Search Results (628)

Despite the availability of a safe and effective measles vaccine for several decades, measles remains a significant cause of morbidity and mortality worldwide, causing 95,000 deaths in 2024 alone. Currently, there is no licensed therapeutic agent against measles, and treatment is only supportive. This is a review of articles published from 2015 to 3 June 2025, on therapeutic agents used or under investigation against measles. Ribavirin has been used in severe measles cases; nevertheless, there are no randomized clinical trials so far. New delivery systems, such as polymer-based formulations and nanoparticles, have markedly increased ribavirin’s efficacy, while cytotoxicity remained low. Viral membrane fusion (F) protein inhibitors and viral RNA polymerase inhibitors are promising next-generation therapeutics against measles and have been tested in animal models with good results. Lastly, interferons (IFNs) are key mediators of the innate immune response against measles, particularly for controlling brain infection. There are few reports indicating that repeated remdesivir courses, as well as intraventricular or intrathecal ribavirin or IFN, may temporarily stabilize the neurologic status of patients with subacute sclerosing panencephalitis. Intracranial administration of protein F inhibitors also demonstrated promising results in mice. Although several antiviral agents and natural products exhibit in vitro efficacy against measles virus, further research is required to determine their safety, pharmacological properties, and clinical efficacy before they can be considered therapeutic options. Overall, the development of antiviral agents against measles has been extremely slow. Therapeutic agents against measles are urgently needed. Full article

The ubiquitin ligase protein tripartite-motif containing 56 (TRIM56) positively regulates Toll-like receptor-3 (TLR3) signaling by forming a complex with Toll-Interleukin-1 receptor domain-containing adapter protein inducing interferon (IFN)-beta (TRIF), independent of its E3 ligase activity. Whether TRIM56 modulates other TLR pathways in innate antiviral immunity, however, is unclear. Herein, we show ectopic expression of TRIM56 augments activation of IFN regulatory factor-3 (IRF3)-dependent promoters following stimulation by lipopolysaccharide (LPS) in HEK293-TLR4-MD2-CD14 cells while leaving activation of NF-κB-dependent promoter unaffected, suggesting TRIM56 specifically promotes immune signaling through the TLR4-TRIF axis but not the MYD88 arm downstream of this TLR. Confirming its impact on endogenous antiviral responses in immune sentinel cells naturally harboring the TLR4 pathway, we demonstrated enforced expression of TRIM56 enhanced LPS-induced expression of IFN-beta and IFN-stimulated genes (ISGs) and establishment of an antiviral state in bone marrow-derived macrophages. Importantly, depletion of endogenous TRIM56 impaired LPS-induced antiviral gene expression and cellular antiviral defense. Altogether, these data add to understanding of the role of TRIM56 in TLR-mediated innate immune responses. Given that TRIM56 is an ISG and that many immune adjuvants and some viral proteins activate TLR4, the findings of this study could have implications for designing immunotherapies, especially those against viral infections. Full article

Ferroptosis has emerged as a promising strategy to overcome resistance to conventional cancer therapies. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia, therapy resistance, and an immunosuppressive microenvironment. Although hypoxia is likely to influence ferroptosis susceptibility and the associated inflammatory pathways that regulate antitumor immunity, their impact on ferroptosis sensitivity and innate immune responses remains poorly understood. In this study, we investigated the effects of hypoxia on the induction of ferroptosis and immune-related signaling in PDAC cell lines. We examined how hypoxia affects the responses of Panc-1, BxPC3, and Capan-1 cells to the ferroptosis inducers RAS-selective lethal 3 (RSL3)/Imidazole ketone erastin (IKE) under normoxic and hypoxic (0.1% O₂) conditions. Cell viability assays were used to assess ferroptosis sensitivity, and rescue experiments were performed using liproxstatin-1 (LIP). Gene expression analysis was conducted to evaluate changes in immune, interferon, inflammatory, and hypoxia-related genes following ferroptosis induction. Panc-1 cells were the most sensitive, whereas Capan-1 cells were resistant, particularly under hypoxia. Ferroptosis triggered cell line-specific responses involving interferon signaling, inflammation, and stress pathways. Panc-1 cells showed over-expression of RIG-I, MAVS, IRF3/7/9, STAT1/2, and CXCL10, particularly under hypoxia, indicating activation of Type I interferon (IFN)-associated transcriptional program. BxPC3 cells demonstrated broader cytokine induction, including IL-8, CCL2, CXCL2, GM-CSF, and IL-11, whereas Capan-1 cells were minimally responsive. Hypoxia also increased ANGPTL4 and GDF15 expression following ferroptosis induction. These findings show that hypoxia differentially affects ferroptosis sensitivity and immune responses in PDAC, revealing complex interactions among ferroptosis, innate immunity, and the tumor microenvironment. Full article

