HSV-1 encephalitis (HSE) remains a devastating viral infection of the central nervous system despite effective antiviral therapy. Increasing evidence indicates that disease outcome is not determined by viral replication alone but by how innate immunity is calibrated within the brain. Studies of host susceptibility in childhood HSE have identified brain-intrinsic antiviral mechanisms, referring to central nervous system (CNS)-localized innate immune pathways that enable resident brain cells to sense and restrict HSV-1 infection, particularly TLR-dependent interferon responses, neuron-associated restriction factors, and other CNS-resident innate immune mechanisms. Host innate immune responses initially contribute to viral restriction, whereas excessive or unresolved activation can promote inflammatory amplification and long-term neurological injury. In parallel, HSV-1-mediated immune remodeling may weaken antiviral control and alter the subsequent inflammatory trajectory. Here, HSE is discussed as a dynamic immunopathological disorder in which protective innate immunity can transition into pathogenic neuroinflammation. Building upon these observations, we propose that host-directed therapeutic strategies should shift from uniform immune modulation toward stage-specific immune recalibration on the basis of viral control, antiviral competence, inflammatory persistence, and tissue repair.
Potyviruses and cucumoviruses (exemplified by cucumber mosaic virus (CMV)) are highly divergent taxa of plant-infecting positive-sense RNA viruses. However, they face similar challenges. They must overcome host antiviral resistance mechanisms, for example, RNA silencing or resistance mediated by the phytohormone salicylic acid, and they must do this across a very diverse range of host species. Although in some hosts potyviruses and CMV are seedborne, they are predominantly transmitted by aphid vectors. Both have acquired mechanisms for subverting host defences, particularly those controlled by jasmonic acid, to manipulate vector behaviour and increase transmission. This article compares how CMV and potyviruses took distinct evolutionary paths to overcome these common challenges. Potyviruses diverged into numerous distinct viral species to exploit different hosts and co-opted many gene products, including P1, HC-Pro, NIa, VPg, 6K2 and NIb, to effector roles. In contrast, CMV strains show less divergence but still exploit wide host ranges, and predominantly use the 2b counter-defence protein for subverting and manipulating host responses.
SUMOylation regulates critical cellular processes, including DNA repair, transcription, and immune responses. Human herpesviruses (HHVs) have evolved mechanisms to hijack the SUMO pathway, promoting viral replication, immune evasion, and establishment of latency. This review explores how HHVs manipulate the host SUMOylation machinery, detailing key viral proteins and their effects, as well as antiviral defense mechanisms.
Plant rhabdoviruses comprise a group of economically important pathogens that exhibit a complex dual-host infection cycle across plants and insect vectors, relying on exquisitely adapted cross-kingdom infection and survival strategies. In this review, we summarize recent advances in understanding plant rhabdovirus-host interactions, with a focus on the molecular basis underlying viral manipulation of host functions. We highlight key host factors or subcellular structures hijacked by plant rhabdoviruses to support robust viral replication and intracellular transport. We further explore the diverse counter-defense mechanisms deployed by plant rhabdoviruses to evade or suppress host immunity, including RNA silencing, phytohormone signaling cascades, and autophagy-mediated degradation. Finally, we discuss the intimate insect-virus interfaces, detailing how viral effectors modulate vector feeding behaviors, physiology, and innate immune responses to facilitate persistent, propagative transmission. Collectively, these advances establish an integrated framework for understanding the cross-kingdom pathogenesis of plant rhabdoviruses and provide insights for developing innovative crop protection strategies.
In recent decades, mass mortality events (MMEs) among aquatic mammals have been caused by morbillivirus or avian influenza virus (AIV) infections. Thus far, AIV infections have been predominantly associated with direct or indirect contact with infected birds, while mammal-to-mammal AIV transmission has not been formally proven in most cases. However, amino acid changes in the HA or PB2 RNA segments previously identified as 'mammalian-adapting mutations' have been documented during AIV epizootics in aquatic mammals. Such mutations are known to increase infectivity and/or virulence of AIV in mammalian species, including humans. Epizootics caused by low-pathogenic AIV (LPAIV) are typically self-limiting respiratory disease outbreaks. In contrast, the ongoing panzootic caused by highly pathogenic AIV (HPAIV) subtype A(H5N1) clade 2.3.4.4b is associated with severe neurological disease and mortality in infected pinniped and cetacean species. The available serological data suggest that enzootic circulation of AIV in aquatic mammals is limited. LPAIV-specific antibodies have been detected in pinniped species only during documented flu outbreaks and have then decreased to undetectable levels, while no AIV-specific antibodies have been detected following recent HPAIV A(H5N1) infections. Since direct interventions in wild pinnipeds are limited, AIV surveillance and investigations into the genetic and phenotypic characteristics of AIVs associated with MMEs in aquatic mammals will be essential to better understand the risk that these viruses pose to often endangered animal populations, as well as to public health.
