Search Results (74)

Background and Objectives: Procalcitonin (PCT), presepsin (PSEP), interferon-λ3 (IFN-λ3), and bioactive adrenomedullin (bio-ADM) are promising sepsis biomarkers. We explored the clinical utility of a multi-marker approach using these four biomarkers in patients with suspected sepsis. Materials and Methods: In a total of 248 patients, the biomarkers were evaluated with the sequential organ failure assessment (SOFA) score. Receiver operating characteristic curves with area under the curve (AUC) were analyzed to diagnose sepsis and predict in-hospital mortality. Survival and reclassification analyses were also used to predict in-hospital mortality. Results: The four biomarkers showed comparable diagnostic performance (AUC = 0.61–0.95, p < 0.001–0.003), and sepsis proportion increased significantly as the number of biomarkers used in the multi-marker approach increased (7.7–91.7%, p < 0.001). The proportion of biomarker quartiles (Q1–Q4) differed significantly according to SOFA score (p < 0.001). The four biomarkers predicted in-hospital mortality (AUC = 0.63–0.84, p < 0.001–0.004). The multi-marker approach performed better than the SOFA score (mortality rate, 58.3% vs. 31.3%; adjusted hazard ratio [HR], 14.7 vs. 4.6), and the addition of biomarkers to the SOFA score increased the performance. The multi-marker approach resulted in a higher HR in patients aged ≥75 years than in the overall population (9.2 vs. 4.2). Conclusions: Each biomarker showed clinical utility in patients with suspected sepsis. The multi-marker approach showed complementary clinical utility in addition to the SOFA score and better prognostic performance in patients aged ≥75 years. The use of biomarkers, alone or in combination, would be a valuable tool in combination with the SOFA score. Full article

Interferons (IFNs) are essential mediators of the innate immune response to viral infections. Among the type III IFNs, the role of IFN-λ4 in respiratory viral infections remains largely understudied. Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are clinically significant pneumoviruses that elicit divergent IFN responses in epithelial cells. Here, we investigate the virus-specific induction and antiviral activity of IFN-λ4 by HMPV and RSV infections. We demonstrate that RSV induces a limited expression of IFN-λ4, which is regulated by the expression of the NS1 protein. Furthermore, RSV and HMPV rely primarily on RIG-I for IFN-λ4 induction. Finally, we show that IFN-λ4 exerts antiviral activity against both viruses, with RSV displaying greater sensitivity. These findings highlight the antiviral role of IFN-λ4 to clinically relevant respiratory viruses. Full article

Respiratory tract infections are a major cause of morbidity and mortality. After the SARS-CoV-2 pandemic, pathogenetic mechanisms leading to more severe outcomes were investigated, including uncontrolled viral replication in the upper airways. This was only partially investigated for other respiratory viruses. We measured mucosal expression of IFN-β1, IFN-λ1, IFN-λ2/3, IL-1β, and IL-6 in patients infected by human metapneumovirus, human rhinovirus, human respiratory syncytial virus or type A influenza virus. A total of 806 nasopharyngeal swabs were collected from patients presenting at emergency departments or hospitalized. Viral load was inferred through cycle threshold determination, whereas cytokine levels were measured through mRNA detection. Each expression pattern was correlated with age, viral load, and specific infecting virus. IFN-β1 and IFN-λ2/3 showed a negative correlation with viral load, while IFN-λ1 and IL-6 exhibited the opposite trend, suggesting increased inflammation with higher viral load. This was more evident in the ≥70-year-old group, with significantly higher IL-6 levels. Higher viral load of potentially more pathogenic viruses was associated with higher IL-6 expression. Cytokine production in the upper respiratory tract is only partially influenced by age per se, with a more relevant role played by viral load and specific infecting virus. In older patients, this response is less coordinated and prone to elicit a proinflammatory response, especially when clinically impacting viruses are involved. Full article

Patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) are at increased risk of severe infections, making effective vaccination strategies essential. While antibody responses to SARS-CoV-2 vaccination have been studied in SLE, less is known about innate immune correlates. Therefore, we evaluated cytokines with a particular emphasis on interferon and chemokine profiles. To fulfill the immunological picture, we also assessed neutralizing antibodies against SARS-CoV-2 variants, lymphocyte subpopulations, and selected gene expression signatures in 33 patients stratified by vaccination status: fully vaccinated (FV, n = 23) and partially vaccinated (PV, n = 10). Serum analyses showed that FV patients exhibited increased type I (IFN-α2, IFN-β) and type III (IFN-λ1, IFN-λ2/3) interferons, as well as elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-12p70) and IL-10, whereas neutralizing antibody (Neut. Ab.) titers against wild-type and variant strains, including Omicron, were comparable between groups. Immunophenotyping demonstrated preserved T- and B-cell subset distributions, except for reduced CD8⁺CD197⁺CD45RA⁻ (central memory) T cells in FV patients. ISG15 gene expression was upregulated in the T cells of FV patients. Correlation analyses linked IL-6 with disease activity and IL-8, GM-CSF, IFN-β, IL-10, and Alpha Neut. Ab. with organ damage. Complement C3 correlated inversely with IFN-α2 and IFN-γ, while C4 correlated positively with Alpha and Omicron Neut. Ab. These findings highlight that vaccination in SLE induces distinct interferon and cytokine signatures without consistent enhancement of neutralizing antibodies against SARS-CoV-2, underscoring the importance of integrated immune correlates in assessing vaccine responses in this population. Full article

This study evaluated whether the combined Lactiplantibacillus plantarum CRL1506 and MPL16 nasal priming more effectively modulated the Toll-like receptor (TLR)-3- and respiratory syncytial virus (RSV)-mediated respiratory immune responses in mice than single strains. The interaction of single and combined strains with porcine alveolar macrophages (AMs) and porcine respiratory epithelial cells (PBE cells) in the context of TLR3 activation and porcine reproductive and respiratory syndrome virus (PRRSV) was also evaluated. The in vivo studies in mice revealed that the CRL1506 + MPL16 combination was more effective than the individual strains at reducing RSV replication, protecting the lung from TLR3-mediated inflammatory injury and modulating innate antiviral responses, particularly in AMs. In vitro, lactobacilli treatment also increased the resistance of porcine AMs to PRRSV infection. Notably, the CRL1506 + MPL16 combination was not more effective than the single strains in modulating AMs antiviral immunity. Complementary assays in PBE cells revealed that L. plantarum CRL1506 induced higher production of IFN-λ than the MPL16 strain in response to TLR3 activation. Thus, the superior in vivo protection against RSV seen with the L. plantarum CRL1506–MPL16 combination likely reflects complementary actions of lactobacilli: MPL16 would efficiently modulate AMs, whereas CRL1506 would be more effective to target respiratory epithelial cells driving greater IFN-λ production that further boosts AM antiviral activity. The results from the animal models of this work furnish the scientific basis for proposing future human trials to assess the efficacy of the CRL1506 + MPL16 combination in improving respiratory antiviral immunity. Full article

Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant is often delayed or functionally impaired. Emerging evidence suggests genetic variation, particularly polymorphisms in the IL28B gene (encoding IFN-λ3), as a critical factor influencing the quality and timing of immune responses during the early post-transplant period. This review explores the role of IL28B polymorphisms in shaping antiviral immunity, in general, as well as after Allo-HSCT. IL28B variants have been implicated in modulating interferon-stimulated gene (ISG) expression, natural killer (NK) cell activity, and type I/III interferon signaling, all central components of innate immune defense against viral infections. Furthermore, IL28B polymorphisms, particularly rs12979860, have been shown in both general populations and limited HSCT cohorts to alter T cell response and interferon production, affecting reactivation and clearance of multiple viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) as well as Graft vs. Host disease, thereby affecting adaptive immune reconstitution and long-term viral control. Understanding how IL28B genotype alters immune dynamics in transplant recipients could enhance risk stratification for CMV and other diseases and inform personalized prophylactic or therapeutic strategies. Therefore, this review highlights IL28B as a promising biomarker and potential immunoregulatory target in the management of viral infection post-Allo-HSCT. Full article

