B cells play a crucial role in humoral immunity, acting as sentinels against viral infections by using their B cell receptors (BCRs) to recognize viral proteins. This recognition typically triggers a response leading to the production of neutralizing antibodies against viral surface proteins, such as the viral envelope proteins. However, recent studies have revealed a surprising dual role for BCRs, showing that some enveloped viruses and viral vectors, such as Dengue virus and lentiviral vectors, can exploit anti-viral BCRs as their attachment and entry receptors to infect/transduce B cells. While these viruses use a simple low-pH-dependent fusion mechanism for entry, it remained unclear whether BCRs could facilitate the entry of viruses with more complex fusion requirements, such as HIV-1 and SARS-CoV-2, which rely on their cognate receptors to activate their fusion machinery. In this study, we investigated the ability of BCRs to mediate viral entry for HIV-1 and SARS-CoV-2, which require specific host receptors (CD4 and ACE2, respectively) to activate their fusion machinery. We found that while anti-HIV-1 envelope protein BCRs can mediate viral attachment, they are unable to facilitate viral fusion and entry. In contrast, anti-SARS-CoV-2 Spike (S) protein BCRs not only mediate attachment but also enable viral entry in the absence of the ACE2 receptor. Our findings demonstrate that the ability of anti-viral BCRs to mediate viral fusion/entry is not universal but depends on the specific viral envelope protein. This novel entry pathway has important implications for both viral replication and the development of B cell-mediated immunity.

Hendra virus (HeV) is a bat-adapted zoonotic henipavirus belonging to the Paramyxoviridae family. It is classified as a biosafety level 4 (BSL-4) pathogen owing to its broad host range and high fatality rate. Currently, no vaccines or therapeutics are approved for human use. Viral entry is mediated by the attachment (G) and fusion (F) glycoproteins; the heavily glycosylated G protein is responsible for receptor binding. The extracellular domain of HeV-G was expressed in Expi293F cells and its glycosylation sites and glycan composition were identified by mass spectrometry. A series of functional assays-including viral entry, receptor binding, cell-cell membrane fusion, antibody neutralization and immunogenicity-were performed to delineate the role of each N-linked glycosylation site. Glycan profiling of HeV-G identified seven N-linked and multiple O-linked glycosylation sites, revealing that the stalk residues (N72, N159) predominantly carry high-mannose glycans, whereas the head-domain N-glycan sites (N306, N378, N417, N481, N529) are primarily modified with complex glycans. Notably, among the head-domain sites, N481 also harbors a substantial proportion of high-mannose glycans. Functional assays revealed that removal of N-glycans at N159, N306 and N417 markedly reduced membrane fusion. The N159 residue is a key site for fusion triggering, and its function is tolerant to specific amino acid substitutions, which may contribute to stabilizing or facilitating the conformational cascade required for F protein-mediated membrane fusion. The N529Q mutant specifically decreased EB3 binding by 2.6-fold, correlating with reduced infectivity. Binding assays with neutralizing antibodies showed that most N-glycan deletions had negligible effects, except that N159Q and N481Q reduced affinity to nAH1.3. Immunization studies in mice demonstrated that N-glycans had minimal impact on humoral immunity, with only minor site-specific differences. These findings provide a comprehensive characterization of HeV-G glycosylation, reveal site-specific roles of N-glycans in viral entry, receptor binding and membrane fusion, and offer new insights for vaccine and antibody development.

Dengue fever continues to exert significant global impact, affecting populations worldwide with considerable public health and economic consequences. There is no antiviral drug for dengue. This study focuses on hypericin, a naturally occurring compound from Hypericum perforatum L. whose anti-dengue properties have been underexplored. We systematically examined its antiviral efficacy against dengue virus (DENV), revealing strong inhibitory effects and clarifying its precise antiviral mechanism. The study assessed the efficacy of hypericin against DENV using various scientific methods like plaque assays and Western blotting. We looked into its antiviral mechanism. We used a time-of-addition approach during our research. Moreover, the basic mechanisms involved were studied through molecular docking, surface plasmon resonance (SPR), and co-immunoprecipitation (Co-IP). This study demonstrated that hypericin exhibits broad-spectrum antiviral activity against DENV-2 in cell lines derived from multiple species. In time-of-addition experiments, it showed inhibitory effects under co-treatment, direct virucidal, and post-treatment conditions. Crucially, hypericin primarily blocked viral attachment and entry stages, thereby effectively reducing intracellular viral load. Mechanistic investigations revealed a interaction between hypericin and the E protein, evidenced by a computational docking score of -7.0kcal/mol and an experimental SPR-derived Kd of 7.18 µM. Furthermore, Co-IP assays demonstrated that hypericin competitively blocks the association between the E protein and its cellular receptor, HSP70. As per these findings, the E protein was seen to be a target of hypericin with an antiviral activity against DENV-2 at multiple stages by limiting viral adsorption and viral entry projecting a molecular basis for the candidate molecule as a possible anti-dengue agent.