The MUCIN 1 (MUC1) gene evolved in eutherian mammals in association with the marked expansion of endogenous retroviruses (ERVs). MUC1 encodes the MUC1-C/M1C protein that protects barrier epithelia from exogenous viruses. Activation of M1C in response to loss of homeostasis induces STAT1 and the type I interferon (IFN-I) pathway. Studies in cancer cells have found that M1C regulates human ERV (HERV) expression by a STAT1-mediated mechanism. These discoveries have uncovered new insights into M1C-induced regulation of HERVs and other retrotransposons, such as LINE-1 (L1) and Alu. M1C signaling integrates retrotransposon transcription with induction of the counteracting apolipoprotein B mRNA-editing catalytic 3 (APOBEC3) genes that, like MUC1, first appeared in placental mammals. Activation of retrotransposons induces viral mimicry characterized as an IFN-I response that promotes innate anti-tumor immunity. Conversely, M1C protects cancer cells by sustained induction of the IFN-I pathway and immune evasion. This review posits that M1C-dependent regulation of retrotransposon and APOBEC3 expression represents an adaptive response exploited by cancer cells that promotes malignant progression. Full article

The concurrent circulation of influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has unveiled complex host–pathogen interactions governed by temporal dynamics of innate immune activation. This narrative review synthesizes evidence from human air–liquid interface (ALI) epithelial models, animal studies (hamster, ferret), clinical cohorts, and randomized controlled trials (2015–2026) to delineate the molecular mechanisms underlying viral interference between these two major respiratory pathogens. Prior IAV infection induces a robust type I/III interferon (IFN) response and broad interferon-stimulated gene (ISG) upregulation that restricts subsequent SARS-CoV-2 replication within a critical 24–72 h temporal window. Conversely, SARS-CoV-2 employs a multi-layered immune evasion strategy that blunts IFN induction, providing minimal heterologous protection. Simultaneous co-infection tends to exacerbate disease severity. Host genetic determinants, including OAS1 and TLR7 variants, modulate interference capacity. Therapeutically, early pegylated IFN-λ shows clinical benefit, while experimental evidence from in vitro and animal models suggests oseltamivir may paradoxically reduce IAV-induced interference. These findings underscore the need for multi-pathogen diagnostics, temporally informed clinical decision-making, and IFN-based therapeutic strategies during co-circulation periods. Full article

