Current topics in microbiology and immunology最新文献

Epstein-Barr virus is a ubiquitous gammaherpesvirus that usually causes an asymptomatic infection followed by lifelong persistence in memory B cells. Virus replication is controlled by a robust antiviral immune response, and EBV-associated lymphoproliferative diseases only develop in immunocompromised individuals. However, systemic chronic active Epstein-Barr virus (CAEBV) disease occurs in individuals without an apparent immunodeficiency or an underlying genetic immune defect. These individuals cannot control EBV infection, leading to life-threatening conditions including haemophagocytic lymphohistiocytosis, organ failure and malignant lymphomas. CAEBV disease is characterized by systemic inflammation, markedly elevated EBV DNA load in the blood, clonal expansion of EBV-infected T cells and/or NK cells, and multi-organ infiltration by the infected cells. Here we summarize the current understanding of the pathogenesis of systemic CAEBV disease, identifying viral, genetic and immunologic changes that could be integral to disease development and progression, as well as targeted by future precision medicine.

EBNA2 and EBNA-LP are the earliest expressed viral latency proteins following Epstein-Barr virus (EBV) infection of B cells and are essential for cellular transformation and immortalization. Both proteins are co-expressed during latency IIb and III states and exhibit temporal regulation from viral promoters Wp to Cp during the initial 24 h of infection. Recent advances have fundamentally transformed our understanding of EBNA2's mechanisms of action, revealing its ability to undergo liquid-liquid phase separation to form nuclear condensates that reorganize host chromatin topology and create accessible chromatin domains. EBNA2 functions through sophisticated partnerships with cellular transcription factors including RBP-Jκ and EBF1, exploiting preexisting B cell transcriptional networks by targeting super-enhancers and establishing new enhancer-promoter contacts that alter over 1700 chromatin looping interactions genome-wide. The protein's unique structural features, including the virus-specific N-terminal END domain and intrinsically disordered regions critical for phase separation, represent potential therapeutic targets. Importantly, EBNA2 has emerged as a critical factor in autoimmune disease pathogenesis, with specific alleles conferring differential multiple sclerosis risk through binding at autoimmune susceptibility loci. While historically viewed as an EBNA2 coactivator, EBNA-LP has been revealed to have essential EBNA2-independent functions, serving as a key viral antagonist of restriction factors Sp100 and Sp140L to prevent innate antiviral sensing and enable successful viral genome establishment. EBNA-LP regulates chromatin architecture through interactions with YY1 and modulates transcription factor-binding accessibility at cellular genes, while both proteins cooperate at EBV super-enhancers to control target gene networks essential for B cell transformation and survival.

Aberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and as such, it has been intensively pursued as a therapeutic target. Despite the high frequency of AKT activation in human tumors, the clinical performance of AKT inhibitors remained largely disappointing for many years. However, the recent approval of the AKT inhibitor capivasertib (formerly AZD-5363) for the treatment of breast cancer provides clinical validation of its therapeutic relevance and raises the possibility that AKT inhibitors could still provide clinical benefit either as monotherapy in patients with the rare AKT-E17K mutation or in broader patient populations when combined with other agents. In this chapter, we review the evidence for AKT dependence in human tumors, the importance of genetic and cellular context in AKT dependence, and the challenges of translating AKT inhibition into therapeutic benefit.

