Search Results (435)

Background/Objectives: Severe bacterial sepsis and arboviral diseases may present with overlapping manifestations of vascular leakage, hemodynamic instability, thrombocytopenia, and organ dysfunction. We examined whether etiologically distinct severe infections may converge on selected components of immunovascular dysfunction and propose the Severe Infection-Mediated Vascular Activation and Collapse (SIMVAC) model as a hypothesis-generating framework. Methods: This narrative mechanistic review integrates human clinical and physiological studies, translational biomarker evidence, experimental models, and pathogen-specific mechanistic studies, with particular attention to the relative strength of evidence across arboviruses. Results: Dengue provides the strongest arboviral mechanistic support, linking plasma leakage with NS1-mediated endothelial barrier disruption, glycocalyx degradation, tissue-specific vascular effects, and inflammatory amplification. Evidence for yellow fever, West Nile virus, and Zika supports distinct organ-specific or systemic pathways but is less complete, whereas evidence for Mayaro, Oropouche, Venezuelan equine encephalitis, and Rocio viruses remains limited or hypothesis-generating. Candidate points of convergence include glycocalyx injury, Ang-2/Tie2 and S1P dysregulation, complement activation, NETosis, and vWF/ADAMTS13 imbalance. Conclusions: SIMVAC should be regarded as a testable conceptual model rather than a validated syndrome or diagnostic tool. Prospective, pathogen-confirmed studies are required to determine whether reproducible immunovascular signatures exist across severe infections and whether they provide clinically meaningful information beyond conventional etiological and severity assessment. Full article

West Nile virus (WNV) is an expanding mosquito-borne orthoflavivirus and an important cause of arboviral neuroinvasive disease. Whether HIV infection modifies WNV susceptibility, severity, or diagnostic performance remains uncertain. This narrative review was supported by structured PubMed/MEDLINE and Scopus searches updated to 22 August 2026 and a supplementary targeted citation search, identifying 23 peer-reviewed reports providing direct clinical or seroepidemiological evidence on WNV in people with HIV (PWH). The evidence remains heterogeneous, but recent data clarify several conclusions. A Northern Italian sero-repository study of 2843 PWH found neutralization-confirmed WNV antibodies in 3.0%, with no neuroinvasive disease and no association with HIV-related immunological variables. Comparative US cohorts likewise do not demonstrate that HIV status alone confers a uniform excess risk of WNV neuroinvasive disease. Conversely, individual reports of advanced HIV disease describe severe neuroinvasive presentations with delayed or absent WNV-specific antibody responses and molecular confirmation. HIV status alone should therefore not be considered a uniform WNV risk marker; the individual immune phenotype may be more clinically informative. In PWH with profound immunosuppression, negative early serology should not prematurely exclude WNV, and molecular testing should be considered when clinical suspicion remains high. Prevention, seasonal vigilance, and prospective HIV-specific studies remain priorities. Full article

Arboviral infections, including West Nile virus (WNV), dengue virus (DENV), chikungunya virus (CHIKV), Zika virus (ZIKV), and, to a lesser extent, Oropouche virus (OROV), pose a heterogeneous and evolving challenge for pediatric health in Europe. The increasing presence of competent vectors and international travel has resulted in both imported infections and, for selected arboviruses, documented autochthonous transmission events. Although pediatric cases are often underrecognized, children may develop severe manifestations, including neuroinvasive disease and congenital infection. Available data on pediatric arboviral infections in Europe remain limited and fragmented, complicating accurate assessment of disease burden and clinical risk. This review summarizes current evidence on the epidemiology, clinical presentation, diagnostic challenges, and prevention of selected arboviral infections in children within the European context, highlighting persistent gaps in pediatric-specific data and implications for preparedness and public health. Full article