Glycan-mediated processes can be critical determinants of viral attachment and entry, yet for enveloped RNA viruses, including SARS-CoV-2, their mechanistic roles remain incompletely defined. This review synthesizes current structural and functional evidence for glycan engagement during SARS-CoV-2 attachment and entry. We describe the general viral entry pathways and their reliance on glycan recognition, followed by the interactions of the SARS-CoV-2 spike glycoprotein with host glycans, including ABO(H) blood group antigens, sialylated glycans, and endogenous lectins. Based on structural biology, glycobiology, and virology, we focus on how the spike protein exploits both glycan motifs and lectin receptors to enhance attachment, promote cellular uptake, or modulate host tropism. We contextualize these mechanisms by comparing glycan dependencies across other human viruses, including the influenza virus, HIV, and norovirus. Finally, we provide a comparative virological perspective to derive broad evolutionary insights into how enveloped viruses exploit the host glycans.

The continuous spread of mpox disease caused by mpox virus (MPXV) has posed great threat to global public health. The postattachment membrane fusion process of MPXV is mediated by a multimeric protein machinery, termed as entry-fusion complex (EFC). Among EFC components, A30 and H2 are the earliest identified interaction pair and play important roles in virus entry. Here, we determine the crystal structure of MPXV A30/H2 subcomplex via the tandem-fusion strategy, and show that A30 undergoes large conformational rearrangements upon H2 binding. Structural analysis reveals extended intersubunit interface and highly conserved intermolecular interactions. In vitro binding data further clarify key residues and elements involved in the A30/H2 subcomplex formation. Finally, we show that the H2-A30 fusion protein, superior to A30 ectodomain alone or the ectodomain-mixture of H2+A30, can induce more potent neutralizing-antibody responses which could inhibit viral infection. These data provide valuable information for the understanding of poxvirus EFC assembly and the H2-A30-based immunogen design and optimization.

The Marburg virus (MARV), responsible for severe hemorrhagic fevers with mortality rates as high as 90%, remains a significant public health threat. This study employs machine learning to identify inhibitors targeting the MARV Gene 4 Small ORF protein, crucial for the virus's replication and immune evasion. The Gene 4 Small ORF protein is pivotal in taking over the host's cellular mechanisms, facilitating unchecked viral replication and significant immune system disruption. Effective targeting of this protein holds promise for mitigating the viral lifecycle and entry, potentially curbing the severity of the disease outbreaks. A dataset from PubChem, including 301,745 compounds, was utilized to train models like Random Forest (RF), Gradient Boosting Machines (GBM), CatBoost (CB), AdaBoost (AB), and Logistic Regression (LR). The activity outcomes were classified with integers active as 1 and inactive as 0, followed by molecular descriptor generation using RDKit and PaDEL. The models were trained on an 80:20 split and validated on a novel dataset to ensure robustness, with performance metrics such as accuracy and AUC-ROC guiding evaluation. Morgan fingerprints outperformed PubChem fingerprints, achieving higher accuracy (76%), precision (80%), and ROC-AUC (84%). Among the machine learning models evaluated, RF and GBM were the best performers, with RF achieving the highest specificity (83%) and ROC-AUC (0.84). Validation on new datasets further confirmed the effectiveness of these models, with RF and GBM demonstrating strong predictive reliability for identifying potential inhibitors of the Marburg virus. A Web Application known as MARVpred was developed to predict the activity of compounds with anti-MARV properties from the ChEMBL database. MARVpred is freely accessible online (https://igmr.org/software/marvpred). This study signifies a critical step forward in the computational prediction of viral inhibitors, offering a valuable tool for accelerating the development of Marburg virus therapeutics.

CD55-displaying oncolytic vaccinia virus treated metastatic cancers by evading the effect of host innate and adaptive humoral responses.