Epstein-Barr virus (EBV) is a potent oncogenic virus capable of manipulating cell death and cell survival pathways in order to persist in human B cells. Since the discovery of EBV in Burkitt's lymphoma cells in 1964, cell culture has played an important role in uncovering EBV's ability to overcome cell death pathways such as apoptosis and ferroptosis. Whilst apoptosis is a genetically defined and developmentally regulated non-immunogenic cell death program, ferroptosis is a mode of necrotic cell death that is closely linked to amino acid, lipid, redox, energy, selenium, and iron metabolism. Such cell culture studies have not only played a pivotal role in our understanding of the role of EBV in growth transformation and cancer but have also enriched knowledge in the fields of cell death. Artificial in vitro cell culture conditions including (i) oxygen partial pressure, (ii) media composition, (iii) cell density, (iv) cell-, and (v) pH-homo- versus heterogeneity have profound effects on cell growth and responses to death stimuli. In fact, a search for pro-survival genes in Burkitt's lymphoma cells plated at low cell density in FCS-supplemented RPMI 1640 medium had revealed two genes, glutathione peroxidase-4 (GPX4) and ferroptosis-suppressor protein-1 (FSP1), that are now well-known master regulators protecting cells from ferroptosis. Here we review those early fundamental studies and reflect on the subsequent literature that seeks to understand how EBV viral products can modulate cellular pathways during transformation and oncogenesis, reducing the requirement for mutations in cellular genes that are found more commonly in EBV-negative Burkitt's lymphomas.

Cell migration is an enormously complex process that requires sophisticated regulation and exquisite coordination of many cellular proteins that must act in a temporally and spatially orchestrated manner to achieve directional motion. Much like neuromuscular control of gait and walking, except within a single cell, a series of rapid feedback mechanisms must act in a cyclical manner to result in movement. The protein-serine kinase Akt/PKB that acts downstream of phosphatidylinositol 3' kinase (PI3K) activation is intricately involved in normal cell migration and in aberrant movement (e.g., cancer metastasis), but its role can be either pro- or anti-migration depending on cellular context. These contradictory effects likely reflect the nature of cellular motion, in that perturbations that disturb the continuity or integrity of migratory machines tend to be inhibitory. In contrast, increasing overall efficiency/coordination of the processes results in greater mobility. The net result of modulating Akt/PKB is therefore highly dependent upon other inputs into the cell and their context. Here, we briefly describe the molecular events associated with cellular migration, then describe current knowledge of Akt/PKB targets involved in this process, and conclude by discussing implications for suppression of cancer dissemination.

Burkitt lymphoma (BL) remains a prevalent pediatric cancer in sub-Saharan Africa and was the first human cancer identified with a virus when Epstein-Barr virus (EBV) was discovered in a Ugandan BL tumor in 1964. The impact of EBV in BL is highlighted by a new molecular tumor classification of EBV positivity versus negativity which is starting to supersede longstanding epidemiologic classifications. The high incidence of EBV-positive BL in Africa and Papua New Guinea has been linked to Plasmodium falciparum (Pf) malaria coinfections in young children. Epidemiologic studies have yielded insight into early-age EBV infections and have demonstrated direct impacts of Pf malaria infections on EBV reactivation and disruptions in EBV persistence. Moreover, when children residing in malaria holoendemic regions are contending with chronic Pf malaria infections, they undergo immune adaptations to mitigate life-threatening immunopathology. We postulate that this malaria-induced immune conditioning leads to diminished EBV-specific cellular immune surveillance, when combined with higher B cell proliferation, and EBV load creates a permissive environment for BL tumorigenesis.

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.

Genomic surveillance has emerged as a fundamental tool in the global response to dengue virus (DENV), enabling the rapid detection of viral strains, monitoring of transmission dynamics, and assessment of evolutionary changes that may impact disease control strategies. This chapter examines the critical role of genomic surveillance in addressing the ongoing dengue crisis, highlighting its contributions to outbreak detection, strain characterization, and vaccine efficacy assessments. We provide a comparative analysis of regional approaches to genomic surveillance, emphasizing disparities in infrastructure, sequencing capacity, and data-sharing frameworks across different epidemiological settings. Despite its transformative potential, the implementation of genomic surveillance faces significant challenges, including logistical constraints, limited sequencing accessibility in resource-limited settings, and issues related to data integration and public health decision-making. We discuss these barriers and propose strategies to enhance genomic surveillance efforts, such as strengthening international collaborations, fostering capacity-building initiatives, and integrating real-time sequencing technologies with epidemiological and ecological modeling. Finally, we explore future directions in genomic surveillance, advocating for a more coordinated and sustainable approach to genomic data generation and utilization, ultimately improving global preparedness and response to dengue and other emerging arboviruses.