Background: Chronic cytomegalovirus (CMV) infection may favor the development of immunosenescence and inflammation that impair vaccine responses, including COVID-19. In addition, the polymorphism of the interferon-lambda gene (IFNλ) affects COVID-19 immune responses in older adults. Objective: We aimed to investigate the impact of IFNλ polymorphism (IL28B gene-rs12979860) on the immune/inflammatory response to vaccination with CoronaVac for COVID-19 in older adults who were CMV-seropositive. Methods: Blood samples from 42 CMV-seropositive older adults (73.7 ± 4.5 years) were collected before and 30 days after immunization with a second dose of the CoronaVac vaccine to evaluate the immune/inflammatory response. Results: At genotyping, 20 subjects were homozygous for the C/C alleles (Allele-1 group), 5 were homozygous for the T/T Alleles (Allele-2 group), and 17 were heterozygous (C/T, Alleles-1/2 group). The Allele-1 group showed higher IgG levels for COVID-19 (p = 0.0269) and intermediate monocyte percentage (p = 0.017), in contrast to a lower non-classical monocyte percentage (p = 0.0141) post-vaccination than pre-vaccination. Also, this group showed that IgG levels for CMV were positively associated with a systemic pro-inflammatory state and senescent T cells (CD4+ and CD8+). The Allele-2 group presented higher IFN-β levels at pre- (p = 0.0248) and post-vaccination (p = 0.0206) than the values in the Allele-1 and Alleles-1/2 groups, respectively. In addition, the Allele-2 and Alleles-1/2 groups showed that IgG levels for COVID-19 were positively associated with a balanced systemic inflammatory state. Conclusion: CMV-seropositivity in older adults who had Allele-1 could lead to an unbalanced systemic inflammatory state, which may impair their antibody response to COVID-19 vaccination compared to other volunteer groups. Full article

The gastrointestinal (GI) tract is a major barrier against pathogens, including viruses. The antiviral responses in the GI epithelium have been broadly investigated, but data on the contribution of the stromal cells remain scarce. Melatonin, widely used to treat insomnia, has recently been proposed as an antiviral agent, yet its effect in the GI tract remains poorly understood. We compared the antiviral responses in Caco-2 monocultures and co-cultures with intestinal fibroblasts (HSIFs) and endothelial cells (HUVECs) after stimulation using Poly I:C. We evaluated the apoptosis, proliferation, key antiviral markers (IRF1, IRF3, IFNs, TBK1, STAT3), and mitochondrial and peroxisomal activation with and without melatonin. The Caco-2 cells cultured with the HSIFs and HUVECs demonstrated enhanced proliferation and reduced Poly I:C-induced apoptosis. The co-culture exhibited a more rapid IRF3-IFNλ1 response, higher TBK1 expression, and enhanced peroxisomal activation compared to these properties in the monoculture. Melatonin further reduced apoptosis and modulated organelle-specific antiviral signaling by suppressing peroxisomal activation and promoting mitochondrial activity. Reduced peroxisomal activation was associated with decreased TBK1, IRF3, and IFNλ1 levels and altered STAT3 signaling. These effects were more pronounced when melatonin was applied post-stimulation compared to that under prophylactic use. Fibroblast–endothelial interactions amplify the antiviral responses in the intestinal epithelial cells by activating the TBK1–IRF3–IFNλ1 axis. Melatonin modulates these responses, highlighting its therapeutic potential in viral GI infections. Full article

Type III interferons (IFN-λ) are the most recently identified members of the interferon family, distantly related to type I interferons and members of the interleukin-10 (IL-10). Unlike type I interferons, which have broadly distributed cellular receptors, IFN-λ signals through a heterodimeric receptor complex with primary expression on epithelial cells. This restricted receptor distribution makes IFN-λ a favorable candidate for therapeutic and antiviral applications with reduced side effects. In this review, we describe the molecular structure, signaling mechanisms, and the role of IFN-λ in the innate immunity of epithelial tissue, which are its primary sites of action. Moreover, this review will summarize and critically examine the antiviral potential of IFN-λ based on all published clinical trials conducted for the treatment of COVID-19, and hepatitis B, C and D virus. Furthermore, this review suggests IFN-λ as a promising therapeutic recombinant protein, with special emphasis on its potential for production using alternative expression and advanced drug delivery systems. To emphasize its potential as a therapeutic intervention, the design and engineering of recombinant IFN-λ will be presented, with a focus on its lower side-effect profile compared to Type I interferons. Full article

