]
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24
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Kanduc D. The Role of Codon Usage, tRNA Availability, and Cell Proliferation in EBV Latency and (Re)Activation. Glob Med Genet 2022; 9:219-225. [PMID: 36118264 PMCID: PMC9477563 DOI: 10.1055/s-0042-1751301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/09/2022] [Indexed: 11/25/2022] Open
Abstract
Epstein–Barr nuclear antigen 1 (EBNA1) protein synthesis is inhibited during Epstein–Barr virus (EBV) latency and is resumed in EBV (re)activation. In analyzing the molecular mechanisms underpinning the translation of
EBNA1
in the human host, this article deals with two orders of data. First, it shows that the heavily biased codon usage of the
EBNA1
open reading frame cannot be translated due to its noncompliance with the human codon usage pattern and the corresponding tRNA pool. The
EBNA1
codon bias resides in the sequence composed exclusively of glycine and alanine, i.e., the Gly-Ala repeat (GAR). Removal of the nucleotide sequence coding for GAR results in an
EBNA1
codon usage pattern with a lower codon bias, thus conferring translatability to EBNA1. Second, the data bring cell proliferation to the fore as a conditio sine qua non for qualitatively and quantitatively modifying the host's tRNA pool as required by the translational needs of EBNA1, thus enabling viral reactivation. Taken together, the present work provides a biochemical mechanism for the pathogen's shift from latency to (re)activation and confirms the role of human codon usage as a first-line tool of innate immunity in inhibiting pathogens' expression. Immunologically, this study cautions against using codon optimization and proliferation-inducing substances such as glucocorticoids and adjuvants, which can (re)activate the otherwise quiescent, asymptomatic, and innocuous EBV infection. Lastly, the data pose the question whether the causal pathogenic role attributed to EBV should instead be ascribed to the carcinogenesis-associated cellular proliferation.
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Affiliation(s)
- Darja Kanduc
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy
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25
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Ma H, Lippolis JD, Casas E. Expression Profiles and Interaction of MicroRNA and Transcripts in Response to Bovine Leukemia Virus Exposure. Front Vet Sci 2022; 9:887560. [PMID: 35928115 PMCID: PMC9343836 DOI: 10.3389/fvets.2022.887560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/08/2022] [Indexed: 12/03/2022] Open
Abstract
Bovine leukemia virus (BLV) infection in cattle is omnipresent, which causes significantly economical losses worldwide. The objective of this study was to determine microRNA (miRNA) and transcript profiles and to establish their relationship in response to exposure to the virus. Small noncoding and messenger RNA were extracted and sequenced from serum and white blood cells (WBCs) derived from seven BLV seropositive and seven seronegative cows. Transcriptomic profiles were generated by sequencing RNA libraries from WBC. Bta-miR-206 and bta-miR-133a-3p were differentially expressed in serum (P < 0.05). In WBC, bta-miR-335-3p, bta-miR-375, and bta-novel-miR76-3p were differentially expressed (P < 0.03). There were 64 differentially expressed transcripts (DETs). Gene ontology (GO) analysis of the DETs overexpressed in the seropositive group with GOs of response to stimulus and immune system process predicted that the DETs could potentially negatively regulate viral life cycle and viral entry or release from host cells. In addition, the DETs depleted in the seropositive group could play a role in the downregulation of antigen processing and presentation of endogenous peptide antigen via MHC class I. The differentially expressed miRNAs targeted 17 DETs, among which the expressions of bta-miR-133a-3p and bta-miR-335-3p were significantly negatively correlated with the expressions of ENSBTAT00000079143 and ENSBTAT00000066733, respectively. Under high prediction criteria, 90 targets of the differentially expressed miRNAs were all non-DETs. The most enriched biological process GO term of the targets was the RNA-dependent DNA biosynthetic process, which could be associated with virus replication. These results suggested that the differentially expressed miRNAs fine-tune most of the target genes in responding to BLV exposure. In addition, Bta-miR-206 interacted with BLV regulatory genes rex and tax by targeting their coding regions. A further study of the miRNAs and the genes may reveal the molecular mechanisms of BLV infection and uncover possible ways to prevent the infection.
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26
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Zhou L, Kong G, Palmisano I, Cencioni MT, Danzi M, De Virgiliis F, Chadwick JS, Crawford G, Yu Z, De Winter F, Lemmon V, Bixby J, Puttagunta R, Verhaagen J, Pospori C, Lo Celso C, Strid J, Botto M, Di Giovanni S. Reversible CD8 T cell-neuron cross-talk causes aging-dependent neuronal regenerative decline. Science 2022; 376:eabd5926. [PMID: 35549409 DOI: 10.1126/science.abd5926] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Aging is associated with increased prevalence of axonal injuries characterized by poor regeneration and disability. However, the underlying mechanisms remain unclear. In our experiments, RNA sequencing of sciatic dorsal root ganglia (DRG) revealed significant aging-dependent enrichment in T cell signaling both before and after sciatic nerve injury (SNI) in mice. Lymphotoxin activated the transcription factor NF-κB, which induced expression of the chemokine CXCL13 by neurons. This in turn recruited CXCR5+CD8+ T cells to injured DRG neurons overexpressing major histocompatibility complex class I. CD8+ T cells repressed the axonal regeneration of DRG neurons via caspase 3 activation. CXCL13 neutralization prevented CXCR5+CD8+ T cell recruitment to the DRG and reversed aging-dependent regenerative decline, thereby promoting neurological recovery after SNI. Thus, axonal regeneration can be facilitated by antagonizing cross-talk between immune cells and neurons.