Arthropod-borne viruses such as Alphaviruses and Flaviviruses are the causative agents of severe human disease, highlighted by fatal encephalitis and neurological sequelae in survivors. The lack of FDA-approved vaccines and therapeutics that can prevent or treat these infections results in a significant global disease burden. An important unmet need to address this capability gap is the need for affordable, scalable, clinically relevant human-based neuronal models to study neuroinvasive viruses and evaluate therapeutic options. Here, we described the application of a human neuronal precursor cell model, LUHMES (Lund human mesencephalic) cells, that can be differentiated into dopaminergic midbrain neurons and used to study virus infections. In this study, we demonstrated the susceptibility of LUHMES cells to infection by three arthropod-borne neurotropic viruses: Venezuelan equine encephalitis virus, dengue virus serotype 2, and West Nile virus. We also demonstrated how the model may be applied to evaluate potential therapeutic options using an FDA-approved small molecule, Omaveloxolone. Finally, we analyzed host cell responses to infection and treatment using gene expression and phospho-signaling analyses. These findings highlight the value of this model to interpret the pathogenic mechanisms of neurotropic viral infections and evaluate potential therapeutic intervention strategies in a clinically relevant in vitro human neuronal model. Full article

West Nile virus (WNV) transmission has intensified and expanded in Italy, but quantitative evidence on how local climatic and environmental conditions influence human risk in southern regions remains limited. This study examined the association between meteorological, environmental, and host-related factors and West Nile virus (WNV) cases at the municipal level in Apulia in 2023. Human WNV cases were georeferenced at the municipal level and linked to monthly indicators (minimum and maximum temperature, precipitation, surface water extent, green area coverage, land-use change, avian occurrence). A Bayesian spatio-temporal Poisson model with a conditional autoregressive structure was fitted to monthly counts of human WNV cases, with equine WNV cases, climatic, environmental and avian indicators included as covariates. Eight human WNV cases were reported between August and October and four equine WNV cases between September and November, with partial spatial and temporal overlap. In univariable analyses, the strongest associations were observed for meteorological variables, particularly temperature. In the final multivariable model, higher maximum temperature at a two-month lag was associated with increased WNV risk (RR = 1.53; 95% CrI: 1.18–2.23), while minimum temperature was excluded due to collinearity with maximum temperature. Green area coverage and water body extent showed uncertain effects. Model-based maps indicated that elevated fitted risk was concentrated in a narrow temporal window between August and October, expanding sharply across the region in September before receding, rather than describing a stable, spatially fixed hotspot. This exploratory analysis suggests that reported human WNV infections in Apulia in 2023 were temporally concentrated during the late summer/early autumn period and that maximum temperature at a two-month lag was positively associated with the outcome in the selected model. The findings are hypothesis-generating and should be interpreted with caution given the very small number of events, but they illustrate the feasibility of integrating multisource epidemiological, climatic, environmental, and veterinary data to support locally tailored early-warning efforts in southern Italy. Full article

Infections caused by flaviviruses, including dengue virus (DENV), Zika virus (ZIKV), and West Nile virus (WNV), can lead to severe hemorrhagic or neurological disease. Antibody-dependent enhancement (ADE) remains a major obstacle to the development of safe flavivirus vaccines and antibody-based therapeutics. ADE includes ADE of infection, in which antibodies increase in viral entry, replication, or infection load, and ADE of disease, in which antibody-dependent inflammatory and immunopathological responses exacerbate disease severity. Previous reviews have largely addressed the general virological and immunological mechanisms of ADE, but few have integrated antibody isotypes and subclasses, Fc-region modifications, Fc receptor diversity, host FcγR polymorphisms, and complement activation within a translational framework. Consequently, how these factors jointly shape ADE of infection, progression to ADE of disease, and individual risk remains incompletely understood. Here, we synthesize evidence linking antibody properties, Fc receptor expression and signaling, FcγR genetic variation, and complement regulation to both forms of ADE. We then discuss how these findings can inform antigen selection, Fc engineering, complement-informed intervention, and systems serology-based risk stratification. By connecting mechanistic evidence with vaccine and therapeutic development, this review offers a framework for designing safer flavivirus interventions and advancing individualized assessment of ADE risk. Full article

