Current topics in microbiology and immunology最新文献

LMP2A is the Rodney Dangerfield of viral oncogenes: It gets no respect. Initial impressions-that it was dispensable for EBV transformation of B lymphocytes and only enhanced transformation efficiency-still shape how this oncogene is viewed. This view needs to be reconsidered in light of a wealth of evidence supporting its role as a key oncogene in EBV-associated malignancies. LMP2A constitutively activates the PI3K/Akt/mTOR pathway, the most frequently mutated pathway in human cancer. In nasopharyngeal and gastric carcinomas, which account for most EBV-associated cancers, LMP2A is expressed much more frequently than LMP1 and is a dependency factor in both malignancies. Additionally, as a B cell receptor (BCR) mimic, LMP2A plays an essential role in EBV's persistence strategy of establishing life-long infection in memory-like B cells by mimicking germinal center reactions and maintaining EBV latency. Finally, recent studies suggest that LCLs are dependent on LMP2A signaling and ΔLMP2A-LCLs are phenotypically distinct from wildtype LCLs. As we seek to define EBV's role in autoimmunity, it will be important to understand the extent to which LMP2A contributes to these diseases as well. As a constitutive BCR mimic, LMP2A may drive aberrant B cell activation and survival, potentially promoting the breakdown of tolerance. We should be cautious not to underestimate its role in autoimmunity as was once done in cancer.

EBV expresses multiple viral noncoding RNAs (ncRNAs) throughout infection with regulatory activities that influence critical stages of the viral life cycle, including the establishment of latent infection and reactivation from latency. Advances in RNA sequencing technologies continue to reveal novel and diverse types of ncRNAs produced by EBV. Among these are the EBV-encoded RNAs (EBERs), the BamHI A rightward transcripts (BARTs), circular RNAs (circRNAs), stable intronic (sis) RNAs, lytic-associated ncRNAs, and viral microRNAs (miRNAs). While exact functions for most EBV ncRNAs are not fully resolved, multiple studies reveal important roles for these molecules in mediating essential aspects of the viral life cycle such as modulation of viral gene expression, cell survival, and immune evasion. This chapter updates our current knowledge of the different types of ncRNAs encoded by EBV and how these molecules critically contribute to viral persistence and disease.

The new era of microbial cell death stems from a flood of new information emanating from the mechanistic and evolutionary life sciences, philosophy, and even sociology. In the shifting landscape, longstanding cell death terminologies and concepts have rightfully been questioned. There is currently very little consensus on how these concepts should be defined. One result of this is that similar findings often prompt different explanations because of the diversity of meanings associated with the terms. In this chapter, we review terms and concepts in microbial cell death that are key to understanding cell mortality. We discuss concepts like cell death, mortality, and the distinction between endogenous and exogenous death. We examine the contentious problem of defining programmed cell death (PCD) and argue that an evolutionary concept of PCD is foundational and applies to all cells across the tree of life, including microbial taxa. Alternative conceptions that define PCD in mechanistic, developmental, and ecological terms are useful tools for dissecting the molecular mechanisms, environmental triggers, and functions of PCD, but they do not define what PCD fundamentally is. Finally, we emphasize the importance of being clear on such concepts in order to achieve an overarching cell mortality framework.

Classical Hodgkin lymphoma (cHL) is a unique B cell malignancy characterised by the presence of Hodgkin/Reed-Sternberg (HRS) cells within an extensive inflammatory microenvironment. In approximately 40% of cases- particularly in the mixed cellularity subtype-HRS cells are infected with the Epstein-Barr virus (EBV). EBV-positive cHL displays a restricted pattern of viral gene expression (latency II), with functional contributions from EBNA1, LMP1, and LMP2A/B, as well as some non-coding RNAs. This review synthesises current knowledge on the role of EBV in the pathogenesis of cHL. It provides an overview of molecular and immunological distinctions between EBV-positive and EBV-negative cHL, highlighting differences in host genomic alterations, immune evasion strategies, and tumour microenvironment composition. EBV+ cHL demonstrates a relatively lower mutational burden but harnesses viral proteins to subvert immune surveillance, recruit regulatory immune subsets, and upregulate checkpoint ligands, such as PD-L1. We also discuss the prognostic significance of EBV in cHL, its epidemiological associations with HLA polymorphisms, and emerging EBV-directed immunotherapies- including virus-specific T cell transfer and engineered TCR approaches.

Epstein Barr virus (EBV) was discovered 60 years ago as the first candidate human tumor virus. Since then, we have realized that this human γ-herpesvirus establishes persistent infection in the majority of adult humans but fortunately causes EBV associated diseases only in a few individuals. This is an incredible success story of the human immune system, which controls EBV infection and its transforming capacity for decades after initial virus encounter. A better understanding of this immune control would not only benefit patients with EBV associated malignancies but could also provide clues on how to establish such a potent, mostly cell-mediated immune control against other pathogens and tumors. However, the functional relevance of EBV specific immune responses can only be addressed in vivo and mice with reconstituted human immune system components (humanized mice) constitute a small animal model that can be infected with EBV, recapitulates some aspects of virus associated tumorigenesis, and mounts mostly cell-mediated immune responses against EBV. This chapter will summarize the insights into EBV immunobiology that have already been gained in humanized mouse models and provide an outlook into promising future avenues to further characterize EBV infection, immune control, and associated pathologies in vivo.