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Affiliation(s)
- Luming Zhou
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Guiping Kong
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Ilaria Palmisano
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Maria Teresa Cencioni
- Division of Neurology, Department of Brain Sciences, Imperial College London, London, UK
| | - Matt Danzi
- Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Francesco De Virgiliis
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Jessica S Chadwick
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Greg Crawford
- Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Zicheng Yu
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Fred De Winter
- Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences, Amsterdam, Netherlands
| | - Vance Lemmon
- Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - John Bixby
- Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Radhika Puttagunta
- Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
| | - Joost Verhaagen
- Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences, Amsterdam, Netherlands
| | - Constandina Pospori
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, UK
- Department of Life Sciences, Imperial College London, South Kensington Campus, London, UK
| | - Cristina Lo Celso
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, UK
- Department of Life Sciences, Imperial College London, South Kensington Campus, London, UK
| | - Jessica Strid
- Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Marina Botto
- Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Simone Di Giovanni
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
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Characterization of an immune-evading doxycycline-inducible lentiviral vector for gene therapy in the spinal cord. Exp Neurol 2022; 355:114120. [DOI: 10.1016/j.expneurol.2022.114120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 11/18/2022]
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The Central Role of the Ubiquitin-Proteasome System in EBV-Mediated Oncogenesis. Cancers (Basel) 2022; 14:cancers14030611. [PMID: 35158879 PMCID: PMC8833352 DOI: 10.3390/cancers14030611] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/19/2022] [Accepted: 01/24/2022] [Indexed: 12/30/2022] Open
Abstract
Simple Summary Epstein–Barr virus (EBV) is the first discovered human tumor virus, which contributes to the oncogenesis of many human cancers. The ubiquitin–proteasome system is a key player during EBV-mediated oncogenesis and has been developed as a crucial therapeutic target for treatment. In this review, we briefly describe how EBV antigens can modulate the ubiquitin–proteasome system for targeted protein degradation and how they are regulated in the EBV life cycle to mediate oncogenesis. Additionally, the developed proteasome inhibitors are discussed for the treatment of EBV-associated cancers. Abstract Deregulation of the ubiquitin–proteasome system (UPS) plays a critical role in the development of numerous human cancers. Epstein–Barr virus (EBV), the first known human tumor virus, has evolved distinct molecular mechanisms to manipulate the ubiquitin–proteasome system, facilitate its successful infection, and drive opportunistic cancers. The interactions of EBV antigens with the ubiquitin–proteasome system can lead to oncogenesis through the targeting of cellular factors involved in proliferation. Recent studies highlight the central role of the ubiquitin–proteasome system in EBV infection. This review will summarize the versatile strategies in EBV-mediated oncogenesis that contribute to the development of specific therapeutic approaches to treat EBV-associated malignancies.
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Granai M, Lazzi S, Mancini V, Akarca A, Santi R, Vergoni F, Sorrentino E, Guazzo R, Mundo L, Cevenini G, Tripodo C, Di Stefano G, Puccini B, Ponzoni M, Sabattini E, Agostinelli C, Bassüllü N, Tecimer T, Demiroz AS, Mnango L, Dirnhofer S, Quintanilla‐Martinez L, Marafioti T, Fend F, Leoncini L. Burkitt lymphoma with a granulomatous reaction: an M1/Th1-polarised microenvironment is associated with controlled growth and spontaneous regression. Histopathology 2022; 80:430-442. [PMID: 33948980 PMCID: PMC9291779 DOI: 10.1111/his.14391] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 03/15/2021] [Accepted: 04/15/2021] [Indexed: 11/30/2022]
Abstract
AIMS Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously. METHODS AND RESULTS All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution. CONCLUSIONS Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy.
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Affiliation(s)
- Massimo Granai
- Department of Medical BiotechnologiesUniversity of SienaSienaItaly
- Institute of PathologyUniversity of TübingenTübingenGermany
| | - Stefano Lazzi
- Department of Medical BiotechnologiesUniversity of SienaSienaItaly
| | - Virginia Mancini
- Department of Medical BiotechnologiesUniversity of SienaSienaItaly
| | - Ayse Akarca
- Department of Cellular PathologyUniversity College LondonLondonUK
| | | | | | - Ester Sorrentino
- Department of Medical BiotechnologiesUniversity of SienaSienaItaly
| | - Raffaella Guazzo
- Department of Medical BiotechnologiesUniversity of SienaSienaItaly
| | - Lucia Mundo
- Department of Medical BiotechnologiesUniversity of SienaSienaItaly
- Health Research InstituteUniversity of LimerickLimerickIreland
| | | | - Claudio Tripodo
- Department of Human PathologyUniversity of PalermoPalermoItaly
| | | | | | - Maurilio Ponzoni
- Department of PathologyUniversity Vita‐Salute San RaffaeleMilanoItaly
| | - Elena Sabattini
- Haemolymphopathology Unit ‐ IRCCS ‐ Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | - Claudio Agostinelli
- Haemolymphopathology Unit ‐ IRCCS ‐ Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | | | - Tülay Tecimer
- Department of PathologyAcibadem UniversityİstanbulTurkey
| | | | - Leah Mnango
- Department of PathologyMuhimbili National Hospital and University for Healthcare and Allied SciencesDar‐es‐SalaamTanzania
| | | | | | - Teresa Marafioti
- Department of Cellular PathologyUniversity College LondonLondonUK
| | - Falko Fend
- Department of Medical BiotechnologiesUniversity of SienaSienaItaly
| | - Lorenzo Leoncini
- Department of Medical BiotechnologiesUniversity of SienaSienaItaly
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Abstract
Viruses are essentially, obligate intracellular parasites. They require a host to replicate their genetic material, spread to other cells, and eventually to other hosts. For humans, most viral infections are not considered lethal, regardless if at the cellular level, the virus can obliterate individual cells. Constant genomic mutations, (which can alter the antigenic content of viruses such as influenza or coronaviruses), zoonosis or immunosuppression/immunocompromisation, is when viruses achieve higher host mortality. Frequent examples of the severe consequenses of viral infection can be seen in children and the elderly. In most instances, the immune system will take a multifaceted approach in defending the host against viruses. Depending on the virus, the individual, and the point of entry, the immune system will initiate a robust response which involves multiple components. In this chapter, we expand on the total immune system, breaking it down to the two principal types: Innate and Adaptive Immunity, their different roles in viral recognition and clearance. Finally, how different viruses activate and evade different arms of the immune system.
