Arboviruses such as dengue (DENV), Zika (ZIKV), chikungunya virus (CHIKV), and Crimean-Congo hemorrhagic fever (CCHFV) have been extensively studied in cell culture and animal models, yet how these findings translate to early infection events in human skin remains largely uncertain. Standard monolayers lack the stratified architecture and resident immune cells of the epidermis and dermis, while rodent skin differs markedly in structure, immunity, and mosquito interactions. Ex vivo human skin explants bridge this translational gap by preserving the native cutaneous microenvironment, including keratinocytes, fibroblasts, Langerhans cells, dermal dendritic cells, and extracellular matrix. Thereby, they enable infection under conditions that approximate natural mosquito bite transmission, including the deposition of virus and saliva during mosquito probing and the accompanying immunomodulatory effects. This review synthesizes insights from human skin explant models and contrasts them with monolayer systems, showing how intact skin architecture reshapes early viral behavior and innate immune activation. It further highlights innovations - such as fluorescent saliva reporter mosquitoes and engineered vascular skin platforms - that enable tracking of arbovirus delivery and host responses at the vector-skin interface. These platforms hold promise not only for defining early determinants of human susceptibility, especially in the light of the recently identified arbovirus receptors, but also for testing topical or locally acting countermeasures at the true portal of viral entry. Major gaps remain, including the absence of blood circulation in currently available human skin explants, underscoring the need to extend skin explant approaches across the broader landscape of vector-borne pathogens.
Vaccine adjuvants play a critical role in enhancing the magnitude and quality of immune responses; however, limitations in the efficacy of current vaccines against certain infectious diseases, together with the ongoing emergence of new pathogens, underscore the need for the continued development of novel vaccine adjuvants. Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that respond rapidly during the early phase of microbial infection to amplify immune responses and bridge innate and adaptive immunity. Molecules capable of activating MAIT cells therefore have the potential to act as efficacious vaccine adjuvants. This review discusses emerging evidence supporting the potential of MAIT cell activators as vaccine adjuvants. Recent advances in the discovery and development of MAIT cell-activating ligands are summarized, highlighting natural ligands derived from microbial riboflavin metabolism, most notably 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU). Several recent studies have demonstrated 5-OP-RU to be an effective adjuvant in vaccines against viral infections, markedly expanding interest in MAIT cell-targeted immunomodulation. Furthermore, ongoing efforts to overcome the intrinsic chemical instability of 5-OP-RU through rational ligand design and related strategies are described. MAIT cell activators are poised to attract increasing attention as a versatile platform for the design of next-generation vaccine adjuvants against infectious diseases.
The development of effective mucosal vaccines has been limited by the limited availability of mucosal adjuvant approaches with established clinical track records and an incomplete understanding of how systemic and mucosal immunity are coordinated. Recent studies indicate that the priming phase of vaccination plays a decisive role in programming the quality, durability, and anatomical distribution of subsequent immune responses. This review discusses emerging evidence that co-adjuvant-based priming strategies can establish long-lasting immune programs that enable adjuvant-free mucosal boosting. Focusing on the combination of CpG DNA and curdlan as a prototypical example, this review highlights how coordinated activation of innate immune receptors during priming imprints dendritic cells, B cells, and T cells to support robust mucosal IgA and tissue-resident immunity. This review further discusses translational advances demonstrating that this immune programming paradigm can be maintained using translationally oriented formulations designed with clinical development in mind and validated in non-human primates. Independent studies using mRNA and protein-based vaccines support the general principle that the quality of priming, rather than the boosting modality, determines successful mucosal immunity. Together, these findings redefine vaccine adjuvants as tools for immune programming and provide a conceptual framework for next-generation vaccine design.