Introduction: Cervical intraepithelial neoplasia (CIN) is a premalignant lesion that is diagnosed by histology as CIN1, CIN2, or CIN3. Cervical intraepithelial neoplasia results from HPV infection within cervical cells[1]. An earlier age at first sexual intercourse (AFSI) is associated with an elevated risk of HPV acquisition due to cervical cellular immaturity and a reduced capacity to clear persistent infections. HPV infections are mainly transmitted through sexual contact and thus all women who are sexually active are at risk of cervical cancer[2]. Among these factors, the relative contributions and impacts of AFSI and HPV infection have attracted significant interest but remain insufficiently investigated. Purpose of the Study: Investigate the association between AFSI and HPV infection as independent and synergistic risk factors for CIN. By assessing various ages at which women experience their first sexual intercourse, this study seeks to evaluate the impact of these ages on the susceptibility to acquiring CIN. Methods and Materials: This correlational study, which utilized a structured questionnaire and a review of theoretical frameworks, was conducted among women of different age groups, specifically those aged 20-30 years old. The study population was restricted to women without a cervical cancer history. Additionally, data were extracted from 8 related scientific journals for comprehensive multivariate analysis. Research Result: This study analyzed 186 women with histologically confirmed CIN. The results demonstrated a significant inverse relationship between AFSI and CIN prevalence. The women with AFSI ≥21 years (n=34, 16,28%) with odds ratio (OR) was (OR: 1.80), while those with AFSI 17-20 years (n=71, 38,17%) showed elevated risk (OR: 2.44), and the youngest debut group AFSI ≤16 years, (n=81, 43,55%) exhibited the highest risk (OR: 4.09). Additionally, the HPV prevalence analysis revealed 17 cases among women with AFSI ≥21 years (OR: 1.00), 36 cases in the AFSI 17-20 years group (OR: 2.10), and 42 cases in the AFSI ≤16 years (OR: 2.48). Questionnaire-derived data from 47 participants showed significant (p<0.05) distribution patterns: 11 participants (23,40%) reported AFSI ≥21 years, 13 (27,66%) reported AFSI 17-20 years, and 23 (48,94%) reported AFSI ≤16 years. The study shows that AFSI and HPV infection were the most important factors in the development of CIN, as indicated by the strong correlation discovered. Conclusion: This study establishes that ASFI and persistent HPV infection as significant risk factors for CIN progression. Early sexual debut potentiates HPV susceptibility through cervical epithelial immaturity and impaired immune clearance, while microtrauma during coitus facilitates viral entry at the transformation zone adjacent to the squamocolumnar junction (SCJ). Adolescent cervical ectopy exposes metaplastic epithelium at the SCJ, creating a vulnerable microenvironment for neoplastic transformation. Hormonal changes promote a thinner squamous epithelium and greater columnar cell presence in the cervix of reproductive-aged women. This reduces transformation zone dynamics, enabling persistent HPV infection to cause CIN. These findings underscore the need for targeted interventions addressing early AFSI in high-risk populations to prevent CIN.

Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging coronavirus that can cause zoonotic disease in humans with lethal severe viral pneumonia. Dromedary camels are the source of zoonotic infection. As of November 2025, MERS-CoV has resulted in a total of 2630 reported cases, 37% of these being fatal. The number of reported human cases has been on a decreasing trend since 2016 and reached a nadir during the COVID-19 pandemic. The reason for the reduction of cases is unclear and may be multifactorial. We hypothesized that mutations accumulating in the virus spike protein may have reduced zoonotic potential. Here, we investigate the impact of recently emerged virus spike-protein mutations on virus replication competence using pseudoviruses and replication-competent recombinant viruses. We found that virus spike variants detected in 2019 and some from 2023 show a reduced cell entry, lower viral replication and reduced fitness in human primary alveolar epithelial cells and multiple cell lines. All the MERS-CoV spikes tested showed a cell-entry pathway preference via the cell-surface TMPRSS2 route. Mechanistically, we showed the V530A mutation in the 2019 spike sequence had a reduced human DPP4 binding phenotype. Our data highlighted MERS-CoV spike mutations can modulate viral fitness in human cells and provide new insights to understand recent MERS epidemiology.

