Diseases caused by Flaviviridae viruses exert profound global health and economic burdens due to their high incidence and associated mortality. Infection by the Flaviviridae family often leads to severe acute or chronic illnesses, including hemorrhagic systemic diseases caused by dengue virus (DENV) and yellow fever virus, neurological complications associated with West Nile virus and Zika virus (ZIKV) infection, as well as liver damage and hepatocellular carcinoma resulting from hepatitis C virus (HCV) infection. Accumulating evidence indicates that a hallmark of Flaviviridae infection is to hijack calcium (Ca2+) signaling of the host cells, consequently facilitating viral entry, RNA replication, viral assembly, and release. Transient receptor potential (TRP) channels, a superfamily of nonselective cation channels, are central regulators of intracellular Ca2+ homeostasis. Recent studies reveal that TRP channels are closely involved in Flaviviridae infection. This comprehensive review synthesizes current findings on the role of TRP channels (e.g. TRPC, TRPV, TRPA, TRPM, and TRPML) in the pathogenesis of Flaviviridae viruses such as DENV, ZIKV, HCV, and Japanese encephalitis virus. Moreover, this review summarizes virus-TRP channel interaction mechanisms and discusses the potential of targeting TRP channels for host-directed antiviral therapies. This review aims to establish a conceptual framework for understanding TRP channel biology in Flaviviridae infection and to guide future research on antiviral strategies. Future directions should highlight the potential utility of TRP channel research for advancing anti-Flaviviridae therapies and clarifying their underlying mechanisms.

Zika virus (ZIKV) is a key member of the Flavivirus genus that has emerged as a major global public health concern. The fusion loop region (residues 98-110), located within domain II of the envelope protein, is highly conserved among flaviviruses, including ZIKV and Japanese encephalitis virus (JEV). However, the functional consequences of such conservation for cross-reactive immunity remains unclear. Here, we integrated bioinformatic analyses, functional assays in vitro and mouse models in vivo to systematically determine the effects of antibodies directed against the JEV fusion loop (FL) region on ZIKV infection. Sequence alignment and structural analysis revealed complete amino acid identity and almost identical three-dimensional conformations between the FL regions of the two viruses, providing a molecular basis for cross-reactivity. Antisera generated against the JEV FL region recognized ZIKV particles and displayed concentration-dependent bidirectional effects. Increased and decreased antibody levels respectively neutralized viral entry and replication, and facilitated infection via antibody-dependent enhancement (ADE). These effects were confirmed in vivo, in which high and low antibody doses reduced tissue pathology and improved survival, and increased viremia and exacerbated inflammatory responses, respectively. These findings highlight the importance of antibody concentration in determining whether cross-reactive responses to conserved structural elements engender neutralization or enhancement response. Our findings provide experimental evidence for assessing ZIKV susceptibility in JEV-vaccinated populations and offer structural insights for designing flavivirus vaccines that maximize protection while minimizing ADE risk. These findings further highlight potential pathogenic and clinical considerations for optimizing vaccine formulations to reduce cross-reactive enhancement risks.

Japanese encephalitis (JE), caused by mosquito-borne Japanese encephalitis virus (JEV), presents significant public health challenges. To facilitate effective prevention and control, this study conducted an epidemiological and genomic characterization of JEV in mosquitoes across China during the period from 2021 to 2022, utilizing the national surveillance system for mosquito-borne pathogens. In total, 832 734 female mosquitoes were collected at 130 surveillance sites spanning 29 provinces. with a minimum infection rate (MIR) of 0.20‰. JEV was detected in 12 provinces and five different mosquito species. The highest MIR was observed in Culex tritaeniorhynchus, reaching 0.73‰. The highest detection rate of JEV was found in the pigsty habitat (MIR: 0.95‰). Notably, peak JEV infections in mosquitoes occurred in July, preceding the peak incidence of human cases observed in August. Eight JEV sequences were obtained from six provinces, seven of which were near full-length. Phylogenetic analysis of the whole genome showed that eight JEV strains obtained from provinces in northern and southern China belonged to the emerging variant of GIb-clade 2. In comparison to vaccine strains, current strains displayed between 12 and 14 amino acid variations within the E protein, and there was an additional glycosylation site at N108 resulting from a G110S mutation. These findings underscore active transmission of JEV across multiple mosquito species within China, highlight critical vector and habitat risks, and advocate for enhanced mosquito surveillance as an early warning system. The nationwide dissemination of GIb-clade 2 strains provides a scientific foundation for targeted control measures against JE.

