Current topics in microbiology and immunology最新文献

Epstein-Barr virus (EBV) infects more than 90% of adults worldwide. Following the initial infection, the host immune system launches an antiviral response involving both innate and adaptive immune functions. EBV establishes a persistent, lifelong infection, and to achieve this, it must carefully regulate the host immune response. By striking a balance between viral replication and immune defense, the pathogenic effects of EBV are minimized while its presence is maintained. This chapter explores some of the immune-modulating strategies employed by EBV, particularly its interference with various arms of innate and adaptive immunity, including the MHC-I and MHC-II antigen presentation pathways.

Epstein-Barr Virus (EBV) establishes latent infection as a circular, chromatinized episome that can persist in the nucleus of dividing and quiescent B cells, as well as in some NK, T, and epithelial cancer cells. During latency, the viral genome can express a diverse program of viral genes that have profound effects on the host cell, including capacity for immortalization, metabolic shifts, and immune evasion. The selective expression of viral genes during latency requires complex coordination between viral and host factors. This coordination is regulated by the chromatin structure and epigenetic programming of the viral genome. Epigenetic programming is determined by chromatin assembly, nucleosome positioning, histone and DNA modifications, transcription factor binding, RNA polymerase signaling, DNA looping, higher-ordered chromatin architecture, and interactions with host chromosome domains and territories. In addition, the latent viral genome divides using host replication and chromosome segregation machinery. Under stress conditions, the viral episome can switch into a lytic cycle where many additional viral factors are expressed to control late gene expression and viral rolling-circle replication followed by virion assembly and packaging. How the chromatin structure of the virus controls and is coordinated with all of these different processes and transitions is the focus of this chapter. Here we highlight recent advances in EBV chromatin control since the first edition of this chapter.

Epstein-Barr virus (EBV) homologues from non-human primates (NHPs) have been studied for nearly as long as EBV itself. Early serologic and DNA hybridization studies uncovered the existence of EBV-like lymphocryptoviruses (LCVs) across multiple NHP species. Subsequent molecular and genomic analyses revealed that LCVs from both humans and NHPs share strikingly similar colinear genome organization and encode homologous proteins expressed during both latent and lytic phases of infection, despite a level of species-specific restriction being present as shown by cross-infection experiments. Importantly, rhLCV infection in rhesus macaques faithfully recapitulates key aspects of EBV infection in humans, allowing for a powerful EBV surrogate animal model to study EBV infection and pathogenesis. In parallel, EBV susceptibility in the common marmoset offers a more accessible platform for EBV vaccine development with the potential to complement rhLCV studies. This chapter builds upon the First Edition of this work by taking the original text, beautifully crafted by Drs. Janine Mühe and Fred Wang, and updating it with relevant new insights and information. The updated chapter reviews over six decades of progress in characterizing LCVs that naturally infect primates, highlights the transformative use of rhesus macaques and common marmosets as experimental models of EBV infection, and explores how these systems are shaping the future of EBV research and vaccine development.

Although the role of Epstein-Barr virus (EBV) in autoimmunity is biologically plausible and evidence of altered immune responses to EBV is abundant in several autoimmune diseases, inference on causality requires the determination that disease risk is higher in individuals infected with EBV than in those uninfected and that in the latter it increases following EBV infection. This determination has so far been obtained compellingly for multiple sclerosis (MS) and, to some extent, for systemic lupus erythematosus (SLE). In contrast, evidence is either lacking or not supportive for other autoimmune conditions. In this chapter, we present the main epidemiological findings that justify these conclusions and their implications for prevention and treatment.

Epstein-Barr virus (EBV) infection has been associated with an expanding range of acute inflammatory, malignant, and autoimmune disorders. Seroepidemiological studies, facilitated by the early identification of key immunodominant targets of the EBV-specific humoral response, have provided invaluable insights into pathogenicity and global prevalence and incidence of EBV infections. These studies have also identified distinct antibody signatures associated with both the acute and persistent phases of infection, as well as EBV-related disorders. Over time, research into the humoral immune response against EBV has progressed from traditional cell-based immunofluorescence methods to high-throughput multiplex assays utilizing recombinant proteins or synthetic peptides as substrates. These improvements have shifted the focus from individual immunodominant antigens to the entire EBV proteome, enhancing our understanding of antiviral antibody responses in both health and disease. Detailed analyses of antigenic epitopes have uncovered significant biochemical and sequence homology between viral and host proteins, providing a conceptual framework for understanding the development of autoimmune diseases by a phenomenon known as antigenic mimicry. Recently, research has shifted toward translating these immune response findings into therapeutic strategies aimed at inducing or restoring immunity in patients with EBV-associated disorders. This chapter seeks to provide a comprehensive overview of the humoral immune response to EBV in healthy virus carriers and patients with EBV-associated disorders, tracing developments from the discovery of the virus 60 years ago to the present day and offering a perspective on future directions.