Ebola virus disease (EVD) is characterized by immune dysregulation and damaging hyperinflammation. We aimed to characterize the signaling pathways and regulatory mechanisms dysregulated during EVD. To avoid hyperinflammation, innate immune signaling is regulated by post-translational modifications (PTMs), including protein phosphorylation. Here, we show that the protein tyrosine phosphatase nonreceptor type 13 (PTPN13) negatively regulates Interferon (IFN)-β while also positively regulating the neutrophil chemoattractant CXCL1. Using vectors encoding IRF3 with mutations on phosphorylation sites, we identified Y292 on IRF3 as a PTPN13 target of dephosphorylation. Knockout of PTPN13 increased IRF3 phosphorylation and expression of IFNβ and IFN-stimulated genes (ISGs) following poly(I:C) stimulation. Intriguingly, depletion of PTPN13 during Ebola virus (EBOV) infection resulted in decreased IFNβ and ISG induction at later time points post-infection, which correlated with increased viral titers. We identified PTPN13-mediated dephosphorylation of the viral protein VP35 as one potential mechanism inhibiting virus replication. Additionally, the induction of inflammatory chemokines, including CXCL1, decreased in PTPN13 knockout cells late during EBOV infection. These effects could be explained by increased phosphorylation of the regulatory p85 subunit of PI3K. Dephosphorylation of p85 promotes its degradation, subsequently enhancing PI3K kinase activity and downstream signaling via AKT. Together, our study suggests that PTPN13 is involved in immune regulation and efficient antiviral responses by dephosphorylation of IRF3, EBOV-VP35 and PI3K-p85. Full article

Virus infection requires coordinated activation of pathogen-sensing, innate immune, and cellular stress response pathways to mount an effective antiviral defense. Recognition of nucleic acid pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) initiates signaling cascades that drive the production of type I interferons (IFNs) and proinflammatory cytokines. These responses are often accompanied by the activation of integrated stress response pathways that help optimize host defense. Cytosolic double-stranded dsDNA, generated during viral infection or released from damaged mitochondria, is sensed by cyclic GMP-AMP synthase (cGAS), which generates 2′3′-cGAMP to activate stimulator of interferon genes (STING). Activated STING translocates from the endoplasmic reticulum to the Golgi, where it drives TBK1-dependent IFN and cytokine production. Previous reports show that cGAS activity is enhanced by Ras-GAP SH3 domain binding protein 1 (G3BP1), a key nucleator of stress granules (SGs), independent of its role in SG assembly. Here, we identify a non-canonical role of G3BP1 as a regulator of DNA sensing responses at multiple levels, including STING intracellular trafficking, in addition to potentiating cGAS activity. Loss of G3BP1 impaired STING-dependent IFN and cytokine responses to HSV-1 infection and viral DNA. G3BP1-deficient cells showed reduced cGAMP-induced STING translocation to the Golgi, induction of type I IFN and proinflammatory cytokines, and activation of the ER stress kinase PERK and stress granule formation. Together, these findings demonstrate G3BP1-STING as a node linking DNA sensing, innate immunity, and stress signaling with broad implications for antiviral defense and diseases characterized by aberrant DNA sensing and stress responses, including neurodegeneration, fibrosis, and autoimmunity. Full article

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to multi-organ dysfunction. Toll-like receptor signaling via MYD88- and TRIF-dependent pathways plays a central role in this process; however, its temporal and tissue-specific dynamics remain incompletely understood. The aim of this study was to investigate time-dependent transcriptional changes in MYD88- and TRIF-dependent signaling pathways across multiple organs in a murine model of sepsis. mRNA expression of MYD88, IRAK1, IRAK4, NF-kB, CCL4, CCL20, CCR2, IFN-β, IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-18, Klotho, KLF4, HOXA5, NANOG and HIF1α was quantified using qRT-PCR in intestinal, kidney, liver and lung tissues at 24, 48, and 72 h following cecal ligation and puncture-induced sepsis in male C57BL/6J mice. Significant upregulation of innate immune signaling molecules, cytokines, chemokines, and interferon-related genes was observed in all tissues compared with controls. Genes associated with hypoxia and cellular regulation were also increased. These responses were tissue-specific and progressively intensified over time. Sepsis represents a dynamic, time-dependent, and tissue-specific process characterized by sustained activation of immune and hypoxic pathways, providing potential targets for time-stratified therapeutic strategies. 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