More than 500 primary immunodeficiencies (PIDs) or inborn errors of immunity (IEIs) have been reported. In general, IEIs are caused by monogenic germinal variants resulting in immunodeficiency and immune dysregulation symptoms. These "in natura" experiments have highlighted selective factors and pathways required for the immune control of a given pathogen, including Epstein-Barr virus (EBV). Several IEIs predominantly predispose to develop severe EBV infections and associated diseases including infectious mononucleosis (IM), hemophagocytic lymphohistiocytosis (HLH) and nonmalignant or malignant B cell lymphoproliferative disorders (B-LPD). Identification of these IEIs revealed critical components/molecules of the immune response to EBV. Notably, these elements differ depending on the type of the EBV viral disease. On one hand, defects in factors involved in the cytotoxic responses of lymphocytes preferentially underlie HLH, whereas, on the other hand, factors implicated in the expansion of EBV-specific T cells are mostly responsible for B-LPD when impaired. IEIs also inform on mechanisms underlying rare EBV viral diseases such as EBV⁺ smooth muscle tumors (EBV⁺SMT) and the "atypical" T/NK cell lymphoproliferative disorders (NK/T-LPD) including chronic active EBV infections (CAEBV). Finally, IEIs not predisposing to EBV provide information on immune components not necessary or redundant for EBV immunity. All these aspects are discussed in this chapter.

Infectious mononucleosis is a clinical entity characterized by a sore throat, cervical lymph node enlargement, fatigue, and fever most often seen in adolescents and young adults. Infectious mononucleosis is most often caused by a primary Epstein-Barr virus (EBV) infection. EBV is a γ-herpesvirus that infects at least 90% of the population worldwide. The virus is spread by intimate oral contact among teenagers and young adults. How preadolescents acquire the virus is not known. A typical clinical presentation with a positive heterophile antibody test is usually sufficient to make the diagnosis, but heterophile antibodies are not specific and do not develop in some patients, especially preadolescent children. EBV-specific antibody profiles are the best choice for confirming and staging EBV infection. Besides causing acute illness during primary infection, there can also be long-term consequences from acquiring this virus, such as certain cancers and autoimmune diseases, as well as complications of primary immunodeficiency in persons with certain genetic mutations. Future challenges are to develop prophylactic and therapeutic vaccines and effective specific treatment strategies.

The rising prevalence of antibiotic resistance is rendering certain antibiotics ineffective in treating bacterial infections of public health importance. Deepening our understanding of how these drugs induce bacterial cell death, and whether antibiotics trigger a cell death program compared to direct killing, could help generate novel antibiotics or modify existing therapeutic approaches to improve clinical outcomes. Among the most widely used bactericidal antibiotics (beta-lactams, aminoglycosides, and fluoroquinolones), the primary drug-target interactions, and how they induce cell death, are well characterized. Additionally, there has been a recent debate as to whether a generalized bacterial cell death mechanism exists, shared among bactericidal antibiotics. The hypothesized mechanism, referred to as the common reactive oxygen species (ROS) pathway in this chapter, argues that certain bactericidal antibiotics have off-target effects that increase ROS generation in an iron- and oxygen-dependent manner. Moreover, this spike in ROS is thought to also contribute to induced bacterial cell death. Here we will discuss the target-specific mechanisms of distinct classes of bactericidal antibiotics, how these promote bacterial cell death, and the data that both support and refute the existence of a common cell death pathway.

Nearly two decades after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) was identified and recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, where it plays a central role in pathogenesis. Over 40 years of research have established LMP1 as a potent driver of cellular transformation and survival, deregulating key signaling pathways, cellular metabolism, and transcription while simultaneously subverting programmed cell death mechanisms. Beyond its role in transformation and immortalization, LMP1 exerts multifaceted biological activities supporting tumorigenesis, including immune modulation, regulation of the tumor microenvironment, and promotion of migration and invasive tumor growth. Functioning as a constitutively active receptor that mimics co-stimulatory CD40 receptor signals in B-lymphocytes, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors (TNFRs), such as TNFR-associated factors (TRAFs) and the TNFR-associated death domain protein (TRADD). It triggers phosphorylation, ubiquitination, and SUMOylation events in the target cell to activate NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), interferon regulatory factor (IRF), and STAT pathways. This review provides an updated and comprehensive overview of the biological and molecular functions of LMP1, highlighting its role as a critical interface in virus-host interactions and its potential as a therapeutic target.

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.