Vaccines for Epstein-Barr virus (EBV) could be prophylactic to prevent primary infection and diseases directly caused by EBV, including mononucleosis and posttransplant lymphoproliferative disease. Prophylactic vaccines might also prevent or reduce diseases in which EBV is a cofactor, including multiple sclerosis and other autoimmune disorders, EBV-positive B cell lymphomas, nasopharyngeal carcinoma, and certain gastric carcinomas. Alternatively, EBV vaccines could be therapeutic to treat autoimmune disease and malignancies associated with EBV. In general, prophylactic vaccines focus on induction of antibody to the virus, while therapeutic vaccines focus on inducing virus-specific T cells to kill or control virus-infected cells.

Some human cancers are caused by coinfections with two viruses. Here we focus on primary effusion lymphomas (PEL), which arise from coinfection of B cells with Kaposi's Sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) and often are accompanied by systemic infections with human immunodeficiency virus (HIV). Both KSHV and EBV contribute to this oncogenesis of a rare B cell subset and HIV, by limiting the host immune response to coinfected cells, can too. Some of the mechanisms underlying the lymphomagenesis mediated by two tumor viruses are clear; some remain to be elucidated.

Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) account for about 10% of gastric cancers globally, with higher prevalence in East Asia and Latin America. These cancers develop through a "gastritis-infection-cancer sequence" and are characterized by unique molecular signatures, including CpG island methylator phenotype and mutations in ARID1A and PIK3CA genes. EBVaGCs typically present in the proximal stomach with diffuse-type histology and dense lymphocytic infiltration. Key viral proteins EBNA1 and LMP2A drive oncogenesis by altering cellular processes and immune responses. The IFN-γ signature and extensive epigenetic modifications contribute to their distinct profile. Despite often presenting at advanced stages, EBVaGCs generally have a more favorable prognosis. EBV employs sophisticated strategies to evade immune detection, utilizing latent proteins and noncoding RNAs. Paradoxically, despite an immune-hot environment, EBVaGCs demonstrate effective immune evasion, partly due to the expression of immune checkpoint molecules like PD-L1 and LAG3. Treatment approaches vary based on disease stage, from endoscopic resection for early-stage cancers to systemic therapies for advanced cases. Immunotherapy, particularly PD-1/PD-L1 inhibitors, shows promising results. Emerging research suggests combining these with LAG3 inhibitors may enhance efficacy. Ongoing research and advanced genomic techniques continue to reveal new insights, paving the way for personalized therapies and novel diagnostic approaches.

There are multiple established risk factors for DLBCL; these risk factors share an underlying biology, which generally cause immune dysfunction, spanning immunosuppression to chronic inflammation. EBV is an established risk factor for DLBCL and approximately 10% of DLBCLs are EBV-positive. EBV is a ubiquitous infection, and it is thus among populations that are immunocompromised, by age or medically defined, where EBV-positive DLBCLs arise. In this chapter, we review the current classification, epidemiology, clinical, pathology, and molecular characteristics of EBV-positive DLBCL, and discuss the role of EBV in lymphoma tumorigenesis. We further discuss current and novel treatments aimed at the NFκB pathway and other targets.

The Epstein-Barr virus (EBV) genetic map underpins all our understanding of the virus biology and its role in disease. EBV was the first large DNA virus to be fully sequenced and this has been followed by many years of detailed mapping of viral genes and other genetic elements. The genetic map of EBV is based on the reference NC_007605 virus genome but now more than 1,000 EBV genomes have been sequenced. Some sequence variations that may be functionally significant either for the biological properties of EBV or its detection by diagnostic procedures are summarised here but are also considered in detail in other chapters in this book.