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), includes clinically relevant intestinal inflammation; however, the mechanisms associated with tissue injury remain incompletely understood. ArtinM is an immunomodulatory lectin with known effects on innate and adaptive immunity, although its intestinal role during acute T. cruzi infection remains unclear. This study investigated whether ArtinM modulates the intestinal inflammatory response during acute experimental T. cruzi infection. In vivo, BALB/c mice were allocated to Saline control, T. cruzi + Saline, and T. cruzi + ArtinM groups. Intestinal inflammatory infiltrate and tissue concentrations of TNF-α, IFN-γ, IL-12p40, and IL-10 were quantified. Acute infection markedly increased TNF-α, IFN-γ, IL-12p40, and inflammatory infiltrate, whereas ArtinM significantly attenuated these responses. TNF-α, IFN-γ, and IL-12p40 remained associated with group after adjustment for infiltrate, whereas IL-10 reached statistical significance only in the adjusted model and was therefore interpreted cautiously. In parallel, an exploratory analysis of a public murine intestinal scRNA-seq dataset (GSE319934; GSM9529706 and GSM9529707), derived from a chronic infection setting, was performed to provide pathway-level context for inflammatory mediators assessed in vivo. This transcriptomic analysis indicated that related inflammatory, innate immune, chemotactic, and adhesion-associated genes were detectable in intestinal single-cell data from T. cruzi infection. However, because this dataset was not temporally matched to the acute model, it was not interpreted as a phase-matched comparator, mechanistic validation, or temporal extension of the experimental findings. Together, the results support that ArtinM treatment is associated with attenuation of acute intestinal inflammatory outcomes in experimental T. cruzi infection. Because local intestinal parasite burden was not measured, these findings should be interpreted as evidence of inflammatory modulation rather than as direct evidence of local antiparasitic activity. The public scRNA-seq analysis provides only exploratory contextual information for related inflammatory pathways. Full article

Background/Objectives: Although influenza A viruses with partially truncated NS1 proteins are substantially attenuated and immunogenic due to enhanced innate immune activation; residual NS1-mediated antagonism of antiviral innate responses may support viral replication in the lower respiratory tract and constrain optimal immune responses. Strategies to further improve their immunogenicity and protective efficacy by incorporating immunomodulatory cytokines, such as IL-2, have been successfully explored. Methods: Here, we extended this approach to chemokine expression by engineering an NS1-truncated PR8-based virus (PR8/NS124) to express the immunomodulatory chemokine CXCL10 from the NS segment and compared it with the parental vector. Results: The recombinant NS124_SS_CXCL10 virus replicated to high titers in embryonated chicken eggs and MDCK cells. In vivo, however, CXCL10 expression reduced viral replication in mouse lungs by ~10⁴-fold, resulting in a near-non-replicating phenotype. In contrast to the parental virus, the vector did not induce weight loss and exhibited a strongly attenuated phenotype. This effect was associated with altered innate immune signaling, including increased IRF7 expression and early induction of IFN-α responses in the lungs, together with modulation of TLR-dependent sensing pathways in the upper respiratory tract. Despite severely impaired replication, intranasal immunization induced antigen-specific T-cell responses comparable to those elicited by the parental vector. Following intraperitoneal immunization, when replication of both vectors was minimal, the CXCL10-expressing vector induced significantly higher frequencies of antigen-specific CD8⁺ and CD4⁺ effector-memory T cells. This was accompanied by enhanced antigen-specific T-cell recall responses in the lungs following intranasal challenge. Importantly, the CXCL10-expressing vector demonstrated protective efficacy comparable to that of the parental NS124 vector against heterologous H3N2 challenge while exhibiting an improved safety profile. Conclusions: These findings support the incorporation of CXCL10 as a strategy to improve the safety and T-cell immunogenicity of NS1-truncated influenza vectors. Full article