Nonstandard viral genomes (nsVGs) are heritable viral genomic forms that differ from the canonical full-length genome through structural rearrangements such as deletions, duplications, copy-back/snap-back structures, or recombination. This definition is genomic rather than functional: some nsVGs are defective, some interfere with helper virus replication, and others may be neutral, conditionally beneficial, or encode functional products. Once considered laboratory artifacts, nsVGs are now recognized as pervasive components of RNA virus populations that reshape viral fitness, within-host dynamics, immune activation, and long-term evolutionary trajectories. High-throughput sequencing has revealed rich nsVG spectra but also exposed a complex measurement problem in which generation, selection, junction-detection bias, and quantification uncertainty jointly determine what is observed. Mathematical models have clarified how helper virus/nsVG interactions generate coexistence, frequency dependence, multistability, oscillations, and, in some regimes, chaos, while multipartite models involving satellites reveal higher-order ecological effects. Here we synthesize experimental, bioinformatic, and theoretical advances to argue that nsVGs are evolving ecological agents whose effects depend on generation, selection, measurement, and nonlinear population dynamics. This framework extends classical quasispecies theory and offers a path toward predicting nsVG amplification, infection outcomes, and nsVG-mediated therapeutic interference with the wild-type virus.
Combination adjuvants enhance vaccine immunogenicity by integrating multiple immunostimulatory signals that shape both innate and adaptive immune responses. In this review, we summarize the clinical evidence supporting the added value of combination adjuvants, including aluminum-Toll-like receptor ligand formulations, oil-in-water emulsions containing immunostimulatory molecules, and saponin-based systems. We further discuss how the most recent mechanistic studies have shown that combination adjuvants act through additive or synergistic effects, engaging distinct molecular and cellular pathways to shape innate immune activation. Moreover, we propose that mRNA vaccines represent a new class of functional combination adjuvants, integrating both mRNA sensing and lipid nanoparticle-driven inflammation. Together, the current evidence supports the value of combination adjuvants in optimizing vaccine responses and underscores the need to continuously understand their mode of action to enable rational adjuvant design.
The complement system constitutes a powerful antiviral defense, centered on C3b-mediated amplification that drives opsonization, inflammation, and membrane attack complex formation. To persist in the eukaryotic host, viruses must neutralize this amplification step, and strikingly diverse evolutionary lineages have converged on inhibiting C3b-mediated amplification. In this review, we compare host and viral regulators of complement activation (RCAs) to reveal the structural and mechanistic principles underlying C3b control. Human RCAs achieve complement regulation through modular assemblies of complement control protein domains whose multivalency, linker-encoded geometry, and domain-specific dynamics enable efficient decay acceleration and factor I cofactor activity. Viruses have independently replicated these principles through distinct evolutionary routes. Poxviruses and gammaherpesviruses acquired host-derived RCA genes via horizontal gene transfer, followed by lineage-specific refinement on extensively different time scales. In contrast, alphaherpesviruses evolved structurally unrelated complement inhibitors, exemplified by glycoprotein C, which suppresses C3b via a binding interface distinct from that used by RCAs. Despite profound structural divergence, most viral strategies converge on inhibition of the C3b amplification loop. This convergence highlights C3b suppression as an evolutionary bottleneck imposed by complement and reveals a fundamental asymmetry between structural innovation and functional constraint. Understanding how viruses repeatedly solve this invariant problem identifies complement regulation as a durable vulnerability and suggests therapeutic strategies resilient to viral diversity and mutation-driven escape.
The hepatitis E virus (HEV) capsid protein, pORF2, mediates virion assembly, attachment and entry, yet the molecular mechanisms underlying these processes remain poorly defined. Structural studies have provided high-resolution views of pORF2 virus-like particles, revealing an architecture like that of the calicivirus VP1. However, while a paradigm has been established for calicivirus capsid dynamicity — environmentally triggered transitions that regulate receptor engagement, uncoating and immune evasion — comparable conformational plasticity has not yet been explored for HEV. At the same time, efforts to map pORF2 interactions with host factors have yielded several candidate attachment and entry molecules, but no definitive receptor. This review summarises the current knowledge of the structure, forms and host interactions of pORF2, contrasting it with the extensive body of work that has revealed the dynamic behaviour of the calicivirus capsid. This ‘dynamic capsid lens’ view of HEV may inspire new approaches to unresolved aspects of HEV entry biology. These include how pORF2 engages with host factors, how quasi-enveloped and non-enveloped particles differ functionally, and whether environmental cues encountered during gut-to-liver transit affect capsid conformation. To determine whether HEV, like its calicivirus relatives, exploits capsid dynamicity to establish infection, it will be key to integrate structural, biophysical and cell-based approaches.
