Search Results (546)

Public health policy foundationally impacts how pathogens spread, yet despite multiple pathogens of broader societal concern emerging, little research has examined how policy affects pathogen evolution. To evaluate this connection, we examine how varying public health approaches impact how viral immune susceptibility, including resistance to vaccines, evolves. Integrating evolutionary epidemiological modeling and critical geography, we compare how distinct public health responses early in the COVID-19 pandemic affected the potential evolution of immune evasion in SARS-CoV-2 across four territories: Costa Rica, Panama, Texas, and Uruguay. We use parameter estimates inferred from confirmed case and vaccination time series via stochastic ensemble Kalman filtering in each territory. Our analyses suggest viral immune resistance was most likely to emerge in Texas, which relied almost exclusively on vaccines for disease control. In contrast, regions with comparatively fewer health disparities that also rigorously applied interventions, such as shelter-in-place orders and household support, may have better prevented vaccine resistance from evolving. These comparative analyses highlight the key role policy choices play, potentially representing different governance goals for population health and wellbeing. We argue that such choices impact not only disease spread but also pathogen evolution along epidemiologically critical dimensions like viral immune susceptibility. Our study thus demonstrates how public health priorities drive social–evolutionary feedbacks. Full article

Background: The HPV16 E6 oncoprotein facilitates the ubiquitin-mediated degradation of the tumor suppressor p53, constituting a pivotal mechanism underlying viral immune evasion, cellular immortalization, and ultimately, malignant transformation. This study aimed to develop a reliable detection tool for the HPV16 E6 protein. Methods: Recombinant GST-E6 and E6-His proteins were expressed and purified using a prokaryotic expression system. Female BALB/c mice were immunized with GST-E6, and two hybridoma cell lines (G11A11 and A4) stably secreting anti-HPV16 E6 monoclonal antibodies were generated via hybridoma technology. Antibody pairing experiments identified A4 and G11A11 as suitable for sandwich ELISA. The optimal detection system was established using A4 antibody at 2 μg/mL for coating, HPV16 E6-His at 5 μg/mL as the detection antigen, and G11A11-HRP at a 1:200 dilution as the detection antibody. To validate the reliability, Hacat-HPV16E6 cell lysates were tested in parallel with a commercial ELISA kit. Results: After purification, the titers of both antibodies reached 1:204,800. The lower limit of quantification (LOQ) was 4.79 ng/mL and the limit of detection (LOD) was 3.39 ng/mL. The comparison with the commercial kit showed good consistency, with percentage differences ranging from 20% to 40%, confirming that the established ELISA is reliable for quantitative detection. Conclusions: This study successfully yielded high-titer and highly specific anti-HPV16 E6 monoclonal antibodies and developed a specific double-antibody sandwich ELISA, thereby furnishing a technical foundation for both fundamental research and laboratory-based applications related to HPV16-associated tumors. Full article

Herpes simplex virus 1 (HSV-1) is a rare cause of acute hepatitis, especially in patients with chronic immunosuppression. We performed whole-genome HSV-1 sequencing with a metagenomics approach on peripheral blood samples from an Italian case of fatal acute liver failure with high circulating HSV-1 (1,129,900,000 copies/mL), followed by phylogenetic analysis. After multiple sequence alignment, a final dataset of 182 whole-genome sequences was selected. The sequenced HSV-1 strain belonged to a phylogenetic clade isolated in Florida in 2002 (OQ724868.1). A characterization of single nucleotide polymorphisms and indels was performed to determine their effects on the viral genome: only one variant, classified as an indel, was detected with a high impact effect (c.905_906insGTTTT) in the UL49A gene, which is known to encode a membrane protein regulating virion morphogenesis, replication and assembly. In addition, this study also detected variants in other genes involved in crucial steps of the HSV-1 life cycle, like alpha-regulation (US7), capsid transport (UL36) and viral polymerase function (UL30). In conclusion, the results of this variant analysis confirmed that in HSV-1 hepatitis, some viral regions may be hotspots for adaptive mutations with a substantial impact on viral replication or immune evasion. Full article