Highly pathogenic avian influenza (HPAI) is a lethal disease of poultry that has recently spilled over into mammals, including dairy cattle and humans, heightening concerns for livestock health, food security, and pandemic emergence. While vaccines that induce neutralizing antibodies against hemagglutinin and neuraminidase provide strain-specific protection, durable cross-subtype immunity requires T-cell responses targeting conserved internal antigens such as nucleoprotein (NP). To leverage these conserved targets, we utilized a previously engineered mosaic nucleoprotein (MNP) incorporating T-cell epitopes from thousands of influenza A virus (IAV) strains, conferring broad protection against epidemic (H3N2) and pandemic (H1N1) IAV in mice. Here, we tested whether precision adjuvancy could differentially imprint adaptive immunity to MNP in cattle. Combination formulations paired the carbomer-based nano-emulsion Adjuplex (ADJ) with either a STING agonist (cyclic dinucleotides; CdN) or a TLR4 agonist (glucopyranosyl lipid A; GLA) to program distinct inflammatory milieus. Both formulations elicited circulating IFN-γ–producing T cell responses and NP-specific antibodies in serum and milk. However, STING activation via CdN generated more potent and consistent cellular and humoral immunity than TLR4 engagement. These data demonstrate that selective activation of innate sensing pathways functionally imprints adaptive immune magnitude and quality in a large animal host. By advancing a broadly protective, T-cell-focused vaccine strategy in cattle, this work supports a One Health framework to mitigate H5N1 transmission risk at the human–animal interface. Full article

The micro-immunotherapy medicine (MIM) 2LEID-N^® was developed to sustain immune response, notably in the framework of respiratory infections. This pilot study investigated the potential effects of one capsule of this MIM, referred to as 2LEID-N-9 throughout the manuscript, containing IL-12 (5 CH), IFN-γ (6 CH), and TNF-α (5 CH). Phagocytosis and surface marker expression were assessed using flow cytometry, and cytokine secretion was assessed by ELISA. Cellular models included human monocyte-derived macrophages, peripheral blood mononuclear cells (PBMCs) from healthy donors, and THP-1 cells. Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS/MS) was used to detect the actives. Compared with vehicle control, 2LEID-N-9 showed a trend towards the enhanced phagocytic activity of macrophages. In PBMCs, 2LEID-N-9 upregulated the secretion of several cytokines, including IL-2, IL-4, IL-13, IFN-γ, and TNF-α in both basal and CD3/CD28-stimulated conditions. Notably, a tendency towards increased secretion of TNF-α was found in LPS-stimulated THP-1 cells. The presence of the three actives, as assessed by LC-HRMS/MS, combined with the functional data, provide promising exploratory evidence of immunomodulatory effects and tendencies towards the stimulation of innate and adaptive immune cells, warranting further investigation. Full article

Chronic respiratory diseases (CRDs) represent a significant global mortality burden, largely driven by viral-triggered exacerbations. In the elderly, susceptibility to viral pathogens is critically linked to the “interferon gap”—a kinetic delay in innate antiviral signaling resulting from immunosenescence and Th2-skewed inflammaging. While traditional vaccines provide pathogen-specific protection, their efficacy is often compromised by age-related immune hyporesponsiveness and antigenic drift. This perspective paper proposes a dual-phase, virus-agnostic immunomodulatory platform designed to restore mucosal immune competence and provide a rapid-response intervention for incipient exacerbations. Rather than acting as a pathogen-specific vaccine, the platform serves as a comprehensive host immune-rejuvenation engine and cellular adjuvant platform. The platform consists of two integrated stages: Allopriming and Alloantigen Inhalation Recall (AIR). Allopriming utilizes AlloStim^® (activated, allogeneic Th1 cells) to leverage the evolutionarily conserved allo-rejection response, establishing a lung mucosal reservoir of allo-specific Th1 tissue-resident memory cells (Trm). Building on previously published Phase I/II data showing that Allopriming reverses biomarkers of immunosenescence and sustains durable heterologous antiviral responsiveness, the AIR strategy is introduced as a patient-administered rescue mechanism for frail CRD patients. AIR is designed to activate pre-positioned Trm cells at the earliest onset of symptoms, inducing a high-magnitude IFN-γ surge in the lung mucosa. By bridging the senescent “interferon gap” with the rapid effector kinetics of Trm activation, this approach represents a novel paradigm toward reconstituting youthful-like antiviral mucosal immunity to both enhance vaccine efficacy in the elderly and protect against both seasonal pathogens and emerging viral triggers (“Disease X”) of CRD. Future randomized studies in long-term care settings are planned to evaluate clinical outcomes in high-risk populations. Full article