The concept of stabilising viral fusion proteins in their prefusion conformation to focus immunogenicity has driven vaccine research across many viruses. However, for herpesviruses, recent findings suggest that this approach may not yield the hoped-for immunological benefits, underscoring the importance of critically assessing the structure of target proteins. This review examines the structural and functional characteristics of herpesvirus glycoprotein B (gB), a key component in herpesvirus entry and fusion, and evaluates recent immunogenicity studies of gB. Despite successes with other viral membrane fusion proteins, multiple studies on herpesvirus gB, including herpes simplex virus 1/2, and human cytomegalovirus, demonstrate that prefusion stabilisation does not increase neutralising antibody responses or improve vaccine efficacy. Factors such as glycan shielding, epitope masking, and structural subtlety between different conformations likely contribute to these outcomes. While for Epstein-Barr virus, there might be a trend towards improved B-cell neutralisation, gB from other herpesviruses is still to be tested. Beyond gB, other glycoproteins like gD and gH/gL complexes show promise as vaccine targets, with some eliciting more neutralising antibodies than gB. The review emphasises that alternative approaches, such as rational immunogen design, oligomerisation, optimised delivery systems, and adjuvants, may improve vaccine effectiveness. Finally, a comprehensive understanding of herpesvirus fusion on a mechanistic and structural level is crucial, as this allows innovative immunogen design, hopefully leading to the development of broad and durable herpesvirus vaccines.
Post-viral neurological syndromes, such as post-acute sequelae of COVID-19, present a paradox of severe symptoms despite minimal CNS viral replication. The ‘protein-as-pathogen’ model, where shed viral proteins act as soluble neurotoxins, is now central to understanding this phenomenon. This review presents the opinion that the most critical recent developments are not that these proteins are toxic, but how their mechanisms converge. We synthesize evidence from the last two years showing that proteins from diverse, highly infectious virus families with zoonotic potential (e.g. Coronaviridae, Flaviviridae, Orthomyxoviridae) engage shared host pathways. We focus on two convergent mechanisms: (1) the activation of glial Toll-like receptor (TLR)4/TLR2 signaling, which initiates a chronic neuroinflammatory cascade, and (2) the disruption of host proteostasis, which seeds neurodegenerative proteinopathies like alpha-synuclein and tau aggregation. This framework positions post-viral syndromes as mechanistically related disorders and identifies pan-viral therapeutic targets, such as TLR inhibitors and autophagy activators.
Populations that are particularly vulnerable to infections, such as neonates, infants, and older adults, exhibit distinct immunological profiles contributing to sub-optimal responses to conventional vaccines. Historically, vaccine development has relied on animal models; however, these are limited by low-throughput, bioethical concerns, and species-specific biological differences that do not reliably predict human responses. Moreover, conventional methods of adjuvant discovery and development have failed to consider that human immune responses vary by a range of demographic features, especially age, leading to failure of multiple candidate adjuvanted vaccines in clinical trials. Spurred in part by the U.S. Food & Drug Administration Modernization Act 2.0, a paradigm shift in preclinical approaches to drug and vaccine discovery and development is taking place. In recognition of the complexity of the human immune system, there is an increase in the development of age-specific human in vitro platforms, such as primary cell assays, tissue-engineered constructs, and organ-on-a-chip technologies, as an alternative to animal models. Such systems enable high-throughput evaluation of population-specific reactogenicity and immunogenicity of vaccines, facilitating the discovery of age-tailored adjuvant formulations. Specifically, these models can capture primary and trained innate immune responses, antigen-presenting cell (APC) activation, and the complex APC-T and T-B cellular crosstalk that shapes adaptive immunity. Despite their potential, challenges remain in standardizing models to reflect the multi-organ interplay underlying vaccine-induced immune responses. In this review, we highlight key technological advances in age-specific adjuvant discovery, with a primary focus on early life and older adulthood — the periods of greatest immunological vulnerability and distinctiveness. We discuss the successes and current limitations of bench-to-bedside translation and explore the evolving regulatory landscape. Integrating human biology early in the vaccine development pipeline at these critical stages of the lifespan can ensure that next-generation adjuvants are optimized for robust, age-appropriate host defense.