The high mortality caused by severe COVID-19 poses great challenges to the public health. However, the underlying pathogenesis of severe cases remains unclear. Here, we find that SARS-CoV-2 infection boosts CD147 inducible up-regulation in the lung tissues of virus-infected rhesus macaques coupled with down-regulated membrane-bound ACE2, which conduces to extended virus infection and severe pathological lesions. Specifically, SARS-CoV-2 infection enhances the expression of transcriptional factor aryl hydrocarbon receptor and facilitates its nucleus translocation, which causes CD147 gene transcription and its up-regulation in protein level, thereby leading to virus susceptibility of the hosts and extended virus infection. Meanwhile, SARS-CoV-2 infection triggers immune imbalance of lung tissues by promoting cell death of CD4 + T cells and B cells and mediating abnormal cell-cell communications, especially for M2 macrophages. Meplazumab, a humanized anti-CD147 antibody, effectively inhibits virus entry and cytokine level, and restores immune balance in the lung tissues of virus-infected rhesus macaque model. Importantly, we further present the cryo-EM structure of CD147-spike complex, and identify five pairs of functional residues for their interaction, which could be interrupted by Meplazumab via steric hindrance effect. Our findings provide direct evidence for CD147-SARS-CoV-2 spike interaction and uncover the pathogenesis of severe COVID-19 caused by CD147-mediated extended virus infection.

Evaluating the impact of NPC1 single nucleotide polymorphisms on entry efficiency of filoviruses in vitro: Agent-based model approach.

Identification of sulfonamide drugs as allosteric inhibitor of Chikungunya virus envelope glycoprotein: An in silico approach for drug repurposing.

Polystyrene nanoplastics promote fish iridovirus replication via inducing inflammatory response, antioxidant damage and enhancing viral entry.

Insights into antiviral activity of chlorpromazine against RNA viruses: Molecular docking, ADME profile, and semi-in vivo study.

Calnexin (CNX) and calreticulin (CRT) are two essential endoplasmic reticulum chaperones involved in the folding pathway dedicated to N-glycosylated proteins. The N-glycosylated protein GP64, located in the budded virus envelope of Bombyx mori nucleopolyhedrovirus (BmNPV), plays a key role in viral entry. However, the roles of CNX and CRT in GP64 processing and maturation, as well as in BmNPV infection, remain incompletely understood. In this study, we identified the two genes BmCNX and BmCRT from a B. mori transcriptome database. Spatiotemporal expression profiles showed that BmCNX and BmCRT displayed similar patterns, with expression detected in all tissues and elevated levels in the gonad, trachea, and malpighian tubule, as well as during the egg and larval stages. Following BmNPV infection, the expression of BmCNX and BmCRT was significantly upregulated in both the midgut and BmN cells. Overexpression of BmCNX and BmCRT enhanced BmNPV proliferation and GP64 expression, while knockdown of either gene suppressed both viral proliferation and GP64 expression. Furthermore, GP64 was shown to interact with BmCNX and BmCRT, respectively. These results suggest that BmNPV infection requires both BmCNX and BmCRT to facilitate GP64 expression and promote viral proliferation. This study lays the foundation for further investigation into the roles of endoplasmic reticulum chaperones in response to BmNPV infection.

Evaluation of the contribution of hemagglutinin-neuraminidase to the endocytic entry of Newcastle Disease Virus.

Zika virus (ZIKV) infection is known to cause microcephaly in newborns, and its outbreaks have previously emerged as a global public health crisis. The lack of a preventive vaccine or specific antiviral drugs underscores the urgency of investigating the detailed mechanisms of pathogenesis. We identified that interferon-induced protein 44 (IFI44) is significantly upregulated following ZIKV infection, but its role in ZIKV pathogenesis remains unclear. Using A549 and 2FTGH cells, we established ZIKV-infected cell models and employed quantitative real-time PCR and Western blotting to demonstrate that IFI44 overexpression suppressed ZIKV replication, whereas IFI44 knockdown via specific small interfering RNA promoted viral replication. Mechanistically, IFI44 inhibited early-stage ZIKV infection, including viral attachment and entry into host cells. Further analyses revealed that IFI44 promoted IFN-β expression, triggering activation of the Jak/STAT signaling pathway-as evidenced by increased phosphorylated STAT1 (p-STAT1), enhanced interferon-stimulated response element activity, and upregulated the downstream interferon-stimulated genes (MX1, OAS2, IFIT2, and RIG-I). Collectively, these findings demonstrate that ZIKV infection induced IFI44 expression, which acts as a positive feedback regulator of the Jak/STAT pathway to restrict viral replication. Our results establish IFI44 as a key component of the host antiviral response against ZIKV, highlighting its potential as a therapeutic target.

Nipah virus as a pandemic threat: Current knowledge, diagnostic gaps, and future research priorities.

Ingestion of polystyrene microplastics by Bombyx mori larvae disrupts midgut epithelial barrier integrity and potentially promotes susceptibility to BmNPV infection.

Spumigins produced by Nodularia spumigena are natural serine protease inhibitors with anti-SARS-CoV-2 activity.