Current topics in microbiology and immunology最新文献

Epstein-Barr virus (EBV) infects nearly every individual whereupon it persists for life under the control of a broad immune response. EBV provides a valuable system for understanding human T cell immunology. It is genetically stable and expresses well-characterised viral proteins, many of which have been mapped for HLA-I- and HLA-II- restricted epitopes allowing the cognate CD8+ and CD4+ T cell response to be measured and characterised. Individuals with symptomatic infectious mononucleosis readily allow primary infection to be studied in both blood and tissues. Here, we describe the T cell response to primary EBV infection in children and adolescents, and to persistent EBV infection over the life course. We also examine the EBV-specific T cell response in multiple sclerosis, now recognised to be strongly associated with EBV and in which certain HLA alleles influence disease risk. Finally, we explore unconventional T cells, including HLA-E-restricted T cells, gamma delta T cells, and NKT cells in the context of EBV infection.

Epstein-Barr virus (EBV) DNA in blood is associated with many diseases, though most often it is not linked to any disease. EBV DNA can be measured in whole blood, PBMCs, serum, or plasma. Using the most sensitive assays, viral DNA can be detected in PBMCs in nearly all individuals who have been infected. Among organ transplant recipients, higher EBV DNA copy numbers in PBMCs may reflect the degree of immunosuppression and could help guide pharmacologic management. In patients with EBV-PTLD, treatment with rituximab or other anti-B cell therapies typically eliminates measurable EBV DNA in PBMCs, even when the disease continues to progress-making further PBMC measurements of limited value. In other settings, such as HIV associated lymphoma, nasopharyngeal carcinoma (NPC), or Hodgkin lymphoma (HL), EBV DNA levels in PBMCs do not appear useful for diagnosis or monitoring. Measurement of viral DNA in cell-free (CF) DNA is fundamentally different from measurement in PBMC or whole blood, as EBV DNA is generally undetectable in CF DNA in most seropositive individuals without EBV associated disease. In NPC and HL, evidence suggests that CF EBV DNA typically originates from tumor cells and is not packaged in virions. Persistence of CF DNA correlates closely with residual tumor presence. In NPC and NK/T cell lymphoma (NK/TCL), CF DNA assays are now commonly used for tumor monitoring. This is not yet standard in EBV-positive HL but represents a promising area for further research. EBV DNA is also assayed in whole blood in many clinical settings. This approach can detect high copy numbers in both cellular and CF compartments with minimal processing, but it obscures compartment-specific differences. Studies of EBV DNA fragmentomics and methylation in plasma offer new insights into tumor presence and potentially tumor type.

Epstein-Barr virus is a master manipulator of B cell biology, provoking the activation and proliferation of infected B cells, while ensuring their survival. Central to this is the epigenetic reconfiguration of the B cell genome and transcriptome, for which the EBV nuclear antigens (EBNAs) are crucial. This chapter focuses on the role of the EBNA3 family of proteins-EBNA3A, EBNA3B and EBNA3C-in EBV's manipulation of B cell biology, building on the previous incarnation of this chapter (Allday et al., Curr Top Microbiol Immunol 391:61-117, 2015). In particular, the chapter discusses the genomic and transcriptomic context of EBNA3 gene expression, mechanisms by which they regulate host genes and how they impact B cell survival, differentiation and function, alongside distinct insights from mouse models, which reveal both pro- and anti-oncogenic roles of EBNA3 proteins. The chapter finishes by considering new insights and proposing key unresolved questions about the roles and regulatory mechanisms of EBNA3 proteins.

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.

This chapter aims to bridge the gap between two fundamental topics in medical entomology-vector surveillance and vector competence-often seen as distinct areas of study. This perceived separation likely stems from the misconception that surveillance falls within the domain of field entomologists, while vector competence is primarily the focus of laboratory-based researchers. Here, we emphasize the necessity of integrating these two fields, highlighting the importance of monitoring the susceptibility of natural Aedes aegypti populations to dengue virus (DENV) and other arboviruses. By incorporating vector competence assessments into surveillance strategies, researchers and public health authorities can improve their ability to evaluate outbreak risks and predict the potential for new epidemics. This integrated approach can enhance early warning systems and inform more effective vector control interventions.

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.

This chapter examines the immunological mechanisms underlying the cross-reactivity and immune enhancement in dengue and how they influence the clinical outcomes. The four DENV serotypes (DENV-1 to DENV-4) share high genetic and antigenic similarity, leading to antibodies and T cells that can recognize multiple serotypes. While this cross-reactive immunity can confer partial or transient protection, it can also result in antibody-dependent enhancement (ADE), wherein non-neutralizing antibodies facilitate viral entry into immune cells, increasing the likelihood of severe disease in secondary infections and in infants carrying maternal anti-DENV antibodies. Furthermore, cross-reactivity with other flaviviruses, such as ZIKV, complicates serological diagnosis by producing false-positive results and uncertain prior exposure histories. These complexities extend to vaccine design, which must induce effective immunity against all four DENV serotypes while minimizing ADE risk. Epidemiological studies confirm that secondary infections, especially when antibody levels have waned, carry an elevated risk of severe clinical manifestations. However, the timing between infections and the specific serotype involved can modulate these outcomes. A thorough understanding of cross-reactivity and immune enhancement is therefore pivotal for advancing diagnostic accuracy, guiding patient care, and informing vaccine strategies and public health policies to better control dengue globally.

In the last decades, we have witnessed the worldwide spread and growing impact of one of the most important neglected tropical diseases, the dengue fever. Even though it continues to be neglected mainly due to its major impact on the more socio and economically vulnerable populations there was progress toward a more complete understanding about the basic biology of dengue infection in mosquitoes and humans as well as translational research to develop antivirals and improved vaccines. Paradoxically, dengue fever incidence has steadily grown globally suggesting that the development/refinement of basic/translational research and control approaches are not keeping the pace of dengue spread. Therefore, in this last chapter, we will discuss the latest developments regarding preparedness and response against dengue, looking into their applicability to reduce dengue fever around the globe.

The investigation and understanding of the immune response to dengue, including its protective and pathogenic functions, present unique challenges, particularly due to the circulation of four distinct serotypes. While infection with one serotype induces long-term protection, including some level of temporary cross-protection against other serotypes, epidemiological evidence suggests an increased risk of severe disease following subsequent heterologous infections. Although the antibody-mediated response has been more extensively studied in this context, it is also evident that T cell immunity contributes to infection resolution and long-term memory, but in some circumstances, it can influence immunopathology. In this chapter, we will present findings regarding T cell-specific DENV epitopes and activated T cell repertoire and discuss the role of distinct T cell subtypes and their functional association with protection, memory response, as well as how altered T cell responses can contribute to disease severity. A deeper understanding of these mechanisms is essential for elucidating disease pathogenesis and identifying key protection and disease markers, which are critical for the development and efficacy assessment of dengue vaccine. In addition, T cell-mediated immunity should be considered in the design and implementation of immunization programs.

Climate plays a crucial role in shaping dengue virus (DENV) transmission dynamics by influencing directly the physical and behavioural traits of mosquito individuals and viral replication. This chapter describes and evidences the intricate relationships between climate variables, mosquito traits and DENV transmission, highlighting the importance of understanding such connections in the context of a growing DENV burden and a global environmental change.