Plant viruses rely on insect vectors to complete their transmission cycles, exploiting a diverse array of vector proteins to enable entry, intracellular movement, replication, and exit. This review synthesizes recent advances in our understanding of plant virus-vector protein interactions across noncirculative (NC) and circulative transmission modes, including vertical transmission. Key viral strategies include binding to surface proteins (e.g. Stylin-01, KRT), traversing epithelial barriers via receptor-mediated endocytosis (e.g. APN, ST6), trafficking through intracellular compartments (e.g. SNARE complexes, flotillin-2), and release through salivary exosomes. Some viruses hijack autophagy and apoptosis machinery to avoid degradation and ensure persistence. Others exploit reproductive proteins such as vitellogenin and sperm-specific serpin proteins - or even symbiont-derived membrane proteins - to achieve vertical transmission. In response, vectors activate immune pathways including RNA interference (RNAi), melanization, and mitogen-activated protein kinase signaling, although these defenses are frequently subverted by viral proteins. Mapping these molecular interactions highlights promising targets for intervention, including vector-targeted antibodies, RNAi-enabled symbionts, and receptor-blocking molecules. Together, these insights offer a path toward molecularly precise, ecologically sustainable strategies for disrupting plant virus transmission at the vector level.
Viral infection-related hospitalization and mortality rates are highest in human newborns and infants compared to older children and adults, suggesting age-specific vulnerability and a non-redundant role for the maternal immune system. However, there is immense interindividual variability of clinical outcomes following early-life exposure to nearly any given virus that cannot be fully explained by variation in maternal immune protection. Inborn errors of immunity underlying defective control of viral replication or insufficient immune regulation following a viral trigger are increasingly recognized as the molecular etiology of severe viral disease in children and adults. In parallel, auto-antibodies (auto-Abs) neutralizing type I interferons (IFNs) are emerging as universal determinants of viral disease. The role of inborn errors of antiviral immunity in the fetus, the newborn, and the infant is starting to emerge or can be inferred from the study of viral disease in older individuals. The investigation of the molecular mechanisms underlying early-life viral disease in individual patients is crucial to the development of effective prevention and treatment strategies. Novel studies addressing the role of inborn errors of antiviral immunity or auto-Abs neutralizing type I IFNs in early-life viral infections should take into account the specific aspects of the neonatal immune system and its complex interactions with the maternal immune system.
Intracranial calcifications (ICCs) are a characteristic neuropathological feature of several congenital viral infections, including Zika virus (ZIKV), cytomegalovirus (CMV), and lymphocytic choriomeningitis virus (LCMV). These lesions are linked to severe neurodevelopmental outcomes, such as microcephaly, epilepsy, and cognitive deficits, yet the mechanisms underlying their formation and resolution remain unclear. ICCs are thought to arise from an imbalance in osteogenic and osteolytic signaling in the developing brain. Recent work implicates pericytes as key targets of ZIKV, capable of osteogenic reprogramming and direct mineral deposition. However, the pathways leading to calcification in CMV and LCMV infections are less well understood. Microglia, the brain's resident immune cells, have emerged as potential regulators of calcification. While microglia can limit mineral deposition in noninfectious models of neurodegeneration and injury, their role in the context of congenital viral infection remains speculative. Whether they act to contain calcification, participate in its resolution, or contribute to pathogenesis via neuroinflammatory signaling is still unknown. This short review summarizes current knowledge of ICC pathogenesis during congenital ZIKV, CMV, and LCMV infections, with a focus on emerging potential cellular mediators, such as pericytes and microglia. We discuss known mechanisms, gaps in knowledge, and opportunities to build more representative animal models to elucidate how different viral infections orchestrate calcification in the fetal brain. Clarifying these pathways may inform future therapeutic approaches to mitigate virus-induced neurodevelopmental disorders.
Inborn errors of immunity can underlie susceptibility to severe viral infection in humans. and the majority relate to defective induction of or response to antiviral type I interferon (IFN). However there is increasing awareness of defects in other cellular processes, that can predispose to severe infectious disease. Recently, defects in autophagy-related genes or -processes have been demonstrated to predispose to life-threatening viral diseases, including defects in autophagy-related genes in patients with herpes simplex virus and varicella zoster virus infections in the central nervous system, as well as impairment of noncanonical antiviral immunity in critical COVID-19. However, the molecular mechanisms and complex intersections between autophagy, metabolism, cell death, and inflammation, and how defects in autophagy-related proteins may interfere with these cellular processes, are only now starting to emerge. This review presents the current knowledge on inborn errors of autophagy discovered in patients with severe viral infection and discusses some of the remaining knowledge gaps in our understanding of how autophagy processes act against viruses, how immunopathology and lack of viral control ensues when they fail, and how these insights may be translated into clinical medicine.