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The Epstein-Barr Virus Oncogene EBNA1 Suppresses Natural Killer Cell Responses and Apoptosis Early after Infection of Peripheral B Cells. mBio 2021; 12:e0224321. [PMID: 34781735 PMCID: PMC8593684 DOI: 10.1128/mbio.02243-21] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The innate immune system serves as frontline defense against pathogens, such as bacteria and viruses. Natural killer (NK) cells are a part of innate immunity and can both secrete cytokines and directly target cells for lysis. NK cells express several cell surface receptors, including NKG2D, which bind multiple ligands. People with deficiencies in NK cells are often susceptible to uncontrolled infection by herpesviruses, such as Epstein-Barr virus (EBV). Infection with EBV stimulates both innate and adaptive immunity, yet the virus establishes lifelong latent infection in memory B cells. We show that the EBV oncogene EBNA1, previously known to be necessary for maintaining EBV genomes in latently infected cells, also plays an important role in suppressing NK cell responses and cell death in newly infected cells. EBNA1 does so by downregulating the NKG2D ligands ULBP1 and ULBP5 and modulating expression of c-Myc. B cells infected with a derivative of EBV that lacks EBNA1 are more susceptible to NK cell-mediated killing and show increased levels of apoptosis. Thus, EBNA1 performs a previously unappreciated role in reducing immune response and programmed cell death after EBV infection, helping infected cells avoid immune surveillance and apoptosis and thus persist for the lifetime of the host. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous human pathogen, infecting up to 95% of the world's adult population. Initial infection with EBV can cause infectious mononucleosis. EBV is also linked to several human malignancies, including lymphomas and carcinomas. Although infection by EBV alerts the immune system and causes an immune response, the virus persists for life in memory B cells. We show that the EBV protein EBNA1 can downregulate several components of the innate immune system linked to natural killer (NK) cells. This downregulation of NK cell activity translates to lower killing of EBV-infected cells and is likely one way that EBV escapes immune surveillance after infection. Additionally, we show that EBNA1 reduces apoptosis in newly infected B cells, allowing more of these cells to survive. Taken together, our findings uncover new functions of EBNA1 and provide insights into viral strategies to survive the initial immune response postinfection.
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SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis. Nat Commun 2021; 12:6602. [PMID: 34782627 PMCID: PMC8594428 DOI: 10.1038/s41467-021-26910-8] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 10/25/2021] [Indexed: 12/15/2022] Open
Abstract
The MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. Here we show that the MHC class I pathway is targeted by SARS-CoV-2. Analysis of the gene expression profile from COVID-19 patients as well as SARS-CoV-2 infected epithelial cell lines reveals that the induction of the MHC class I pathway is inhibited by SARS-CoV-2 infection. We show that NLRC5, an MHC class I transactivator, is suppressed both transcriptionally and functionally by the SARS-CoV-2 ORF6 protein, providing a mechanistic link. SARS-CoV-2 ORF6 hampers type II interferon-mediated STAT1 signaling, resulting in diminished upregulation of NLRC5 and IRF1 gene expression. Moreover, SARS-CoV-2 ORF6 inhibits NLRC5 function via blocking karyopherin complex-dependent nuclear import of NLRC5. Collectively, our study uncovers an immune evasion mechanism of SARS-CoV-2 that targets the function of key MHC class I transcriptional regulators, STAT1-IRF1-NLRC5. The presentation of viral antigens to T cells via the MHC molecules is a critical component of the host response to viral infection. Here the authors suggest SARS-CoV-2 possesses the immune evasion strategy against the MHC class I pathway by targeting key transcriptional regulators.
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Marongiu L, Allgayer H. Viruses in colorectal cancer. Mol Oncol 2021; 16:1423-1450. [PMID: 34514694 PMCID: PMC8978519 DOI: 10.1002/1878-0261.13100] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/15/2021] [Accepted: 09/10/2021] [Indexed: 12/23/2022] Open
Abstract
Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these – Epstein–Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) – have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes – such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis – not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53‐/pRb‐driven, epithelial–mesenchymal transition (EMT)‐/EGFR‐associated and especially Wnt/β‐catenin‐driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.