Japanese encephalitis (JE) remains a significant threat to the human, horse, and pig industries throughout the Asia-Pacific region. Emerging genotype V and IV JE virus (JEV) can evade vaccine-induced immunity and exacerbate the disease burden after spreading into JE-naïve or epidemic areas through the movement of mosquitoes, pigs, and birds. This study aimed to assess the risk of viral importation into Taiwan by conducting mosquito-based surveillance. Our phylogenetic results revealed that at least six JEV importation events occurred in Taiwan between 1958 and 2024. Over the past 16 years of mosquito-based surveillance, three imported events of two genotype I (GI) subclusters (Sub I and Sub II) were detected and sustained local transmission in Taiwan from the first identification in 2008 and 2009 to 2024, without evidence of repeated importations. We further identified three distinct evolutionary stages of local GI JEVs: (1) an initial decade (2009-2018) characterized by co-circulation of Sub I and Sub II; (2) a reduction in viral population size, a decline in genetic heterogeneity, and the extinction of Sub II after 2018; and (3) emergence of a novel, dominant Sub I-I cluster bearing the E-V441I substitution in the stem region of envelope (E) protein. Our findings suggest that Taiwan has faced a low risk of JEV importation over the past 67 years. However, when the virus was introduced, it could subsequently establish a long-term circulation and overwinter in Taiwan. These findings underscore the importance of ongoing surveillance of potential JEV overwintering hosts to guide future control strategies.

Parvovirus B19 infection is mostly asymptomatic in immunocompetent individuals but may cause severe manifestations when humoral immunity is impaired. Anti-CD20 therapies such as rituximab induce prolonged B-cell depletion and hypogammaglobulinemia, affecting the immune coordination and lowering the threshold for viral neuroinvasion and persistence within the central nervous system (CNS). We present a case of a 61-year-old patient who developed new-onset seizures 9 months after completing rituximab as fourth-line therapy for immune-mediated thrombocytopenia. Brain MRI showed a focal hyperintense lesion in the left peri-insular region with edema. Parvovirus B19 DNA was detected in the cerebrospinal fluid via polymerase chain reaction, while extensive testing for other infectious and autoimmune causes of encephalitis was negative. Immunological work-up demonstrated persistent depletion of CD19[+] B lymphocytes and severe hypogammaglobulinemia. This case highlights the role of impaired humoral immunity in facilitating viral persistence within the CNS and emphasizes the need to consider parvovirus B19 and other uncommon pathogens as a potential cause of encephalitis in patients with prior anti-CD20 therapy, even months after treatment completion.

Arthropod-borne pathogens, many of which are neurotropic, can disseminate beyond the central nervous system to infect peripheral organs. In recent years, an increasing number of cardiac dysfunctions have been reported following arthropod-borne viral infections; however, the mechanism underlying these cardiac manifestations remains poorly understood. In this study, we investigated the impact of Venezuelan Equine Encephalitis Virus (VEEV) TC-83 infection on cardiac function and immune-response of human induced-pluripotent stem cell (hIPSC)-derived cardiomyocytes (hIPSC-CMs). We first confirmed the successful differentiation of hIPSCs into spontaneously beating hIPSC-CMs. We then demonstrated that these cells are highly susceptible to VEEV TC-83 infection, which induced pronounced arrhythmias and complete cessation of beating within 24 hours post-infection. To quantify these functional changes, we developed a segmentation-free computational pipeline that converts frame-to-frame motion in brightfield time-lapse movies into a one-dimensional signal reflecting contractile activity and extracts beat timing, beat rate, and rhythm-regularity features in the time and frequency domains. This analysis revealed progressive disruption of beating dynamics following VEEV TC-83 infection, with early rhythm instability and complete loss of coordinated beating by 24 hours post-infection. Furthermore, mass spectrometry analysis of VEEV TC-83-infected hIPSC-CMs supernatants revealed the presence of biomarkers typically associated with heart failure in patients, underscoring a virus-induced cardiac functional impairment. Together, these findings provide new insight into cardiac complications associated with arthropod-borne viral infections and may support advances in preventive medicine.