Host defense against intracellular pathogens, including viruses and mycobacteria, requires not only antibody production but also T cell-mediated cellular immunity, which is often overlooked in current vaccine strategies. C-type lectin receptors (CLRs) are one of the innate immune receptors that can promote adaptive immunity through the induction of co-stimulatory molecules or soluble factors in antigen-presenting cells. This review focuses on the potential of CLR ligands, specifically those for macrophage-inducible C-type lectin (Mincle), as next-generation vaccine adjuvants. Mincle recognizes glycolipids such as trehalose dimycolate (TDM) from mycobacteria and induces Th1 and Th17 responses, crucial mechanisms for countering intracellular pathogens. We discuss the structural basis of the ligand-recognition modes of Mincle, which involves both sugar-binding pockets and hydrophobic grooves to accommodate acyl chains. Additionally, we discuss efforts to develop synthesizable and highly active ligands such as trehalose dibehenate (TDB) and lipidated brartemicin (C18Brar). We further highlight novel strategies to enhance immunostimulatory efficacy, including the concept of dual-ligand adjuvants (e.g. C18Brar-muramyl dipeptide conjugate) and the use of nanoparticle/liposome delivery systems (e.g. CAF formulations). Collectively, these advancements highlight the potential of Mincle ligands as candidates for effective adjuvants. For clinical application, species-specific differences in adjuvant effectiveness between humans and experimental animals must be addressed, and highly functionalized Mincle ligands must be developed. Future research should establish Mincle-targeting ligands as indispensable tools for the development of next-generation vaccines.
Arthritogenic alphaviruses, including chikungunya (CHIKV), Ross River, and Mayaro viruses, are emerging global viruses responsible for causing arthralgia and chronic arthritis. Following mosquito-borne transmission, they quickly initiate infection in the skin, including in resident immune cells, and disseminate systemically into musculoskeletal tissues. The innate immune system responds rapidly through the activation of interferons, the production of inflammatory cytokines, and the recruitment of monocytes, macrophages, neutrophils, and dendritic cells, while the adaptive immune response, particularly virus-specific T and B cells, is critical for viral clearance. However, excessive immune activation can lead to both acute and chronic musculoskeletal pain through cytokine storm, tissue damage, and supporting immunopathology. Additionally, viral persistence and immune evasion may contribute to the development of chronic synovitis and cartilage degradation, leading to persistent joint pain. Despite recent advances, antiviral treatments remain unavailable, and to date, there is only one vaccine licensed (VIMKUNYA™ in 2025, against CHIKV), underscoring the urgent need for further research. This review explores the complex interplay between host immune responses and viral factors that lead from acute infection to chronic inflammation. Furthermore, it highlights key gaps in understanding viral persistence and immune evasion, and how to predict chronic diseases to improve therapeutic and preventive strategies against arthritogenic alphaviruses.
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.
