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.

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.

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.

Phytoplankton are aquatic unicellular eukaryotic (i.e. protists) or prokaryotic photosynthetic organisms thriving in the world oceans. They are at the base of aquatic food webs and play a key role in determining the effects of the environmental change on the ocean surface. Phytoplankton are responsible for around 50% of the net amount of carbon assimilated annually by photoautotrophs. The removal of atmospheric CO does not only depend on CO fixation, but long-term carbon sequestration also requires the export of the organic matter fixed by phytoplankton in the surface layer (euphotic zone) into the deep ocean via a suite of processes collectively referred to as the biological carbon pump (BCP). The BCP likely transports 5-12 Pg C year into the deep ocean where it is buried and where it remains between thousands and millions of years. Approximately 50% of the CO emitted by human activity accumulates in the atmosphere, causing an increase in the average temperature of the Earth's surface and oceans. Around 40% of the CO emitted into the atmosphere is absorbed by the surface layers of the oceans, causing ocean acidification (OA) due to the increase in CO concentration in the water. We are therefore currently facing one of the greatest challenges of the twenty-first century. The scenario based on the SSP5-8.5 climate simulation (IPCC, AR6 2021) closely matches the total historical accumulated CO emissions (within 1%); moreover, this SSP5-8.5 scenario best represents mid-century greenhouse gas concentrations with current and declared emission policies, while forecasting very plausible atmospheric CO levels of 1,200 μatm by 2,100. Considering that even small changes in the BCP can have substantial effects on atmospheric CO levels, thus, the response of the BCP to future climate change is uncertain. Phytoplankton dynamics are driven by imbalances between growth and loss processes that are controlled by a combination of physical, chemical, and biological factors (drivers). Usually, grazing by zooplankton and viral infections stand at the base of phytoplankton population collapses. However, cell death (CD) also accounts for phytoplankton losses. Accumulating evidence suggests that CD, accidental (ACD) or regulated (RCD), occurs in phytoplankton under diverse environmental stresses, both in natural phytoplankton communities and in laboratory controlled experiments. GC affects phytoplankton species composition and size structure and favours species traits best acclimated and/or adapted to changing conditions associated with global change. Shifts in phytoplankton can have far-reaching consequences for the entire food web. The way phytoplankton dies critically determines marine ecosystem structure, functioning, and services. We aim in this chapter at capturing, re-grouping, and thoroughly analysing all the GC drivers studied up to date that cause cell death and/or severe stress in phytoplankton, trying to gain further insight on what could be the subsequent cell death outcome regarding the BCP.

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.

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.

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.

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.

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.

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.

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.

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 (EBVSMT) 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.

This chapter offers an overview of dengue vaccines that have advanced to clinical trials, addressing the intricate challenges in their development. It details the complexities of the dengue virus, including its four serotypes and the phenomenon of antibody-dependent enhancement (ADE), which significantly impacts vaccine design. The chapter reviews the historical trajectory and current landscape of vaccine candidates, such as Dengvaxia, Qdenga, and Butantan-DV, analyzing their efficacy, safety profiles, and the lessons learned from their clinical trials. It also discusses other hurdles like suitable animal models and viral interference. Ultimately, the chapter highlights the advancements made and outlines future research directions crucial for a universally effective dengue vaccine.

Dengue is the most common arboviral infection in the world, causing up to 400 million cases per year. Although most cases are asymptomatic, the virus can cause a wide range of symptoms varying from high fever and pain, common to several arbovirus infections, to hemorrhagic fever and shock syndrome, which can often be fatal. Despite the association of some genotypes with disease severity, most symptom varieties can be traced to the interaction of the virus with the immune system. As early as viral entry, Dengue virus co-evolved with humans to evade the innate immune system, especially the antiviral response triggered by type I and III interferons, posing a strict bottleneck to its host range. This directly affects our ability to study the virus interaction with the innate immune system. Here, we will explore how dengue virus is recognized by pattern recognition receptors and triggers an immune response and how cells associated with innate immunity influence the course of infection, culminating with the inflammatory response, key to understanding the spectrum of dengue disease.

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.