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus responsible for sporadic outbreaks of severe disease with high case fatality rates in South and Southeast Asia. Human infection occurs through spillover from natural reservoirs, primarily fruit bats, or via human-to-human transmission, and is characterized by a broad clinical spectrum ranging from asymptomatic infection to acute respiratory disease and fatal encephalitis. Following entry via ephrin-B2 and ephrin-B3 receptors, NiV exhibits marked endothelial and neuronal tropism, leading to systemic vasculitis, disruption of the blood-brain barrier, and direct infection of the central nervous system. Disease progression is driven by a complex interplay between viral replication strategies and host immune responses. NiV effectively counteracts innate immunity through multiple viral proteins that inhibit interferon signaling, while simultaneously inducing dysregulated inflammatory responses that contribute to tissue damage and multi-organ failure. Neurological involvement represents the most severe manifestation, often resulting in acute or relapsing encephalitis with long-term sequelae among survivors. Despite the severity of the disease, no licensed antiviral therapies or human vaccines are currently available. Therapeutic development has focused on neutralizing monoclonal antibodies targeting viral glycoproteins and small-molecule antivirals that inhibit viral RNA synthesis, both of which show promising results in preclinical models, but remain limited by timing and translational challenges. In parallel, several vaccine platforms-including viral vectors, mRNA-based constructs, and recombinant protein subunits-have advanced to early-phase clinical trials, demonstrating encouraging immunogenicity. Beyond biomedical interventions, effective outbreak containment relies on integrated public health strategies. The "Kerala model" highlights the importance of rapid case identification, isolation, contact tracing, and community engagement within a One Health framework to mitigate transmission and reduce mortality. This review synthesizes the current knowledge on NiV pathogenesis, immune evasion, clinical manifestations, and emerging therapeutic and vaccine strategies, while highlighting critical gaps and future directions for improving the preparedness and response to this high-consequence emerging pathogen.

Infections caused by arboviruses, a diverse group of viral pathogens transmitted by biting arthropod vectors, mainly mosquitoes, ticks, and midges, can cause a range of illnesses in humans, from mild, influenza-like symptoms to severe neurological complications including encephalitis and viral hemorrhagic fever. According to 2024 World Health Organization statistics, vector-borne diseases collectively account for over 700,000 human deaths annually, with mosquito-borne infections such as dengue, chikungunya, Zika, and yellow fever constituting a growing and significant proportion of this burden. What was once considered a problem localized to poorly resourced settings in tropical and subtropical regions is now becoming a pervasive global challenge. This is due largely to a combination of factors including climate change, transcontinental travel, and urbanization, with the geographical spread and intensity of arboviral outbreaks reaching unprecedented levels during the current century. In much the same way that the escalating global burden of bacterial infections resistant to antibiotics has been described as a silent pandemic, the insidious rise of arboviruses begs questions regarding outbreak preparedness, prevention and control. Here, we highlight the pressing need for comprehensive strategies that incorporate various health sectors to mitigate the emergence and resurgence of arboviral diseases. Future directives that should be prioritized are outlined. As demonstrated by epidemiological trends and historical outbreak data, an orchestrated global response is critical not only for managing current threats but also for preventing future epidemics.

Tick-borne encephalitis virus (TBEV) is primarily transmitted by Ixodes spp. and poses significant health risks, leading to morbidity and mortality in humans. Two of the five subtypes, Siberian and Far Eastern are known to circulate in Mongolia. In 2021, Ixodes persulcatus ticks were collected from Bulgan aimag (province) using flagging and dragging methods and subsequently screened for TBEV using PCR. Positive samples underwent sequencing using an Oxford Nanopore Technologies-based hybrid capture approach, resulting in two coding-complete TBEV genomes from separate tick pools. Phylogenetic analysis classified both genomes within the Siberian subtype, grouping them with other Mongolian sequences from I. persulcatus collected in 2014, 2020, 2021, and 2023. The study sequences, PX654173 and PX654174, showed high genetic similarity (99.9% and 99.8%, respectively) to the sequence PQ479142, obtained from I. persulcatus ticks in Selenge, Mongolia, in 2021. The estimated time to most recent common ancestor (TMRCA) of the Siberian genotype was approximately 981 CE (95% HPD: 646-1347) with the emergence of a distinct Mongolian clade of TBEV around 1888 CE (95% HPD: 1834-1934). These findings highlight the value of expanded whole-genome sequencing to improve our understanding of TBEV's genetic diversity and evolutionary history in Central Asia.