5′-Adenosine monophosphate-activated protein kinase (AMPK) is the principal cellular energy sensor that coordinates metabolic adaptation by balancing anabolic and catabolic pathways in response to energic stress. Beyond its canonical role in maintaining energy homeostasis, AMPK has emerged as a central regulator of host–pathogen interactions by integrating lipid metabolism, autophagy, mitochondrial dynamics, oxidative stress, and innate immune signaling. Flaviviruses, including dengue virus, Zika virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus, extensively remodel host metabolism to establish productive infection. As a master regulator of cellular metabolism, AMPK can either restrict or facilitate flavivirus replication in a context-dependent manner by regulating lipid droplet biogenesis, fatty acid synthesis and beta-oxidation, autophagy, mitochondrial homeostasis, and interferon-mediated antiviral responses. Conversely, flaviviruses actively manipulate AMPK signaling and its downstream metabolic networks to promote endoplasmic reticulum remodeling, replication organelle biogenesis, energy production, and immune evasion. In this review, we summarize recent advances in understanding the multifaceted roles of AMPK during flavivirus infection, with an emphasis on its regulation of metabolic reprogramming, organelle remodeling, and antiviral immunity. We further discuss the therapeutic potential of pharmacologically targeting AMPK and its downstream pathways as a host-directed strategy for broad-spectrum antiviral intervention against flaviviruses. Full article

Japanese encephalitis virus (JEV), the prototype member of the JEV serogroup within the genus Orthoflavivirus (family Flaviviridae), is closely related to West Nile virus (WNV), Murray Valley encephalitis virus (MVEV), and St. Louis encephalitis virus (SLEV). To characterize antigenic cross-reactivity within this group, we evaluated 15 region-specific rabbit antisera, previously generated against nearly the entire JEV protein-coding region, by immunoblotting whole-cell lysates from BHK-21 cells infected with WNV, MVEV, or SLEV, with JEV included as a reference. Six antisera (α-E^N-term, α-NS2B, α-NS3^N-term, α-NS3^C-term, α-NS5^N-term, and α-NS5^C-term) robustly recognized homologous proteins across all three viruses. The remaining nine antisera displayed lineage-restricted or virus-specific reactivity: (a) α-C cross-reacted strongly with WNV and MVEV but weakly with SLEV; (b) α-M, α-NS1, α-NS4A, and α-NS4B^C-term cross-reacted with WNV and MVEV but not SLEV; (c) α-E^C-term and α-NS1′ cross-reacted only with WNV; (d) α-Pr cross-reacted exclusively with MVEV; and (e) α-NS4B^N-term showed no detectable cross-reactivity under the experimental conditions used. Notably, α-NS1 and α-NS1′ detected heat-labile multimers of NS1 and NS1′. These serological patterns mirror the established phylogeny of the JEV serogroup, with JEV clustering most closely with MVEV, followed by WNV and then SLEV. Together, these findings provide a comprehensive cross-reactivity map of JEV antigen-directed antisera and establish a practical framework for dissecting antigenic relationships among JEV serogroup members. These results enhance our understanding of orthoflavivirus antigenic evolution and support the future development of improved diagnostics, broad-acting vaccines, and experimental reagents for emerging and re-emerging encephalitic orthoflaviviruses. Full article

West Nile virus (WNV) is a mosquito-borne pathogen of escalating epidemiological importance and a growing global health concern, driven by the climate-associated expansion of its Culex mosquito vectors. Although WNV is an extensively studied flavivirus, most host–pathogen interaction studies focus on static and structural aspects rather than dynamic and functional ones. Delineating phosphorylation-mediated interactions between WNV proteins and human kinases bridges a critical gap by providing important insight into the molecular mechanisms underlying infection. In this study, we investigated potential phosphorylation-mediated interactions between WNV proteins and human kinases using an integrative computational framework combining motif prediction, phosphoproteomic data analysis and structural docking. Key interactions were predicted between viral proteins and regulatory kinases within the AKT-ERK pathway and the AMPK-mediated autophagy, including major network kinases such as RAF1, IKBKB, and ULK1. In addition, experimentally validated phosphorylation sites in viral proteins were found to be associated with multiple candidate host kinases, including MAP2K7 and MAP2K9, suggesting complex regulatory networks. Integration with phosphoproteomic datasets supported the relevance of multiple predicted kinases, including those associated with antiviral responses and translational regulation. Protein–protein docking demonstrated stable, energetically favorable interactions between selected host kinases and viral proteins, particularly the viral polymerase (NS5), helicase (NS3), and NS1. The findings of this study establish a framework for future research on the development of host-directed antiviral strategies. Full article