Interferons (IFNs) are antiviral cytokines that serve as key mediators of the innate immune response, and their production is induced in the majority of cells within hours of pathogen entry. IFNs are predominantly produced by pathogen-infected cells; however, their antiviral effects extend to surrounding cells through autocrine and paracrine signaling mechanisms, inducing the transcription of hundreds of antiviral genes. Numerous gene products either interfere directly with viral replication or play regulatory roles that influence the progression and strength of the ensuing immune response. Viruses, on the other hand, have devised techniques to circumvent the host antiviral immune response and establish infection. This review focuses on the current state of evidence demonstrating how certain viral proteins block antiviral responses via immunomodulatory strategies and discusses how to overcome these immune evasion tactics. Full article

Autophagy is a conserved catabolic process that degrades damaged proteins and organelles to preserve cellular homeostasis. Autophagy plays two opposing roles during viral infection. On the one hand, it can be subverted by viruses to facilitate replication and immune evasion. On the other hand, it limits viral infection by delivering viral components to lysosomes. The interaction between autophagy and important picornaviruses that infect cattle and poultry, such as SVV, EMCV, FMDV, and DHAV, is the main topic of this paper. However, comprehensive summaries focusing specifically on livestock and poultry remain limited. We summarize current research showing that these viruses evade host protection by manipulating several steps of the autophagic pathway, from initiation to lysosomal fusion, to produce replication-favorable environments. Notably, by directing the breakdown of viral capsid proteins, specific autophagy receptors such as SQSTM1/p62, NDP52, and optineurin (OPTN) serve as antiviral effectors. In response, picornaviruses have developed proteolytic strategies to inactivate these receptors, such as SVV 3C-mediated cleavage of SQSTM1 and OPTN. Moreover, different immune evasion tactics are shown by virus-specific engagement of organelle-selective autophagy, such as ER-phagy (SVV) or mitophagy (DHAV). The development of broad-spectrum antiviral treatments and autophagy-based biomarkers for livestock disease progression may benefit from an understanding of the convergent and different ways picornaviruses take advantage of the autophagic machinery. Full article

Background/Objectives: As important post-transcriptional and epigenetic regulators of gene expression, miRNAs play a pivotal role in modulating host–virus interactions. While prior reviews have addressed either direct miRNA–HIV genome interactions or miRNA-mediated immune modulation in isolation, the integrated dual functionality of these molecules has not been systematically characterized. This review aimed to comprehensively explore how miRNAs that target the HIV-1 genome simultaneously modulate key innate and adaptive host immune signaling pathways. The conceptual novelty of this study is determined not by the identification of previously unknown miRNA-target gene pairs, but by the systemic integration of two regulatory levels (direct inhibition of the viral genome and modulation of the host cell immune signaling pathways) within a unified analytical framework. Such an integrated approach reveals a proviral regulatory network that remains non-obvious when each of these levels is examined separately. Methods: A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar (all years through 2025). In Stage 1, publications reporting experimentally confirmed interactions between host miRNAs and the HIV-1 genome were identified, yielding a curated set of 15 miRNAs. In Stage 2, target genes for each miRNA were retrieved from miRTarBase, TarBase (experimentally validated) and TargetScan 8.0 (in silico predicted). In Stage 3, target genes were manually mapped to key immune signaling pathways (TLR, NF-κB, JAK-STAT). In Stage 4, targeted literature searches were performed for each miRNA–target gene pair to identify direct experimental evidence of interaction. All stages were performed by two independent researchers, with discrepancies resolved by a third. Results: Fifteen host miRNAs with experimentally confirmed binding to the HIV-1 genome were identified, targeting viral genes including nef, pol, vpr, gag, env, vif, and the 3′-UTR. Thirteen of these miRNAs were found to regulate components of major immune pathways. miR-92a-3p, miR-29a/b-3p, miR-150-5p, and miR-125b-5p emerged as the most pleiotropic regulators, simultaneously suppressing TLR signaling (TLR3, TLR7, TLR8, MyD88, TRAF3/6, IRAK1/4), NF-κB components (REL, RELA, NFKB1), JAK-STAT effectors (STAT1–3, STAT5A/B, JAK2), and negative regulators of cytokine signaling (SOCS and PIAS family proteins). miR-133b and miR-196b-5p were found to selectively regulate SOCS/PIAS proteins without involvement in other analyzed pathways, suggesting potential for selective therapeutic targeting. Conclusions: The analyzed miRNAs exhibit functional dualism, acting as direct post-transcriptional suppressors of the HIV-1 genome while simultaneously functioning as epigenetic modulators of host immune signaling. These two modes of action are not independent but together form a conceptual framework of a self-reinforcing proviral regulatory network that, based on the synthesis of published evidence, is proposed to promote viral latency and immune evasion. The identified miRNAs represent promising, albeit complex, targets for novel therapeutic strategies aimed at eliminating latent HIV reservoirs. Full article