Type I interferons (IFN-Is) are critical antiviral cytokines that restrict viral replication and limit viral disease. A remarkable recent discovery is that human autoantibodies (autoAbs) neutralizing the activities of IFN-Is phenocopy inborn errors of immunity and markedly exacerbate susceptibility to life-threatening infections. Development of these pathogenic autoAbs in humans is strongly linked to genetic and nongenetic factors affecting thymic function, and they are estimated to be present in >100 million people worldwide with a prevalence that increases with age. Here, we review major advances from the last few years that have improved our mechanistic understanding of human IFN-I autoAb development and function, as well as their association with a significant proportion of different severe viral diseases. In particular, we highlight how neutralizing IFN-I autoAbs can persist in individuals for decades, compromising IFN-I-mediated defenses, and underlying subsequent critical infections with diverse pathogens, including SARS-CoV-2, West Nile virus, tick-borne encephalitis virus, seasonal influenza viruses, herpesviruses, and rare zoonoses caused by MERS-CoV, flaviviruses, and avian H5N1 influenza A virus. Furthermore, we discuss how neutralizing IFN-I autoAbs facilitate severe adverse events with live-attenuated viral vaccines, such as the yellow fever or chikungunya virus vaccines, and suggest how implementation of IFN-I autoAb diagnostics in at-risk populations may be clinically beneficial with current prophylactic or therapeutic options. Finally, in the context of new experimental insights into how autoAbs block the ability of IFN-Is to engage with the IFNAR1/IFNAR2 receptors, we detail future opportunities to design advanced novel therapeutic strategies that might specifically mitigate IFN-I autoAb pathogenic effects.
The coronavirus disease 2019 (COVID-19) pandemic emphasized the need to study coronaviruses more thoroughly. Next to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), humans can be infected by SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and various seasonal coronaviruses. It is likely that all human coronaviruses have a zoonotic origin and circulated in animal reservoirs before crossing the species barrier into humans. Historically, these viruses have been investigated in vitro and in vivo, mainly utilizing immortalized cell lines and animal models, respectively. Recently, more advanced physiological model systems have been developed to study coronavirus host interactions, with human organoids serving as innovative in vitro tissue culture system that closely mimics human physiology. Organoids provide a promising platform for investigating coronavirus infections, exploring viral tropism, studying host immune responses, and evaluating potential therapeutic interventions. This review explores the origins and use of airway organoids in studying coronaviruses. Additionally, it outlines prospects for leveraging airway organoids for examination of both innate and adaptive immune responses, evaluation of antiviral drugs, and creating intricate co-culture models for enhanced insight into coronavirus infections of the respiratory tract.
Vaccine adjuvants play a central role in shaping the magnitude, quality, and durability of vaccine-induced immune responses, yet their rational design and selection remain major challenges. Although the adjuvant repertoire has expanded substantially over the past two decades, this growth has not yielded broadly predictive frameworks capable of matching adjuvants to antigens, vaccine platforms, disease contexts, or populations. Advances in innate immunology and systems vaccinology have revealed early immune signatures associated with vaccine efficacy, but translating these insights into generalizable design rules has proven difficult due to context dependence, population heterogeneity, and the complexity of immune pathways. To address these limitations, the Division of Allergy, Immunology, and Transplantation (DAIT) within the National Institute of Allergy and Infectious Diseases (NIAID), a component of the U.S. National Institutes of Health, has established coordinated adjuvant discovery, development, and comparative research programs that emphasize standardized study designs, harmonized immune profiling, and cross-platform data integration that enable the systematic evaluation of adjuvant mechanisms and biological activities. Here, we examine conceptual and practical lessons emerging from DAIT/NIAID-supported programs and the adjuvant field more broadly, focusing on comparative immune profiling, adjuvant mimics, and combination adjuvants. Collectively, these efforts illustrate how harmonized datasets, shared infrastructure, and mechanism-guided analyses can transform adjuvant selection from an empirical process into a data-driven component of rational vaccine design, supporting precision immunomodulation across infectious, immunologic, and other non-infectious diseases.
RNA viruses have compact genomes that typically encode only a few proteins, but these viruses orchestrate complex replication cycles while concurrently exercising control over multiple aspects of the biology of the infected host cell, including the evasion of antiviral responses. Central to this functional diversity is the evolution of multifunctional proteins, which integrate diverse roles in replication and host subversion through structural, regulatory, and spatial versatility. The rabies virus P-protein exemplifies these principles. In addition to serving as an essential cofactor and chaperone in viral transcription and replication, the P-protein also antagonizes type I interferon responses, modulates intranuclear processes, and targets multiple host membrane-less organelles via liquid-liquid phase separation. These diverse functions are mediated by a combination of mechanisms, including expression as multiple isoforms, modular domain architecture, intrinsic disorder, dynamic subcellular trafficking, post-translational modifications, conformational plasticity, and RNA binding. In this review, we discuss established and recently emerging mechanisms underlying P-protein multifunctionality, which is likely to provide a model for understanding the multifunctionality of other viral, and likely cellular proteins. We also highlight how similar strategies are employed across RNA viruses to overcome genomic constraints, and discuss how these mechanisms may represent promising targets for future antiviral interventions.