Infectious diseases constitute a major public health concern and a leading cause of morbidity and mortality worldwide. The eye, by virtue of its rich vascularity and unique immunological microenvironment, is susceptible to involvement by a broad spectrum of bacterial, viral, fungal, and parasitic systemic infections, which may lead to diverse ocular and visual manifestations through direct pathogen invasion, immune-mediated mechanisms, or complications of therapy. Notable systemic infections with potential ocular involvement include tuberculosis; the spirochetal illnesses syphilis, Lyme disease, and leptospirosis; brucellosis; cat-scratch disease; leprosy; infective endocarditis; human immunodeficiency virus, cytomegalovirus, West Nile virus, and adenovirus infections; rubeola; dengue fever; candidiasis; cryptococcosis; aspergillosis; mucormycosis; toxoplasmosis; malaria; onchocerciasis; and cysticercosis. Ocular manifestations can serve as early diagnostic clues to underlying systemic infections, whereas, conversely, systemic features can help interpret ocular findings. Effective investigation and management of systemic infections benefit from a multidisciplinary approach, in which ophthalmologists can contribute substantially and help optimize both visual and overall health outcomes. Full article

Background and Objectives: West Nile virus (WNV) infection has a broad clinical spectrum ranging from asymptomatic or mild disease to severe neuroinvasive forms. Data on hospitalized patients with atypical or non-neurological presentations remain limited. Materials and Methods: We conducted a retrospective multicenter observational study including 30 patients with laboratory-confirmed WNV infection admitted to internal medicine wards during a seasonal outbreak in Southern Italy. Clinical characteristics, hematological parameters, and in-hospital outcomes were analyzed. Results: Median age was 77 years, and 53% of patients were male. Neurological involvement was observed in 50% of patients, whereas 37% presented with septic-like manifestations. Overall in-hospital mortality was 43%, and early mortality within 10 days occurred in 17%. Neurological involvement was significantly more frequent among non-survivors and was associated with increased in-hospital mortality. Higher monocyte percentages were associated with overall mortality, whereas eosinopenia, leukopenia, and thrombocytopenia were associated with early mortality in exploratory analyses. Conclusions: Hospitalized patients with WNV infection may present with heterogeneous clinical phenotypes extending beyond classical neuroinvasive disease. Neurological involvement appears to be the main clinical marker of adverse outcome, while selected hematological parameters may provide preliminary prognostic information. Given the limited sample size and retrospective design, these findings should be considered hypothesis-generating. Full article

Flaviviruses, encompassing notable pathogens, like Dengue, Zika, West Nile, and tick-borne encephalitis viruses, elicit complex cellular stress responses, involving pathways such as the unfolded protein response (UPR), integrated stress response (ISR), apoptosis, autophagy, and the antiviral immune response. These pathways regulate cell fate by either promoting survival to counteract virus-induced damage or triggering cell death programs under prolonged and irreparable stress. Therefore, the primary aim of flavivirus-induced cellular responses is to protect cells and hinder viral propagation. Despite cellular defenses, flaviviruses have evolved various subversion strategies, mainly involving viral proteins, which enable successful infections even when cellular responses are activated. While these cellular pathways were previously perceived as separate entities, recent studies suggest interplay and dynamic shifts among these stress response pathways, underscoring the need for further investigation in this area. In this review, we explore the key pathways activated during flavivirus infections, examine mechanisms of viral subversion, and delve into the synergy of these pathways, thereby elucidating the impact on the progression of infection. A deeper understanding of these interactions will guide future efforts to define how cellular stress responses shape flavivirus infection and leverage this knowledge toward the development of targeted antiviral strategies. Full article