Lassa mammarenavirus (LASV), a member of the family Arenaviridae, is a highly pathogenic virus capable of causing severe systemic infections in humans. The primary host reservoir is the Natal multimammate mouse (Mastomys natalensis), with human infections typically occurring through mucosal exposure to virus-containing aerosols from rodent excretions. To better understand the molecular mechanisms underlying LASV replication in the respiratory tract, we utilized differentiated primary human airway epithelial cells (HAECs) grown under air–liquid interface conditions, closely mimicking the bronchial epithelium in vivo. Our findings demonstrate that HAECs are permissive to LASV infection and support productive virus replication. While LASV entry into polarized HAECs occurred through both apical and basolateral surfaces, progeny virus particles were predominantly released from the apical surface, consistent with an intrinsic apical localization of the envelope glycoprotein GP. This suggests that apical virus shedding from infected bronchial epithelia may facilitate LASV transmission via airway secretions. Notably, limited basolateral release at later stages of infection was associated with LASV-induced rearrangement of the actin cytoskeleton, resulting in compromised epithelial barrier integrity. Finally, we demonstrate that LASV-infected HAECs exhibited a pronounced type III interferon response. A detailed understanding of LASV replication and host epithelial responses in the respiratory tract could facilitate the development of targeted future therapeutics. Full article

Recent studies have shown that long noncoding RNAs (lncRNAs) play pivotal roles in the development and progression of cancer. In the present study, we aimed to identify lncRNAs associated with lymph node metastasis in pancreatic ductal adenocarcinoma (PDAC). We analyzed data from The Cancer Genome Atlas (TCGA) database to screen for genes overexpressed in primary PDAC tumors with lymph node metastasis. Our screen revealed 740 genes potentially associated with lymph node metastasis, among which were multiple lncRNA genes located in the HOXA locus, including HOXA11-AS. Elevated expression of HOXA11-AS was associated with more advanced tumor stages and shorter overall survival in PDAC patients. HOXA11-AS knockdown suppressed proliferation and migration of PDAC cells. RNA-sequencing analysis revealed that HOXA11-AS knockdown upregulated interferon lambda (IFNL) family genes and downregulated high-mobility group box (HMGB) family genes in PDAC cells. Moreover, HMGB3 knockdown suppressed proliferation and migration by PDAC cells. These results suggest that HOXA11-AS contributes to PDAC progression, at least in part, through regulation of IFNL and HMGB family genes and that HOXA11 AS is a potential therapeutic target in PDAC. Full article

Melatonin is a hormone naturally produced by the body that has recently been found to have antiviral properties. However, its antiviral mechanisms are not entirely understood. Using Caco-2 cells, we developed a gastrointestinal organoid model to investigate the impact of melatonin on cellular organoid culture response to Poly I:C-induced viral inflammation in the gastrointestinal tract. Melatonin was found to have different effect when applied as a pretreatment before the induction of viral inflammation or as a treatment after it. Melatonin pretreatment after Poly I:C stimulation did not protect organoids from size reduction but enhanced cell proliferation, especially when lower (1 and 10 µM) melatonin concentrations were used. On the other hand, treatment with melatonin after the induction of viral inflammation helped to maintain the size of the organoids while reducing cell proliferation. In pretreated cells, reduced IFNLR1 expression was found, while melatonin treatment increased IFNLR1 expression and reduced the production of viral cytokines, such as IFNλ1 and STAT1-3, but did not prevent from apoptosis. The findings of this study emphasize the importance of type III IFNs in antiviral defense in epithelial gastrointestinal cells and shed more light on the antiviral properties of melatonin as a potential therapeutic substance. Full article