Background: Fermented polysaccharides derived from Morinda citrifolia (noni) have been suggested to modulate innate immune responses, but clinical evidence remains limited. Objectives: This randomized, double-blind, placebo-controlled trial evaluated the effects of fermented noni polysaccharides on natural killer (NK) cell activity and immune-related biomarkers in adults with recurrent upper respiratory tract infections (URTIs). Methods: A total of 100 adults aged 40 to <75 years with a documented history of ≥2 episodes of upper respiratory tract infection in the prior 12 months were randomly assigned to receive fermented noni polysaccharides (487.5 mg/tablet, two tablets once daily; 975 mg/day of FNP extract) or a matched placebo for 8 weeks. The primary endpoint was the change in NK cell activity at effector-to-target (E:T) ratios of 50:1, 25:1, and 12.5:1, assessed using K562 NK-sensitive target cells. Secondary endpoints included circulating cytokines (IFN-γ, TNF-α, IL-2, IL-6, IL-10, IL-12, IL-1β) and immunoglobulin G (IgG). Eighty-four participants (43 treatment, 41 placebo) were included in the modified intention-to-treat/full analysis set (mITT/FAS); 81 participants (41/40) constituted the per-protocol set (PPS). Primary efficacy was analyzed in the mITT/FAS. This trial was retrospectively registered at CRiS (KCT0011316) after trial completion; the IRB-approved protocol was finalised before enrolment and remained unchanged thereafter. Results: NK cell activity in the treatment group increased from baseline at all three E:T ratios, whereas it slightly decreased in the placebo group. Adjusted between-group LS mean differences (95% CI) were +8.94 (−0.61, 18.50; p = 0.066) at E:T 50:1, +7.68 (−1.14, 16.50; p = 0.087) at 25:1, and +3.29 (−2.95, 9.54; p = 0.145) at 12.5:1, all favouring treatment but not reaching the conventional threshold for significance in the mITT/FAS. Prespecified PPS sensitivity analyses reached significance at E:T 50:1 (+11.03; p = 0.025) and 25:1 (+9.94; p = 0.028). Selected cytokines (IFN-γ, IL-2, IL-6, IL-10, IL-1β) increased to a greater extent in the treatment group than in the placebo group, whereas TNF-α, IL-12, and IgG were unchanged. URTI incidence at week 4, week 8, and cumulatively did not differ significantly between groups. The intervention was well tolerated, with no serious adverse events and no treatment-related discontinuations. Conclusions: Compared with placebo, fermented noni polysaccharide supplementation showed numerically greater increases in NK cell activity at all three E:T ratios (50:1, 25:1, and 12.5:1) in the primary mITT/FAS analysis, although these between-group differences did not reach statistical significance. Prespecified per-protocol set (PPS) sensitivity analyses showed significant between-group differences at E:T ratios of 50:1 and 25:1. The treatment group also showed greater increases in selected cytokines (IFN-γ, IL-2, IL-6, IL-10) relative to placebo. No significant between-group differences were observed in URTI incidence, IgG, GARS, WBC, or leukocyte subset proportions. These exploratory biomarker findings, in the absence of safety signals, suggest a possible immunomodulatory profile but do not establish clinical efficacy. Confirmation in larger, prospectively registered trials with clinically adjudicated infection-related endpoints is warranted. Full article