Background/Objectives: West Nile virus (WNV) remains a significant threat to human health, with no approved antiviral treatments or vaccine available. A better understanding of the molecular mechanisms governing flavivirus–host interactions is needed to identify host regulatory pathways involved in infection. This study aimed to investigate how WNV infection remodels the host miRNA–mRNA regulatory landscape. Methods: WNV-induced changes in host miRNA expression in HEK-293 cells were profiled using miRNA-Seq. Transcriptome-wide host gene expression changes in WNV-infected cells were analysed using RNA-Seq. Gene Ontology and pathway enrichment analyses were conducted using DAVID. Integrated miRNA–mRNA network reconstruction was performed using Cytoscape based on the experimentally validated miRNA–mRNA interactions in miRNet database. Results: WNV infection induced global changes in host miRNA expression, with pathogenic NY99 and non-pathogenic Kunjin strains of the virus producing overlapping and strain-specific alterations in the miRNA landscape. Transcriptome analysis showed strong induction of interferon-related responses and activation of NF-κB and MAPK signalling pathways in the infected cells. In contrast, pathways associated with RNA processing, splicing, and proteasomal degradation were downregulated. Integrated miRNA–mRNA network analysis identified miR-197-3p, miR-301b-3p, miR-129-3p, miR-3662, and miR-128-5p as candidate regulatory hubs involved in WNV-induced transcriptome remodelling. These networks suggested that miRNA-mediated regulation may influence antiviral signalling, apoptosis, and RNA metabolism during infection. Conclusions: These findings suggest that WNV infection broadly remodels host miRNA–mRNA regulatory networks and identifies candidate miRNAs that may contribute to the regulation of antiviral and cellular stress responses. These predicted regulatory interactions provide a foundation for future experimental validation. Full article

Background/Objectives: Opportunistic infections remain clinically important after kidney transplantation and may contribute to morbidity and graft dysfunction in pediatric recipients. Data regarding their timing, spectrum and clinical course in children remain limited. Methods: We retrospectively reviewed pediatric kidney transplant recipients followed at a single tertiary center between 2014 and 2024. Demographic and clinical characteristics, infection type, timing after transplantation, management and outcomes were recorded. Infection incidence was assessed at the patient level, whereas pathogen distribution and timing were analyzed per infection episode. Results: Twenty-seven pediatric kidney transplant recipients were included, with a mean follow-up of 5.6 years. Ten patients (37.0%) developed at least one clinically significant opportunistic infection, and one patient experienced two distinct episodes, resulting in 11 infection events. BK virus was the most frequent pathogen, followed by fungal infections and cytomegalovirus (CMV). Five episodes (45.5%) occurred within the first post-transplant year, whereas six (54.5%) occurred later during follow-up. Late infections included CMV, fungal infections, BK virus and West Nile virus. Most infections resolved after targeted management without persistent graft impairment; however, one patient developed biopsy-confirmed BK virus-associated nephropathy with sustained graft dysfunction. No infection-related mortality was observed. Conclusions: Clinically significant opportunistic infections occurred both early and late after pediatric kidney transplantation, with more than half of all infectious episodes developing beyond the first post-transplant year. Although overall outcomes were favorable, BK virus-associated nephropathy remained clinically relevant because of its impact on graft function. Full article

Mechanisms of arboviral neuroinvasion are still incompletely resolved, despite longstanding emphasis on the blood-brain barrier (BBB) as the principal interface for central nervous system (CNS) entry. While BBB-centered models have been highly informative, they may underrepresent the contribution of other CNS border structures, particularly the choroid plexus and the blood-cerebrospinal fluid barrier (BCSFB). Here, we re-examine the BCSFB as a relevant but unevenly supported neuroinvasion interface in arboviral encephalitis. The strongest direct evidence is currently available for Zika virus (ZIKV), for which experimental studies support infection of choroid plexus-associated cells and CNS access through the blood-CSF axis. Semliki Forest virus (SFV) provides additional direct, although still limited, support for this concept. In contrast, for West Nile virus (WNV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV), evidence for choroid plexus involvement remains indirect or insufficiently resolved, even though neuroinvasion itself is well established. We therefore argue not for replacement of BBB-centered models, but for broader integration of the BCSFB into current frameworks of arboviral CNS invasion. This evidence-based perspective supports a hierarchical, virus-dependent view of choroid plexus involvement and highlights the need for mechanistic studies that directly test when and how this interface contributes to encephalitic disease. Full article