Recognition of viral nucleic acids by multiple pattern-recognition receptors converges on TANK-binding kinase 1 (TBK1) to initiate type I interferon responses and antiviral immunity. While this canonical role is well established, recent studies using genetic ablation and pharmacological inhibition have reframed TBK1 as a context-dependent regulator of both innate and adaptive immunity across distinct cell lineages. Here, we review emerging cell-type-specific functions of TBK1 that extend beyond classical interferon signaling, repositioning it as a central coordinator of immune cell survival, differentiation, and effector function. We further discuss how pathways that signal through TBK1 may, thus, contribute to vaccine adjuvanticity, emphasizing this kinase as a potential target for vaccine-induced immunity. Finally, we outline how TBK1-dependent pathways may be harnessed for the design of next-generation vaccines.
Epstein-Barr virus (EBV) infects the vast majority of humans and establishes lifelong latency, yet causes disease in only a minority of individuals, underscoring the critical role of host determinants. This review examines the recent advances in how host genetics and immunological variation shape susceptibility to EBV across three major disease contexts. First, inborn errors of immunity have revealed essential CD8+ T-cell pathways governing control of EBV-driven B-cell lymphoproliferative disorders, through antigen recognition, co-stimulation, and cytokine signaling. EBVpositive T- and natural killer-cell lymphoproliferative disorders represent a second, more complex disease spectrum that arises through a multistep pathogenesis involving atypical viral entry, impaired immune control and homeostasis, and acquisition of somatic genetic alterations. Finally, we review new mechanistic evidence linking EBV to the development of autoimmune diseases, in particular multiple sclerosis and systemic lupus erythematosus, highlighting how EBV-mediated cell reprogramming amplifies immune dysregulation and selfreactivity. Together, these conditions establish EBV-associated diseases as powerful models for uncovering the complex genetic and immunological principles governing antiviral immunity and immune dysregulation.
While injectable vaccines can prevent respiratory pathogens from causing severe disease, their ability to elicit protective local immunity in the respiratory mucosa is more limited. For viral pathogens, infection outcome is often determined at the site of entry, where innate immune sensing within the airway mucosa precedes and conditions adaptive immune responses. At these surfaces, epithelial cells and antigen-presenting cells express a wide repertoire of pattern recognition receptors (PRRs), positioning innate immune activation as a central determinant of vaccine efficacy and durability of mucosal immunity. Recent advances in mucosal immunology facilitate the progression of mucosal vaccine development from empirical formulation toward mechanism-informed targeting of innate immune pathways. This review highlights emerging evidence supporting targeted engagement of cytosolic and endosomal PRRs to enhance intranasal vaccine efficacy. We focus on the cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway, highlighting how spatially and temporally constrained STING activation can drive interferon-mediated antiviral immunity, enhance antigen presentation and promote tissue-resident T cells. We also discuss how complementary targeting of endosomal PRRs, including TLR3 and TLR9, further reinforces antiviral programming and adaptive immunity at mucosal sites.
Until relatively recently, treatment for filovirus infections was limited to supportive care measures, but the occurrence of several large outbreaks in past years, including a multinational epidemic in West Africa from 2013 to 2016, has spurred the advancement of several therapeutic approaches into clinical trials, and even led to the recent licensure of two monoclonal antibody-based therapies against the Ebola virus. However, there are still significant gaps in our preparedness, in particular with respect to our ability to treat infections with other filoviruses, such as Marburg virus and Sudan virus. To address this, continuing research is focused on both leveraging what we have learned from these recent successes treating Ebola virus disease and exploring novel approaches for the management of filovirus infections. One promising approach toward the development of broad-spectrum therapeutics is focused on targeting the virus-host interface rather than directly targeting the virus itself. This review summarizes the currently licensed treatments, discusses current gaps, and highlights promising new directions in antiviral therapy both for EBOV and other filoviruses.
Recent studies have revealed that cells of the innate immune system can adapt to previous insults (such as infections) and build a de-facto innate immune memory termed trained immunity. This process enables enhanced responses to homologous or heterologous microbial stimuli and is primarily driven by long-lasting epigenetic remodeling coupled with metabolic reprogramming. Vaccine adjuvants are well recognized for their ability to amplify adaptive immune responses by stimulation of antigen-presenting cells, making them a critical component of modern vaccine design. There is increasing evidence suggesting that certain adjuvants can also induce trained immunity, highlighting their ability to enhance vaccine efficacy beyond classical adaptive immune responses. This emerging concept provides new opportunities for antigen selection and adjuvant development with higher immunogenicity in future vaccines.