Coronavirus infections pose a significant threat to both human and animal health, causing widespread morbidity, mortality, and substantial economic losses. While vaccines are crucial for prevention, their efficacy is often limited by the high mutation rate of these viruses. This underscores the urgent need for anti-coronavirus drugs, particularly broad-spectrum antiviral agents. In this study, we demonstrated for the first time that Biochanin A (BCA), a bioactive isoflavonoid found in legumes, exhibits broad-spectrum antiviral activity against coronaviruses. BCA potently inhibits porcine epidemic diarrhea virus (PEDV), as well as human coronaviruses HCoV-OC43 and HCoV-229E in vitro, with EC50 values of 6.90, 2.80 and 15.4 μM, respectively. In a lethal mouse model of HCoV-OC43-induced encephalitis, oral administration of BCA (40-60 mg/kg) significantly improved animal survival and reduced cerebral viral loads. Mechanistic studies revealed that BCA upregulates the AMPK/Nrf2 signaling pathway, thereby increasing expression of the glutamate-cysteine ligase catalytic subunit (GCLC) and enhancing glutathione (GSH) biosynthesis. Our findings identify BCA as a promising host-directed antiviral agent and highlight its therapeutic potential against coronavirus infections.

The manipulation of host cellular metabolism is a key strategy for flaviviruses like Japanese encephalitis virus (JEV) to establish a productive infection. This study identifies the host NADase CD38 as a central regulator of this process. Using a CRISPR/Cas9-generated CD38 knockout (KO) TM3 cell model, we found that CD38 deficiency significantly restricted the production of infectious viral particles. While loss of CD38 also partially impaired viral entry, our central finding is that CD38 primarily promotes JEV infection by suppressing a host-intrinsic metabolic defense. We show that CD38 deficiency leads to a surge in intracellular NAD+, which sustains SIRT1 activity and inactivates p53, thereby blocking the mitochondrial apoptosis required for viral propagation. The dominance of this metabolic axis was confirmed through bidirectional pharmacological interventions; while SIRT1 inhibition using EX527 restored JEV replication, SIRT1 activation using SRT1720 suppressed it in wild-type cells. Our work reveals that JEV hijacks the CD38-NAD+-SIRT1-p53 axis to overcome host metabolic defenses in reproductive cell models, establishing CD38 as a promising therapeutic target.

Host lipid metabolism is a critical determinant of viral pathogenesis. Although the interferon-inducible cholesterol 25-hydroxylase (CH25H) typically acts as a broad-spectrum antiviral protein, its expression and regulatory patterns during Japanese Encephalitis Virus (JEV) infection display unique features. Here, we demonstrate that 25-hydroxycholesterol (25HC), the product of CH25H, potently inhibits JEV proliferation by suppressing SREBP2 activation. Distinct from the majority of viral infections that induce CH25H upregulation, JEV infection elicits a transient reduction in CH25H abundance immediately after infection, coupled with a persistent elevation in SREBP2 expression. This inverse correlation suggests that JEV actively suppresses the CH25H-mediated metabolic checkpoint to maintain a cholesterol-synthetic environment favorable for replication. By pharmacologically simulating the activity of 25HC, we further verify that targeting the SREBP2 signaling axis can efficiently counteract this virally induced metabolic reprogramming. Our study identifies CH25H downregulation and concomitant SREBP2 activation as a key metabolic signature of JEV pathogenesis.

Chandipura virus (CHPV) is a neurotropic rhabdovirus associated with recurrent outbreaks of acute encephalitis in children and a high case fatality rate, particularly in India. Despite its public health relevance, the host molecular processes governing CHPV infection and disease progression remain poorly defined. To address this gap, we conducted a time-resolved transcriptomic analysis to characterize host responses to CHPV infection and to explore host-directed therapeutic opportunities. Human HEK293T cells were infected with CHPV, followed by RNA sequencing (RNA-seq) at 6, 12, 18, and 24 h post infection (hpi). Transcriptome profiling revealed a temporally ordered host response. At 6 hpi, CHPV infection was dominated by strong activation of innate immune and inflammatory pathways, including interferon-stimulated genes and cytokine signaling. Antiviral responses persisted at 12 hpi, accompanied by suppression of metabolic and translational processes, indicating a shift in host cellular priorities. By 18 hpi, metabolic reprogramming-particularly involving lipid and sphingolipid metabolism-was observed alongside altered immune signaling, consistent with viral exploitation of host cellular machinery. At 24 hpi, repression of genes involved in chromatin organization, RNA processing, spliceosome assembly, and ribosome biogenesis reflected a global transcriptional shutdown associated with cytopathic effects. Integration of temporal transcriptomic signatures enabled identification of host pathways amenable to pharmacological targeting. Selected host-directed compounds were evaluated in vitro and exhibited antiviral activity against CHPV in a neuronal cell line. Collectively, this study provides the first time-resolved transcriptomic landscape of CHPV infection in human cells and identifies host-targeted strategies relevant for antiviral development.