Human T-cell leukemia virus type I (HTLV-1) was the first human pathogenic retrovirus to be discovered. HTLV-1 induces a T-cell malignancy, adult T-cell leukemia-lymphoma (ATL), and inflammatory diseases, such as HTLV-1-associated myelopathy (HAM), HTLV-1 uveitis (HU), and HTLV-1-associated pulmonary disease (HAPD). Importantly, HTLV-1 maintains persistent infection by regulating viral gene expression and disrupting host signaling pathways - activities that are closely linked to its pathogenicity. By modulating the expression of viral genes, including tax and HTLV-1 bZIP factor (HBZ), HTLV-1 enables itself to evade host immune attack and to promote the clonal expansion of infected cells. In addition, HTLV-1 perturbs host signaling pathways, such as the transforming growth factor (TGF)-β signaling pathway, the IL-10/JAK/STAT signaling pathway, the nuclear factor-kappa B signaling pathway, the Wnt signaling pathway, and the Rb/E2F signaling pathway. Among these pathways, the first two have recently been demonstrated to be significant in the development of ATL. HBZ enhances the activation of the TGF-β signaling pathway and the production of an immunosuppressive cytokine, IL-10, activities which not only help the virus evade the host immune system but also contribute to the proliferation of HTLV-1-infected cells themselves. In addition, HBZ converts HTLV-1-infected cells into Treg-like cells, which further enhances their survival. Overall, HTLV-1 promotes the long-term survival of infected cells in vivo by regulating viral gene expression and disrupting host signaling pathways, thereby accelerating the development of HTLV-1-associated disease.
Sandfly-borne phleboviruses (SBPs) are an important cause of febrile diseases and neuroinvasive infections in humans, especially in endemic regions. They have been described in Central Asia, Africa, the Middle East, and the Mediterranean regions. Current investigations suggest that SBPs originated from Africa, albeit with little zoonotic threat information. Particularly pertinent is the recent identification of genetically diverse SBPs associated with human infection circulating in North and East Africa. Spread of these viruses to new regions may pose a significant risk to the local populations with little or no pre-existing immunity. Additionally, the lack of SBP detection methods at the point of care may lead to an incorrect diagnosis of malaria and influenza, inappropriate treatment, and an underestimated disease burden. Despite the availability of a wide range of analytic approaches that include cell culture, electron microscopy, and serological screening, diagnosis remains a challenge. Application of new molecular techniques such as next-generation sequencing (NGS) would enable description of new SBPs; however, correlation with additional field clinical data is needed to evaluate the zoonotic significance of any new SBPs. In this review, we provide a summary of the disease ecology of SBPs in Africa to concatenate the existing knowledge on transmission dynamics. The review also highlights the limited surveillance of SBPs in Africa, thus confirming the need for enhanced virus characterization incorporating advanced approaches such as capture-based target enrichment NGS, allowing for the detection of existing and novel SBPs, in addition to epidemiologic data on their clinical relevance.