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Affiliation(s)
- Luigi Marongiu
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany
| | - Heike Allgayer
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany
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Abu Ahmad Y, Oknin-Vaisman A, Bitman-Lotan E, Orian A. From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization. Cells 2021; 10:2374. [PMID: 34572023 PMCID: PMC8469536 DOI: 10.3390/cells10092374] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/30/2021] [Accepted: 09/04/2021] [Indexed: 12/11/2022] Open
Abstract
A hallmark of cancer is dysregulated protein turnover (proteostasis), which involves pathologic ubiquitin-dependent degradation of tumor suppressor proteins, as well as increased oncoprotein stabilization. The latter is due, in part, to mutation within sequences, termed degrons, which are required for oncoprotein recognition by the substrate-recognition enzyme, E3 ubiquitin ligase. Stabilization may also result from the inactivation of the enzymatic machinery that mediates the degradation of oncoproteins. Importantly, inactivation in cancer of E3 enzymes that regulates the physiological degradation of oncoproteins, results in tumor cells that accumulate multiple active oncoproteins with prolonged half-lives, leading to the development of "degradation-resistant" cancer cells. In addition, specific sequences may enable ubiquitinated proteins to evade degradation at the 26S proteasome. While the ubiquitin-proteasome pathway was originally discovered as central for protein degradation, in cancer cells a ubiquitin-dependent protein stabilization pathway actively translates transient mitogenic signals into long-lasting protein stabilization and enhances the activity of key oncoproteins. A central enzyme in this pathway is the ubiquitin ligase RNF4. An intimate link connects protein stabilization with tumorigenesis in experimental models as well as in the clinic, suggesting that pharmacological inhibition of protein stabilization has potential for personalized medicine in cancer. In this review, we highlight old observations and recent advances in our knowledge regarding protein stabilization.
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Affiliation(s)
| | | | | | - Amir Orian
- Rappaport Faculty of Medicine, R-TICC, Technion-IIT, Efron St. Bat-Galim, Haifa 3109610, Israel; (Y.A.A.); (A.O.-V.); (E.B.-L.)
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EBNA2 driven enhancer switching at the CIITA-DEXI locus suppresses HLA class II gene expression during EBV infection of B-lymphocytes. PLoS Pathog 2021; 17:e1009834. [PMID: 34352044 PMCID: PMC8370649 DOI: 10.1371/journal.ppat.1009834] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/17/2021] [Accepted: 07/23/2021] [Indexed: 11/18/2022] Open
Abstract
Viruses suppress immune recognition through diverse mechanisms. Epstein-Barr Virus (EBV) establishes latent infection in memory B-lymphocytes and B-cell malignancies where it impacts B-cell immune function. We show here that EBV primary infection of naïve B-cells results in a robust down-regulation of HLA genes. We found that the viral encoded transcriptional regulatory factor EBNA2 bound to multiple regulatory regions in the HLA locus. Conditional expression of EBNA2 correlated with the down regulation of HLA class II transcription. EBNA2 down-regulation of HLA transcription was found to be dependent on CIITA, the major transcriptional activator of HLA class II gene transcription. We identified a major EBNA2 binding site downstream of the CIITA gene and upstream of DEXI, a dexamethasone inducible gene that is oriented head-to-head with CIITA gene transcripts. CRISPR/Cas9 deletion of the EBNA2 site upstream of DEXI attenuated CIITA transcriptional repression. EBNA2 caused an increase in DEXI transcription and a graded change in histone modifications with activation mark H3K27ac near the DEXI locus, and a loss of activation marks at the CIITA locus. A prominent CTCF binding site between CIITA and DEXI enhancers was mutated and further diminished the effects of EBNA2 on CIITA. Analysis of HiC data indicate that DEXI and CIITA enhancers are situated in different chromosome topological associated domains (TADs). These findings suggest that EBNA2 down regulates HLA-II genes through the down regulation of CIITA, and that this down regulation is an indirect consequence of EBNA2 enhancer formation at a neighboring TAD. We propose that enhancer competition between these neighboring chromosome domains represents a novel mechanism for gene regulation demonstrated by EBNA2.
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36
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Atkins JF, O’Connor KM, Bhatt PR, Loughran G. From Recoding to Peptides for MHC Class I Immune Display: Enriching Viral Expression, Virus Vulnerability and Virus Evasion. Viruses 2021; 13:1251. [PMID: 34199077 PMCID: PMC8310308 DOI: 10.3390/v13071251] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/11/2021] [Accepted: 06/19/2021] [Indexed: 01/02/2023] Open
Abstract
Many viruses, especially RNA viruses, utilize programmed ribosomal frameshifting and/or stop codon readthrough in their expression, and in the decoding of a few a UGA is dynamically redefined to specify selenocysteine. This recoding can effectively increase viral coding capacity and generate a set ratio of products with the same N-terminal domain(s) but different C-terminal domains. Recoding can also be regulatory or generate a product with the non-universal 21st directly encoded amino acid. Selection for translation speed in the expression of many viruses at the expense of fidelity creates host immune defensive opportunities. In contrast to host opportunism, certain viruses, including some persistent viruses, utilize recoding or adventitious frameshifting as part of their strategy to evade an immune response or specific drugs. Several instances of recoding in small intensively studied viruses escaped detection for many years and their identification resolved dilemmas. The fundamental importance of ribosome ratcheting is consistent with the initial strong view of invariant triplet decoding which however did not foresee the possibility of transitory anticodon:codon dissociation. Deep level dynamics and structural understanding of recoding is underway, and a high level structure relevant to the frameshifting required for expression of the SARS CoV-2 genome has just been determined.
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Affiliation(s)
- John F. Atkins
- Schools of Biochemistry and Microbiology, University College Cork, T12 XF62 Cork, Ireland; (K.M.O.); (P.R.B.); (G.L.)
| | - Kate M. O’Connor
- Schools of Biochemistry and Microbiology, University College Cork, T12 XF62 Cork, Ireland; (K.M.O.); (P.R.B.); (G.L.)
| | - Pramod R. Bhatt
- Schools of Biochemistry and Microbiology, University College Cork, T12 XF62 Cork, Ireland; (K.M.O.); (P.R.B.); (G.L.)
- Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland
| | - Gary Loughran
- Schools of Biochemistry and Microbiology, University College Cork, T12 XF62 Cork, Ireland; (K.M.O.); (P.R.B.); (G.L.)
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Sun C, Chen XC, Kang YF, Zeng MS. The Status and Prospects of Epstein-Barr Virus Prophylactic Vaccine Development. Front Immunol 2021; 12:677027. [PMID: 34168649 PMCID: PMC8218244 DOI: 10.3389/fimmu.2021.677027] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/20/2021] [Indexed: 12/30/2022] Open
Abstract
Epstein–Barr virus (EBV) is a human herpesvirus that is common among the global population, causing an enormous disease burden. EBV can directly cause infectious mononucleosis and is also associated with various malignancies and autoimmune diseases. In order to prevent primary infection and subsequent chronic disease, efforts have been made to develop a prophylactic vaccine against EBV in recent years, but there is still no vaccine in clinical use. The outbreak of the COVID-19 pandemic and the global cooperation in vaccine development against SARS-CoV-2 provide insights for next-generation antiviral vaccine design and opportunities for developing an effective prophylactic EBV vaccine. With improvements in antigen selection, vaccine platforms, formulation and evaluation systems, novel vaccines against EBV are expected to elicit dual protection against infection of both B lymphocytes and epithelial cells. This would provide sustainable immunity against EBV-associated malignancies, finally enabling the control of worldwide EBV infection and management of EBV-associated diseases.
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Affiliation(s)
- Cong Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Xin-Chun Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Yin-Feng Kang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
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The nonclassical immune surveillance for ERAAP function. Curr Opin Immunol 2021; 70:105-111. [PMID: 34098489 DOI: 10.1016/j.coi.2021.05.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/11/2021] [Accepted: 05/17/2021] [Indexed: 01/04/2023]
Abstract
The peptide repertoire presented by MHC class I molecules on the cell surface is essential for the immune surveillance of intracellular pathogens and transformed cells. The generation of this peptide repertoire is critically dependent on the endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP). Loss of ERAAP function leads to the generation of a profoundly disrupted peptide repertoire including many novel and immunogenic peptides. Strikingly, a large fraction of these novel peptides on ERAAP-KO cells are presented by the nonclassical MHC Ib molecule, Qa-1b. One immunodominant Qa-1b-restricted novel peptide is recognized by a unique CD8+ T cell population showing features of both conventional cytotoxic T cells and unconventional innate-like T cells. While much remains to be uncovered, here we summarize the latest discoveries of our lab on the important immune surveillance of ERAAP function mediated by nonclassical MHC Ib molecules and their unusual cognate T cells.
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Hepatitis C virus modulates signal peptide peptidase to alter host protein processing. Proc Natl Acad Sci U S A 2021; 118:2026184118. [PMID: 34035171 PMCID: PMC8179148 DOI: 10.1073/pnas.2026184118] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The mechanism by which hepatitis C virus (HCV) evades immune surveillance and causes chronic infection is unclear. We demonstrate here that HCV core protein interferes with the maturation of major histocompatibility complex (MHC) class I catalyzed by signal peptide peptidase (SPP) and induces degradation via HMG-CoA reductase degradation 1 homolog. In addition, we found that the core protein transmembrane domain is homologous to the human cytomegalovirus US2 protein, whose transmembrane region also targets SPP to impair MHC class I molecule expression in a similar manner. Therefore, our data suggest that SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses. Immunoevasins are viral proteins that prevent antigen presentation on major histocompatibility complex (MHC) class I, thus evading host immune recognition. Hepatitis C virus (HCV) evades immune surveillance to induce chronic infection; however, how HCV-infected hepatocytes affect immune cells and evade immune recognition remains unclear. Herein, we demonstrate that HCV core protein functions as an immunoevasin. Its expression interfered with the maturation of MHC class I molecules catalyzed by the signal peptide peptidase (SPP) and induced their degradation via HMG-CoA reductase degradation 1 homolog, thereby impairing antigen presentation to CD8+ T cells. The expression of MHC class I in the livers of HCV core transgenic mice and chronic hepatitis C patients was impaired but was restored in patients achieving sustained virological response. Finally, we show that the human cytomegalovirus US2 protein, possessing a transmembrane region structurally similar to the HCV core protein, targets SPP to impair MHC class I molecule expression. Thus, SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses.
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Regulation of the Macroautophagic Machinery, Cellular Differentiation, and Immune Responses by Human Oncogenic γ-Herpesviruses. Viruses 2021; 13:v13050859. [PMID: 34066671 PMCID: PMC8150893 DOI: 10.3390/v13050859] [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: 04/19/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 11/21/2022] Open
Abstract
The human γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) encode oncogenes for B cell transformation but are carried by most infected individuals without symptoms. For this purpose, they manipulate the anti-apoptotic pathway macroautophagy, cellular proliferation and apoptosis, as well as immune recognition. The mechanisms and functional relevance of these manipulations are discussed in this review. They allow both viruses to strike the balance between efficient persistence and dissemination in their human hosts without ever being cleared after infection and avoiding pathologies in most of their carriers.
