Current topics in microbiology and immunology最新文献

Dengue is the most important viral disease transmitted to humans by mosquitoes and is caused by the dengue virus (DENV), which belongs to the Orthoflavivirus genus within the Flaviviridae family. The DENV RNA genome encodes ten proteins: three structural (C, prM, and E) and seven nonstructural (NS1-NS5) proteins. A comprehensive understanding of DENV interactions with both mammalian and mosquito cells is essential for the development of specific antivirals, which are currently lacking. In this chapter, we provide an overview of the viral replicative cycle, with a strong emphasis on the viral RNA genome, the composition of the replicative complexes, and the replication mechanisms. In addition, we discuss DENV-induced remodeling of cellular membranes and cellular responses to infection. Finally, key knowledge gaps and research priorities in the study of virus-cell interactions are highlighted.

Dengue is a mosquito-borne viral disease that poses a global public health problem, particularly in tropical and subtropical regions. It is caused by the dengue virus (DENV), which comprises four antigenically distinct serotypes. The clinical manifestations of the disease overlap with those of other febrile diseases, including other arboviruses such as Zika and chikungunya, making clinical and epidemiological diagnosis difficult. Therefore, an accurate laboratory diagnosis is essential for effective clinical management, especially during the early stages of the disease, to prevent progression to severe forms.Over the years, significant advancements have been achieved in dengue diagnostics. This chapter provides a comprehensive overview of current diagnostic techniques, detailing their principles, applications, and limitations. It covers a range of methodologies, including virus isolation, nucleic acid amplification tests (NAATs), nonstructural protein 1 (NS1) antigen detection assays, immunohistochemistry, serological tests for IgM and IgG antibodies, and lateral flow point-of-care tests. Additionally, novel approaches such as multiplex platforms, next-generation sequencing (NGS), and biosensor-based tests are explored for their potential to address existing challenges and improve diagnostic accuracy.The choice of diagnostic strategy largely depends on the time course of infection and the available methodologies, resources, infrastructure, and technical expertise. Furthermore, the high degree of cross-reactivity between flaviviruses makes diagnosis by serological assays difficult, particularly in regions where multiple flaviviruses co-circulate. Dengue vaccination is also expected to influence the results of serological assays, requiring adjustments to algorithms and careful interpretation of results. By tailoring diagnostic approaches to local capabilities and accounting for the effects of vaccination, dengue diagnosis, and disease management can be improved.

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.

To write about dengue retrospective epidemiology is a challenging subject because until laboratory diagnosis tests were developed to confirm human infections by dengue virus (DENV) between 1940 and 1950, all reports about disease or epidemics referred to a generic "dengue/break bone fever/contagious fever/bilious remitting fever." These nomenclatures employed in past times had perspectives based on medical reports, letters and diaries of people living in the affected areas at the time, and local newspaper reports. As Packard (Bull Hist Med 90(2):193-221) highlighted, the difficulty of using historical sources and "the ambiguous nature" of eighteenth-century disease categories turns the analysis puzzling. Nevertheless, if judiciously used, it can illuminate the history of dengue epidemics over time.In this chapter, we will focus on three periods that were pivotal to shaping our current understanding of dengue disease and epidemiology: (1) First reports of a dengue-like disease and the impact of the infection during the seventeenth and eighteenth centuries; (2) The impact of the II World War (II WW) on the spread of the DENV and its vector worldwide; and (3) The re-introduction of dengue in the Americas and the challenge of Public Health services to control the dramatic escalation of cases and the introduction of new serotypes/genotypes. It is worth mentioning that in the last years, South and Central America and Caribe account for more than 80% of dengue cases in the world (PAHO).

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.

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.