West Nile Virus (WNV) belongs to the orthoflavivirus genus and is part of the Flaviviridae family, which includes the Japanese encephalitis virus, Dengue virus, Zika virus, and yellow fever virus. WNV circulates among birds and mosquitoes, posing infection risks to humans and mammals. The significant rise in WNV’s geographic spread and infection rates over the past five decades has prompted urgent public health concerns, driving the need for accelerated vaccine research. The development of a vaccine for WNV infection presents several challenges, primarily due to the virus’s complex biology, the risk of cross-reactivity with other flaviviruses, safety concerns such as antibody-dependent enhancement (ADE), and the economic and logistical hurdles in vaccine production. Despite significant research efforts, no human vaccine has been approved, although several candidates are in various stages of development. The current review offers a comprehensive summary of the latest progress and the concomitant challenges in the development of vaccines. It also discusses the role of host–pathogen interaction, host immunity, viral immune evasion, and disease pathogenesis in facilitating the advancement of vaccines. Full article

Persistence of human papillomavirus (HPV) infection leading to cervical carcinogenesis can be attributed to the action of high-risk HPVs, but there are still some unclear factors involved in the mechanisms of either viral clearance or persistence. Although many infections may be self-limiting and cleared successfully by the immune response of the infected individuals, other infections result in persistent HPV infection. Recent studies indicate that microbiota in the gut and cervicovaginal tract modulate host immune status, mucosal inflammation, and epithelial barrier integrity. All these factors determine susceptibility to persistent infection. Inflammation, overproduction of reactive oxygen species (ROS), genomic instability, and impaired antiviral transcription pathways are associated with dysbiosis. In parallel, redox imbalance contributes to mitochondrial dysfunction, impairing mitochondrial antiviral signaling (MAVS)-dependent interferon responses and attenuating induction of interferon-stimulated genes. Additionally, extracellular vesicles (EVs) further promote immune evasion, metabolic programming, and epigenetic regulation by facilitating the intercellular exchange of viral constituents, microRNAs, and signaling molecules. Through this interconnected network of mechanisms, microbial dysbiosis, mitochondrial disruption, and EV signaling collectively shape a niche conducive to persistence. Unlike previous reviews that primarily examine microbiome alterations, oxidative stress (OS), mitochondrial dysfunction, extracellular vesicles, or immune responses as separate processes, this review integrates clinical and omics findings into a systems-based conceptual framework of HPV persistence. By emphasizing the potential interactions among these interconnected biological systems, we aim to identify points of biological convergence, generate mechanistic hypotheses, and highlight opportunities for future biomarker development and therapeutic intervention. Full article

Bovine viral diarrhea virus (BVDV), a significant global pathogen threatening cattle industries worldwide, presents substantial challenges for disease control. Its ability to infect cattle across all age groups, coupled with incompletely understood transmission mechanisms, complicates prevention and treatment strategies. We previously reported that BVDV induced tunneling nanotubes (TNTs)—F-actin-rich cytoplasmic connections between adjacent cells—and utilizes these structures for intercellular transmission. In this study, we used lentiviral transfection to express various structural and non-structural proteins of BVDV and identified NS5A as a critical viral protein that induces the formation of TNTs. RNA-seq analysis revealed that CKAP2, a host protein, plays a key role in TNT generation, with the PI3K/AKT/mTOR signaling pathway being essential for this process. Further investigation demonstrated that CKAP2 interacts with BVDV NS5A, triggering the activation of the PI3K/AKT/mTOR pathway, thereby promoting TNT formation and enhancing viral dissemination. Our data highlight a previously unknown mechanism of BVDV spreading and replication, which could have significant implications for within-host spread and immune evasion. Full article

The Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) has evolved sophisticated immune-evasion strategies to establish a productive infection in the host, primarily by counteracting the innate antiviral response. Here, we demonstrate for the first time that the PRRSV non-structural protein NSP8 suppresses NF-κB-dependent antiviral signalling by hijacking the host ubiquitin-conjugating enzyme UBE2K and inducing the degradation of IKKα, a pivotal kinase in the NF-κB pathway. PRRSV infection led to significant upregulation of host UBE2K, which in turn facilitated viral replication. Mechanistically, we found that NSP8 interacts directly with IKKα, triggering its degradation by the proteasome. Furthermore, we revealed that this process was facilitated by the host protein UBE2K, which acted as a crucial cofactor by directly interacting with NSP8 and thereby enhancing its activity against IKKα. This disruption blocked the activation of the NF-κB pathway and suppressed the expression of downstream antiviral factors, such as TNF-α, IL-6 and IFN-β, ultimately facilitating PRRSV replication. All of these findings showed that NSP8 is an important part of the process by which the host NF-κB pathway is blocked by viruses. This is a new way in which PRRSV avoids the immune system. Full article

Suppressors of cytokine signaling (SOCSs) are negative feedback regulators of the JAK-STAT pathway and are often exploited by viruses to evade host antiviral immunity. Unlike other SOCS members, the role of SOCS2 in viral infection remains poorly understood. Here, we report that overexpression of silkworm SOCS2 isoforms, SOCS2L and SOCS2S, promotes Bombyx mori nucleopolyhedrovirus (BmNPV) replication at multiple stages, including viral DNA replication, late gene (VP39) transcription, and virion egress, while their knockdown suppresses these processes. Overexpression of SH2 domain mutants (R123Q in SOCS2S, R142Q in SOCS2L) reduced viral DNA replication to baseline and VP39 expression below baseline, drastically decreased infectious progeny titers, but unexpectedly increased viral DNA release to wild-type levels, suggesting that the SH2 domain may differentially regulate distinct steps of viral replication. Furthermore, SOCS2 isoforms, alone or cooperatively with BmNPV, modulate the mRNA levels of SOCS-STAT network members in an isoform-, dose-, and target-specific manner. Collectively, this study reveals for the first time the multiple proviral functions of silkworm SOCS2 isoforms, with differential effects on distinct stages of the viral life cycle, and highlights their potential as transcriptional modulators exploited by viruses for immune evasion. Full article

Ubiquitination is a key post-translational modification regulating cellular signaling and innate immunity, and its reversal by deubiquitinases (DUBs) represents a critical mechanism exploited by pathogens for immune evasion. While ovarian tumor (OTU) domain-containing DUBs are well characterized in viral systems, their roles in fungal pathogens remain largely unexplored. In this study, we investigated two putative OTU domain-containing proteins derived from the plant pathogenic fungi Melampsora larici-populina (MlpOTU, EGG09943.1) and Taphrina deformans (TdOTU, CCG84064.1). Recombinant MlpOTU and TdOTU proteins were successfully expressed and purified from E. coli and exhibited high solubility and proper folding. Functional analyses in HEK293T cells demonstrated that both proteins significantly reduce global ubiquitination levels, confirming their deubiquitinase activity in vivo. Despite this shared enzymatic function, the two proteins displayed markedly distinct effects on host immune gene expression. MlpOTU selectively suppressed key antiviral effectors, most notably MX1, suggesting a targeted immune evasion strategy. In contrast, TdOTU induced robust upregulation of multiple immune-related genes, including type I interferons, indicating a divergent role. Neither MlpOTU nor TdOTU triggered robust apoptosis, supporting their role as modulators of host signaling rather than cytotoxic effectors. Collectively, these findings provide the first functional evidence that fungal OTU domain-containing proteins act as active deubiquitinases and reveal distinct strategies by which plant pathogens may manipulate host immune responses. This study establishes fungal OTU domains as promising targets for antifungal intervention and broadens our understanding of cross-kingdom evasion mechanisms. Full article