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Abstract
Purpose of Review Virus-associated malignancies are a global health burden, constituting 10-12% of cancers worldwide. As these tumors express foreign viral antigens that can elicit specific T cell responses, virus-directed immunotherapies are a promising treatment strategy. Specifically, adoptive cell transfer of virus-specific T cells (VSTs) has demonstrated the potential to eradicate cancers associated with certain viruses. Recent Findings Initial studies in 1990s first showed that VSTs specific for the Epstein-Barr virus (EBVSTs) can induce complete remissions in patients with post-transplant lymphoproliferative disease. Since then, studies have validated the specificity and safety of VSTs in multiple lymphomas and solid malignancies. However, challenges remain to optimize this platform for widespread use, including enhancing potency and persistence, overcoming the immunosuppressive tumor microenvironment, and streamlining manufacturing processes that comply with regulatory requirements. Summary This review focuses on data from clinical trials evaluating VSTs directed against three viruses (EBV, HPV and MCPyV), as well as recent preclinical and clinical advances, and potential future directions.
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Campion NJ, Ally M, Jank BJ, Ahmed J, Alusi G. The molecular march of primary and recurrent nasopharyngeal carcinoma. Oncogene 2021; 40:1757-1774. [PMID: 33479496 DOI: 10.1038/s41388-020-01631-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 01/30/2023]
Abstract
Nasopharyngeal carcinoma (NPC) results from the aberrant and uncontrolled growth of the nasopharyngeal epithelium. It is highly associated with the Epstein-Barr virus, especially in regions where it is endemic. In the last decade, significant advances in genetic sequencing techniques have allowed the discovery of many new abnormal molecular processes that undoubtedly contribute to the establishment, growth and spread of this deadly disease. In this review, we consider NPC as EBV induced. We summarise the recent discoveries and how they add to our understanding of the pathophysiology of NPC in the context of genomics first in primary and then in recurrent disease. Overall, we find key early events lead to p16 inactivation and cyclin D1 expression, allowing latent viral infection. Host and viral factors work together to affect a variety of molecular pathways, the most fundamental being activation of NF-κB. Nonetheless, much still yearns to be discovered, especially in recurrent NPC.
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Affiliation(s)
- Nicholas J Campion
- Department of Otorhinolaryngology and Head and Neck Surgery, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1BB, UK. .,Department of Otorhinolaryngology, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
| | - Munira Ally
- Department of Otorhinolaryngology and Head and Neck Surgery, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1BB, UK
| | - Bernhard J Jank
- Department of Otorhinolaryngology, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Jahangir Ahmed
- Department of Otorhinolaryngology and Head and Neck Surgery, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1BB, UK
| | - Ghassan Alusi
- Department of Otorhinolaryngology and Head and Neck Surgery, Barts Health NHS Trust, The Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1BB, UK
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43
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Strumillo ST, Kartavykh D, de Carvalho FF, Cruz NC, de Souza Teodoro AC, Sobhie Diaz R, Curcio MF. Host-virus interaction and viral evasion. Cell Biol Int 2021; 45:1124-1147. [PMID: 33533523 PMCID: PMC8014853 DOI: 10.1002/cbin.11565] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 01/24/2021] [Indexed: 12/12/2022]
Abstract
With each infectious pandemic or outbreak, the medical community feels the need to revisit basic concepts of immunology to understand and overcome the difficult times brought about by these infections. Regarding viruses, they have historically been responsible for many deaths, and such a peculiarity occurs because they are known to be obligate intracellular parasites that depend upon the host's cell machinery for their replication. Successful infection with the production of essential viral components requires constant viral evolution as a strategy to manipulate the cellular environment, including host internal factors, the host's nonspecific and adaptive immune responses to viruses, the metabolic and energetic state of the infected cell, and changes in the intracellular redox environment during the viral infection cycle. Based on this knowledge, it is fundamental to develop new therapeutic strategies for controlling viral dissemination, by means of antiviral therapies, vaccines, or antioxidants, or by targeting the inhibition or activation of cell signaling pathways or metabolic pathways that are altered during infection. The rapid recovery of altered cellular homeostasis during viral infection is still a major challenge. Here, we review the strategies by which viruses evade the host's immune response and potential tools used to develop more specific antiviral therapies to cure, control, or prevent viral diseases.