Human Immunodeficiency Virus Type 1 (HIV-1) continues to pose a significant global public health challenge. Marked inter-individual variability in susceptibility to infection, viral load, and disease progression has long highlighted an important role for host genetic factors. To date, only a small number of germline loci show consistent, reproducible effects on HIV-1 control, most notably CCR5 and HLA class I genes. Recent studies have refined the mechanistic basis of these associations, clarifying how CCR5 regulation and specific HLA-B residues shape CD8⁺ T-cell and natural killer cell responses. Beyond these loci, emerging population-specific associations, including variants at the CHD1L/PRKAB2 locus, underscore the importance of studying diverse populations and highlight novel pathways influencing viral replication and evolution. In parallel, attention has shifted toward somatic genetic variation and aging-related processes in people living with HIV-1. HIV-1 infection and chronic immune activation are associated with genomic instability, accelerated accumulation of mitochondrial DNA mutations, telomere shortening, and increased prevalence of clonal hematopoiesis, processes that may contribute to inflammation and non-communicable comorbidities despite effective viral suppression. As well, the growing application of polygenic risk scores to predict cardiometabolic and renal disease in treated populations has implications for precision HIV-1 medicine. As universal antiretroviral therapy reduces opportunities to study natural HIV-1 progression, future genetic research will increasingly focus on how host germline and somatic variation influence therapeutic outcomes and viral reservoir dynamics to shape long-term health outcomes and emerging treatment strategies.
Flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein that is pivotal to viral replication and pathogenesis in dengue, Zika, yellow fever, and other flaviviral infections. Recent structural studies reveal that NS1 can adopt multiple oligomeric assemblies, switching between these states to mediate membrane remodeling and systemic immune modulation. NS1 dampens innate antiviral responses by interfering with pathogen-sensing pathways, including RIG-I/MDA5 and cGAS-STING signaling. It further subverts complement by recruiting factor H and cleaving C4, and it disrupts the endothelial glycocalyx, thereby precipitating the capillary leakage that correlates with high serum NS1 levels and severe disease. High-resolution epitope mapping has enabled the development of protective monoclonal antibodies that exploit Fc-mediated effector functions without eliciting antibody-dependent enhancement. Targeting NS1, therefore, offers exciting opportunities for next-generation vaccines, antivirals, and diagnostics. However, key knowledge gaps remain, including the role of lipoprotein-mediated trafficking, the feasibility of small-molecule inhibitors targeting NS1 oligomerization, and the optimal therapeutic window for NS1-directed interventions.
mRNA vaccines have been proven to be highly effective; however, they are often more reactogenic than several older platforms, and systemic symptoms can limit their acceptance. Lipid nanoparticles (LNPs) are at the center of this tradeoff; they enable mRNA delivery, while also providing adjuvant-like innate stimulation. In this review, we summarize recent progress in understanding how LNPs shape innate immune sensing and inflammatory signatures and how these responses relate to adjuvanticity and reactogenicity. We discuss why LNP adjuvanticity is not a single fixed property; different formulations can elicit distinct innate programs, and consequently, different profiles of adjuvanticity and reactogenicity. In addition, the possibility that adjuvanticity and reactogenicity may be partially uncoupled is discussed. Even if the mechanisms driving inflammatory responses and adjuvanticity are not fundamentally distinct, these outcomes may diverge depending on when, where, and how strongly innate signals are triggered, which can be tuned through formulation, including the control of in vivo distribution. Finally, we outline the design principles and experimental requirements for linking LNP behavior to specific pathways and outcomes, enabling safer and more effective LNP-based vaccines. These insights support a rational formulation to expand future vaccine options.
The global prevalence of neurotropic viruses is increasing annually, with no effective treatments available. Viral entry into the brain involves a complex interplay of host and viral factors, such as tight junction complexes, immune regulators, and viral protein polymorphisms. After establishing an infection in the brain, neurotropic viruses can trigger immune cell activation, robust inflammatory responses, and synaptic disruption, contributing to both acute and chronic neuropathology, including accelerated neuronal ageing and neurodegeneration. A wealth of studies has focused on the molecular mechanisms underlying the neurovirulence and neuropathogenesis of clinically relevant neurotropic RNA viruses, revealing critical insights into their interactions with host cells and immune response. However, despite such advances, a disparity in knowledge on how these viruses enter the brain remains. In this review, significant progress within the last 2 years, as well as research niche and challenges in unravelling the neuropenetrance of clinically relevant neurotropic flaviviruses and enteroviruses in causing neuro-associated pathology will be discussed.