Dengue virus (DENV) is a rapidly evolving arbovirus responsible for significant morbidity and mortality worldwide. Understanding its evolutionary trajectory is essential for tracking viral emergence, transmission dynamics, and the factors driving its geographic expansion. This chapter provides a comprehensive overview of the genetic diversification and phylogenetic pathways of DENV, focusing on serotype evolution and the classification of genetic lineages. We discuss molecular phylogenetics as a key tool for elucidating the evolutionary relationships among DENV strains and highlight the application of phylodynamic approaches to infer viral dispersal patterns in endemic and newly affected regions. Furthermore, we examine the historical spread of DENV, with particular attention to cross-border transmission events facilitated by human mobility and trade. Additionally, we explore the role of climatic and ecological drivers, such as temperature fluctuations, vector adaptation, and urbanization, in shaping the evolutionary dynamics of the virus. By integrating genomic, epidemiological, and ecological data, this chapter underscores the importance of a multidisciplinary approach to dengue surveillance and control, ultimately contributing to the refinement of predictive models and public health interventions aimed at mitigating the impact of DENV outbreaks.

Dengue virus (DENV), the most prevalent arbovirus worldwide, continues to pose a major public health threat with no approved antiviral therapy to date. Despite decades of research, therapeutic development remains stalled at the preclinical stage, hindered by the virus's genetic variability, narrow therapeutic window, and complex interplay with the host immune system. This review offers a comprehensive overview of current antiviral strategies, covering both direct-acting antivirals (DAAs) targeting viral proteins (E, prM/M, C, NS2B/NS3, NS4A/B, and NS5) and host-targeting antivirals (HTAs) interfering with viral entry, replication, assembly, and immune modulation. Across 11 mechanistic categories, we observe a strong prevalence of natural products with in vitro efficacy, but limited advancement to in vivo or clinical testing. This translational gap reflects key limitations: restricted compound availability, lack of pharmacokinetic data, and insufficient collaboration between pharmacognosy, virology, and medicinal chemistry. We highlight the urgent need for integrated efforts to optimize promising leads and promote their clinical development. This review outlines the main challenges and perspectives to reinvigorate antiviral discovery against DENV.

Fungal infections pose an important threat to public health and food security, and with the rise in antifungal drug and fungicide resistance, we are faced with a global crisis. Currently, humanity is at an intersection of global climate change driving the expansion of species range distributions, emergence of novel pathogenic fungi, and changing at-risk populations. Here, we review the main mechanisms of antifungal drug and fungicide resistance, new drugs and mode-of-action drug classes, and future topics for risk reduction. We propose that integrating One Health and surveillance is a crucial first step in addressing this issue. Additionally, we emphasise that global collaboration among multiple stakeholders is essential to reverse the current upward trend in observed resistance. Finally, plant and medical mycologists can and should work together for the creation of a common language and antifungal stewardship plan.

Fungi are essential for a wide variety of food products and processes. They have a major role in the production of many fermented foodstuffs, may be eaten directly as fruit bodies and mycelium, and are used to produce food additives. They contribute to food production worldwide, even in cultures which do not typically consume mushrooms, because yeasts and edible moulds are utilised in a great variety of fermentation processes. Most fungal cultures used in food production at industrial scale show evidence of selection and domestication. However, other strains may still be obtained from the wild, either through incidental colonisation of a fermentation substrate as a result of a traditional preparation method or due to the inability to reliably cultivate a given organism, necessitating collection from its native habitat. This review provides an overview of the uses of fungi, both yeasts and filamentous fungi, in food production with a focus on research findings over the past decade. This includes a review of the production of foodstuffs through the fermentation of a wide variety of substrates, particularly dairy, but also including meat and plant matter. In addition, the use of fungi in the production of secreted enzymes and food additives is considered. Finally, the cultivation and harvesting of fungal fruiting bodies and mycoprotein are reviewed. The review aims to capture the breadth of the field by covering examples from every inhabited continent, including reference to fungal food systems which have historically been under-studied.

Fungi occupy many niches, are a major component of life, and contribute significantly to biodiversity. While fungi are rarely associated with human and animal diseases, they are often associated with diseases of plants as well as decay and nutrient cycling in the environment. Fungal diseases in agricultural crops can cause reductions in crop production and quality. In the context of human health, some fungi can also produce toxins that can accumulate in agricultural products, thereby affecting food safety and health. This chapter focuses on the complex interactions between fungi and agricultural crops in the context of human health, using fungi that infect and contaminate grain crops as examples.