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Affiliation(s)
- Scheilla T Strumillo
- Department of Biochemistry, Laboratory of Cell Signaling, Federal University of São Paulo, São Paulo, Brazil
| | - Denis Kartavykh
- Department of Medicine, Laboratory of Retrovirology, Federal University of São Paulo, São Paulo, Brazil
| | - Fábio F de Carvalho
- Departament of Educational Development, Getulio Vargas Foundation, São Paulo, Brazil
| | - Nicolly C Cruz
- Department of Medicine, Laboratory of Retrovirology, Federal University of São Paulo, São Paulo, Brazil
| | - Ana C de Souza Teodoro
- Department of Biochemistry, Laboratory of Cell Signaling, Federal University of São Paulo, São Paulo, Brazil
| | - Ricardo Sobhie Diaz
- Department of Medicine, Laboratory of Retrovirology, Federal University of São Paulo, São Paulo, Brazil
| | - Marli F Curcio
- Department of Medicine, Laboratory of Retrovirology, Federal University of São Paulo, São Paulo, Brazil
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44
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Ylä-Anttila P, Gupta S, Masucci MG. The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit selective autophagy. Autophagy 2021; 17:3461-3474. [PMID: 33509017 PMCID: PMC8632276 DOI: 10.1080/15548627.2021.1874660] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Macroautophagy/autophagy plays an important role in the control of viral infections and viruses have evolved multiple strategies to interfere with autophagy to avoid destruction and promote their own replication and spread. Here we report that the deubiquitinase encoded in the N-terminal domain of the Epstein-Barr virus (EBV) large tegument protein, BPLF1, regulates selective autophagy. Mass spectrometry analysis identified several vesicular traffic and autophagy related proteins as BPLF1 interactors and potential substrates, suggesting that the viral protein targets this cellular defense during productive infection. Direct binding of BPLF1 to the autophagy receptor SQSTM1/p62 (sequestosome 1) was confirmed by co-immunoprecipitation of transfected BPLF1 and by in vitro affinity isolation of bacterially expressed proteins. Expression of the catalytically active BPLF1 was associated with decreased SQSTM1/p62 ubiquitination and failure to recruit LC3 to SQSTM1/p62-positive aggregates. Selective autophagy was inhibited as illustrated by the accumulation of large protein aggregates in BPLF1-positive cells co-transfected with an aggregate-prone HTT (huntingtin)-Q109 construct, and by a slower autophagy-dependent clearance of protein aggregates upon transfection of BPLF1 in cells expressing a tetracycline-regulated HTT-Q103. The inhibition of aggregate clearance was restored by overexpression of a SQSTM1/p62[E409A,K420R] mutant that does not require ubiquitination of Lys420 for cargo loading. These findings highlight a previously unrecognized role of the viral deubiquitinase in the regulation of selective autophagy, which may promote infection and the production of infectious virus.Abbreviations: BPLF1, BamH1 fragment left open reading frame-1; EBV, Epstein-Barr virus; GFP, green fluorescent protein; HTT, huntingtin; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; PB1, Phox and Bem1 domain; PE, phosphatidylethanolamine; SQSTM1/p62, sequestosome 1; UBA, ubiquitin-associated domain.
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Affiliation(s)
- Päivi Ylä-Anttila
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Soham Gupta
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Maria G Masucci
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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45
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Heslop HE, Sharma S, Rooney CM. Adoptive T-Cell Therapy for Epstein-Barr Virus-Related Lymphomas. J Clin Oncol 2021; 39:514-524. [PMID: 33434061 DOI: 10.1200/jco.20.01709] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Helen E Heslop
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX
| | - Sandhya Sharma
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX
| | - Cliona M Rooney
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX
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46
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Zhang F, Chen L, Zhou Y, Ding D, Hu Q, Liu Y, Li K, Wu S, He L, Lei M, Du R. Dexamethasone prevents the Epstein-Barr virus induced epithelial-mesenchymal transition in A549 cells. J Med Virol 2020; 92:3697-3708. [PMID: 32396272 DOI: 10.1002/jmv.25999] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/10/2020] [Indexed: 01/16/2023]
Abstract
Clinical data have shown that pulmonary interstitial fibrosis is likely to occur in the later stages of viral pneumonia. While viral infections are thought to cause chronic pulmonary interstitial inflammation and pulmonary fibrosis, it remains unclear if they promote pulmonary fibrosis by epithelial-mesenchymal transition (EMT). In this study, human epithelial cell line A549 has been used to model the infection of the Epstein-Barr virus (EBV) and the respiratory syncytial virus (RSV). Their differences were compared and the possible infection mechanisms analyzed by randomly assigning cells to one of five treatments. Exposure of the LMP1 is thought to be the key gene during EBV-induced EMT in the A549 cells. Enzyme-linked immunosorbent assay analysis revealed that the EBV infection was associated with the induction of a number of cytokines (interleukin-8 [IL-8], IL-13, tumor necrosis factor-α, and transforming growth factor-β) and dexamethasone (DXM) could significantly prevent the phenotypic changes, and partly the mechanisms related with the IL-13 pathway. Surprisingly, different results were seen with the RSV infection as the A549 cells still displayed an epithelial morphology but the levels of E-cadherin, α-SMA, vimentin, and fibronectin did not change. This is the first study demonstrating the different reactions induced by different viruses, and the protective effects of DXM on the EBV-induced EMT in the A549 cells by partially inhibiting the IL-13 pathway. These findings suggest a novel mechanism, by which DXM or anti-IL-13 may delay the progression of pulmonary fibrosis by preventing the progress of EBV-induced EMT.
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Affiliation(s)
- Fengqin Zhang
- Department of Respiratory and Critical Care Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Chen
- Department of Respiratory and Critical Care Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Zhou
- Department of Respiratory and Critical Care Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Ding
- Department of Respiratory and Critical Care Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiongjie Hu
- Department of Radiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiwen Liu
- Department of Radiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaiyan Li
- Department of Radiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sisi Wu
- Department of Critical Medicine, Wuhan Central Hospital, Wuhan, China
| | - Li He
- Department of Respiratory and Critical Care Medicine, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - Mei Lei
- Department of Respiratory and Critical Care Medicine, Pulmonary Hospital, Wuhan, China
| | - Ronghui Du
- Department of Respiratory and Critical Care Medicine, Pulmonary Hospital, Wuhan, China
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47
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Epstein-Barr Virus-Associated Post-transplant Lymphoproliferative Disease. Recent Results Cancer Res 2020. [PMID: 33200367 DOI: 10.1007/978-3-030-57362-1_9] [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: 10/03/2023]
Abstract
Epstein-Barr virus (EBV) is associated with a variety of malignancies including post-transplant lymphoproliferative disease (PTLD). These include B and T cell lymphomas, epithelial, and mesenchymal tumors. The virus is ubiquitous, transmitted in saliva, and not usually associated with the development of malignancy. PTLD is usually associated with EBV when it occurs soon after the transplant. Measurement of viral DNA in blood, especially plasma, may be useful in the diagnosis of PTLD. Treatment approaches include withdrawal of immunosuppression, monoclonal antibodies or antibody conjugates, cytotoxic chemotherapy, and a variety of virus-specific treatments such as adoptive cellular therapy with EBV-specific T cells. Approaches to prevention include selection of immunosuppressive regimens that minimize the risk. In the future, EBV vaccines may be available for potential transplant recipients.