The hemagglutinin (HA) of influenza A/H3N2 virus evolves rapidly, with glycosylation driving immune evasion. However, how host microenvironmental cues influence this process remains poorly understood. We identified a novel N-linked glycosylation site at position 110 (N110) in contemporary H3N2 viruses (NSS genotype) that enhances viral fitness by increasing receptor-binding signal, HA cleavage, and replication. Remarkably, hypoxia, which mimics the respiratory tract microenvironment, significantly augments N110 glycosylation. Mechanistically, we identified the B4GAT1-B4GALT1 complex as the key mediator of this modification. Hypoxia upregulates their expression and strengthens their interaction with HA. In ferret models, N110-glycosylated viruses exhibit heightened pathogenicity and evade ancestral antibodies. Furthermore, immunization with N110-containing HA confers broad-spectrum protection, whereas reciprocal immunization is ineffective. Our findings reveal hypoxia-driven glycosylation as a previously unrecognized mechanism of H3N2 adaptation, providing critical insights for vaccine efficacy and highlighting the importance of integrating microenvironmental factors into future antiviral strategies. Full article

The innate immune system serves as the primary barrier against viral invasion, utilizing pattern recognition receptors (PRRs) to orchestrate a rapid defense. Among these, the nucleotide-binding domain and leucine-rich repeat (NLR) containing proteins function as central signaling scaffolds, assembling into multiprotein complexes known as inflammasomes. These complexes drive the maturation of pro-inflammatory cytokines IL-1β and IL-18, and initiate gasdermin D (GSDMD)-mediated pyroptosis, a lytic cell death pathway that eliminates intracellular replication niches. This comprehensive review synthesizes the diversified landscape of inflammasome activation during viral infections, extending beyond the canonical NLRP3 inflammasome to include specialized sensors such as NLRP6, NLRP9, NLRP1, NLRP12, and NLRC4. We critically evaluate the evolutionary “arms race” between host defenses and viral pathogens, detailing the sophisticated immune evasion strategies employed by viruses—ranging from the expression of decoy proteins and direct proteolytic cleavage of immune sensors to the manipulation of post-translational modifications (PTMs). Furthermore, we discuss the dual nature of inflammasome activation, which balances protective viral clearance against pathological hyperinflammation, and provide an exhaustive analysis of novel therapeutic strategies, including direct NLR inhibitors and downstream cytokine blockers, currently navigating clinical transition. Full article

Dengue infection remains a major global health concern, with a subset of patients progressing from self-limited dengue fever to severe disease characterised by plasma leakage, shock, and organ dysfunction. The dengue non-structural protein 1 (NS1), a multifunctional glycoprotein expressed on infected cells and secreted into circulation, has emerged as a key mediator linking viral infection to immune-driven vascular pathology. This review synthesises experimental, animal, and human clinical evidence on NS1-driven immunopathogenesis, focusing on mechanisms leading to endothelial dysfunction and increased vascular permeability. NS1 modulates the complement system in a context-dependent manner, contributing to immune evasion by inhibiting terminal complement complex formation, while also promoting antibody-dependent complement activation associated with severe disease. Additionally, NS1 directly disrupts endothelial barrier integrity through disruption of adherens and tight junction architecture, Ang-2/Tie2 imbalance, activation of RhoA/ROCK (RhoA/Rho-associated coiled-coil-containing protein kinase) signalling, and enzymatic degradation of the endothelial glycocalyx, with further amplification through inflammatory mediators. In addition, evidence shows that NS1 activates innate immune signalling, perturbs platelet biology and haemostasis, and forms pro-inflammatory complexes with lipoproteins. Moreover, anti-NS1 antibodies may be both protective and pathogenic. Collectively, these data position NS1-linked pathways as rational targets for adjunctive therapies and next-generation vaccines aimed at preventing vascular leakage and severe dengue infection. Full article