Ongoing outbreaks and often rapid spread of infections caused by coronaviruses, influenza, Nipah, Dengue, Marburg, monkeypox, and other viruses are a concern for health authorities in most countries. Therefore, the search for and study of new antiviral compounds are in great demand today. Since almost all viruses with pandemic potential have immunotoxic properties of various origins, particular attention is paid to the search and development of immunomodulatory drugs. We have synthesised a new compound related to indole-3-carboxylic acid derivatives (hereinafter referred to as the XXV) that has antiviral and interferon-inducing activity. The purpose of this work is to study the effect of the XXV on the stimulation of the expression of toll-like receptor genes, interferons, and immunoregulatory cytokines in a macrophage-like cell model. In this study, real-time PCR methods were used to obtain data on the transcriptional activity of genes in macrophage-like cells. Stimulation of the genes of toll-like receptors TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 was detected. A high-fold increase in stimulation (from 6.5 to 16,000) of the expression of the TLR3 and TLR4 genes was detected after 4 h of exposure to the XXV. Increased activity of interferon (IFNA1, IFNA2, IFNB1, IFNK, and IFNλ1) genes with simultaneous stimulation of the expression of interferon receptor (IFNAR1 and IFNAR2) genes and signalling molecule (JAK1 and ISG15) genes was detected. Increased fold stimulation of the expression of the cytokine genes IL6, TNFA, IL12A, and IL12B was also observed. Thus, it is shown that the XXV is an activator of TLR genes of innate immunity, which trigger signalling mechanisms of pathogen “recognition” and lead to stimulation of the expression of genes of proinflammatory cytokines and interferons. Full article

Rhinovirus C (RV-C) infection can trigger asthma exacerbations in children and adults, and RV-C-induced wheezing illnesses in preschool children correlate with the development of childhood asthma. Surfactant protein A (SP-A) plays a critical role in regulating pulmonary innate immunity by binding to numerous respiratory pathogens. Mature SP-A consists of multiple isoforms that form the hetero-oligomers of SP-A1 and SP-A2, organized in 18-mers. In this report, we examined the efficacy of SP-A to antagonize RV-C infection using the wild-type (RV-C15) and reporter-expressing (RV-C15-GFP) viruses in differentiated nasal epithelial cells (NECs) from asthmatic and non-asthmatic children. We also determined the antiviral mechanism of action of SP-A on RV-C15 infection. The native SP-A was purified from alveolar proteinosis patients. The recombinant (r) SP-A1 and SP-A2 variants were expressed in FreeStyle™ 293-F cells. SP-A reduced the fluorescent focus-forming units (FFUs) after RV-C15-GFP infection of NECs by 99%. Both simultaneous and 4 h post-infection treatment with SP-A inhibited RV-C15 and RV-C15-GFP viral RNA load by 97%. In addition, the antiviral genes and chemokines (IFN-λ, IRF-7, MDA-5, and CXLC11) were not induced in the infected NECs due to the inhibition of RV-C propagation by SP-A. Furthermore, SP-A bound strongly to RV-C15 in a dose- and Ca²⁺-dependent manner, and this interaction inhibited RV-C15 binding to NECs. In contrast, rSP-A1 did not bind to solid-phase RV-C15, whereas the rSP-A2 variants, [A₉₁, K₂₂₃] and [P₉₁, Q₂₂₃], had strong binding affinities to RV-C15, similar to native SP-A. This study demonstrates that SP-A might have potential as an antiviral for RV infection and RV-induced asthma exacerbations. Full article

Avoidance of an immune response is critical to completion of the human papillomavirus (HPV) life cycle, which occurs in the stratified epithelium and is linked to epithelial differentiation. We previously demonstrated that high-risk HPVs use apoptotic caspases to suppress an antiviral innate immune response during the productive phase of the life cycle. We found that caspase-8 and caspase-3 suppress a type I IFN-β and type III IFN-λ response by disabling the MDA5/MAVS double-stranded RNA (dsRNA) sensing pathway, indicating that immunogenic RNAs increase upon differentiation in HPV+ cells. In this study, we demonstrate that caspase inhibition results in aberrant transcription of a subset of endogenous retroviruses (ERVs) that have been shown to activate an IFN response through dsRNA-sensing pathways. We show that the increase in ERV transcription is accompanied by an enrichment in dsRNA formation. Additionally, we demonstrate that the robust increase in ERV expression requires activation of the JAK/STAT-signaling pathway, indicating that this subset of ERVs is IFN-inducible. Overall, these results suggest a model by which caspase activity blocks the reactivation of ERVs through the JAK/STAT pathway, protecting HPV+ cells from an increase in immunogenic dsRNAs that otherwise would trigger an IFN response that inhibits productive viral replication. Full article