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48
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Schneider SM, Lee BH, Nicola AV. Viral entry and the ubiquitin-proteasome system. Cell Microbiol 2020; 23:e13276. [PMID: 33037857 DOI: 10.1111/cmi.13276] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/17/2020] [Accepted: 09/19/2020] [Indexed: 02/06/2023]
Abstract
Viruses confiscate cellular components of the ubiquitin-proteasome system (UPS) to facilitate many aspects of the infectious cycle. The 26S proteasome is an ATP-dependent, multisubunit proteolytic machine present in all eukaryotic cells. The proteasome executes the controlled degradation of functional proteins, as well as the hydrolysis of aberrantly folded polypeptides. There is growing evidence for the role of the UPS in viral entry. The UPS assists in several steps of the initiation of infection, including endosomal escape of the entering virion, intracellular transport of incoming nucleocapsids and uncoating of the viral genome. Inhibitors of proteasome activity, including MG132, epoxomicin, lactacystin and bortezomib have been integral to developments in this area. Here, we review the mechanistic details of UPS involvement in the entry process of viruses from a multitude of families. The possibility of proteasome inhibitors as therapeutic antiviral agents is highlighted.
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Affiliation(s)
- Seth M Schneider
- Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.,School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA
| | - Becky H Lee
- Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA
| | - Anthony V Nicola
- Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.,School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA
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49
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KSHV LANA acetylation-selective acidic domain reader sequence mediates virus persistence. Proc Natl Acad Sci U S A 2020; 117:22443-22451. [PMID: 32820070 PMCID: PMC7486799 DOI: 10.1073/pnas.2004809117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Viruses modulate biochemical cellular pathways to permit infection. A recently described mechanism mediates selective protein interactions between acidic domain readers and unacetylated, lysine-rich regions, opposite of bromodomain function. Kaposi´s sarcoma (KS)-associated herpesvirus (KSHV) is tightly linked with KS, primary effusion lymphoma, and multicentric Castleman's disease. KSHV latently infects cells, and its genome persists as a multicopy, extrachromosomal episome. During latency, KSHV expresses a small subset of genes, including the latency-associated nuclear antigen (LANA), which mediates viral episome persistence. Here we show that LANA contains two tandem, partially overlapping, acidic domain sequences homologous to the SET oncoprotein acidic domain reader. This domain selectively interacts with unacetylated p53, as evidenced by reduced LANA interaction after overexpression of CBP, which acetylates p53, or with an acetylation mimicking carboxyl-terminal domain p53 mutant. Conversely, the interaction of LANA with an acetylation-deficient p53 mutant is enhanced. Significantly, KSHV LANA mutants lacking the acidic domain reader sequence are deficient for establishment of latency and persistent infection. This deficiency was confirmed under physiological conditions, on infection of mice with a murine gammaherpesvirus 68 chimera expressing LANA, where the virus was highly deficient in establishing latent infection in germinal center B cells. Therefore, LANA's acidic domain reader is critical for viral latency. These results implicate an acetylation-dependent mechanism mediating KSHV persistence and expand the role of acidic domain readers.
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50
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Mosaheb MM, Brown MC, Dobrikova EY, Dobrikov MI, Gromeier M. Harnessing virus tropism for dendritic cells for vaccine design. Curr Opin Virol 2020; 44:73-80. [PMID: 32771959 DOI: 10.1016/j.coviro.2020.07.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 07/17/2020] [Indexed: 01/13/2023]
Abstract
Dendritic cells (DCs) are pivotal stimulators of T cell responses. They provide essential signals (epitope presentation, proinflammatory cytokines, co-stimulation) to T cells and prime adaptive immunity. Therefore, they are paramount to immunization strategies geared to generate T cell immunity. The inflammatory signals DCs respond to, classically occur in the context of acute virus infection. Yet, enlisting viruses for engaging DCs is hampered by their penchant for targeting DCs with sophisticated immune evasive and suppressive ploys. In this review, we discuss our work on devising vectors based on a recombinant polio:rhinovirus chimera for effectively targeting and engaging DCs. We are juxtaposing this approach with commonly used, recently studied dsDNA virus vector platforms.
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Affiliation(s)
- Mubeen M Mosaheb
- Departments of Molecular Genetics & Microbiology and Neurosurgery, Duke University Medical School, MSRB1 Room 423, Box 3020 Durham, NC 27710, United States
| | - Michael C Brown
- Departments of Molecular Genetics & Microbiology and Neurosurgery, Duke University Medical School, MSRB1 Room 423, Box 3020 Durham, NC 27710, United States
| | - Elena Y Dobrikova
- Departments of Molecular Genetics & Microbiology and Neurosurgery, Duke University Medical School, MSRB1 Room 423, Box 3020 Durham, NC 27710, United States
| | - Mikhail I Dobrikov
- Departments of Molecular Genetics & Microbiology and Neurosurgery, Duke University Medical School, MSRB1 Room 423, Box 3020 Durham, NC 27710, United States
| | - Matthias Gromeier
- Departments of Molecular Genetics & Microbiology and Neurosurgery, Duke University Medical School, MSRB1 Room 423, Box 3020 Durham, NC 27710, United States.
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