Search Results (5,601)

Coronavirus disease 2019 (COVID-19) has been associated with an increased long-term cardiovascular risk, potentially mediated by magnitude of the acute inflammatory response inflammation. Interleukin-6 (IL-6) and serum amyloid A (SAA) are key components of the inflammatory cascade and may serve as biomarkers of post-COVID cardiovascular vulnerability. This longitudinal observational study investigated the association between post- COVID-19 infection IL-6 and SAA levels and major cardiovascular events over a six-year follow-up period. A total of 97 individuals with documented prior SARS-CoV-2 infection were included. Circulating IL-6 and SAA concentrations were measured in the acute phase. The composite endpoint included incident arrhythmia, myocardial infarction, and all-cause mortality. Biomarker distributions were right-skewed and were therefore analyzed using non-parametric methods and penalized logistic regression models. During follow-up, 14.4% of participants experienced the composite endpoint. Individuals with adverse outcomes had significantly higher IL-6 and SAA levels compared with event-free participants. IL-6 demonstrated the strongest association with mortality, whereas SAA showed particularly robust associations with the composite endpoint, and with myocardial infarction. Both biomarkers independently predicted long-term adverse events. Circulating IL-6 and SAA concentrations measured during the acute phase of SARS-CoV-2 infection were analyzed in relation to long-term cardiovascular outcomes. These findings support the hypothesis that the magnitude of the acute inflammatory response during SARS-CoV-2 infection may be associated with long-term cardiovascular outcomes and suggest that combined assessment of IL-6 and SAA may have potential utility for hypothesis-generating prognostic signal requiring validation, pending validation in larger studies. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has greatly impacted public health due to high rates of transmissibility and mutation during the COVID-19 pandemic. Macrodomain 1 (Mac1) of non-structural protein 3 remained well conserved across variants and is critical to suppression of host immune response to infection, making Mac1 a promising target for therapeutic development. Mac1 binds and cleaves the post-translational modification ADP-ribose and is hypothesized to have a downstream effect on the host interferon response, but the exact cellular targets of Mac1 are still unknown. Characterizing the substrates of Mac1 ADP-ribosyl hydrolase activity using a catalytically inactive mutant N40D can reveal critical virus–host interactions to identify protein targets of Mac1 and reveal mechanisms of host interferon suppression. Here, we performed affinity enrichment with WT Mac1 and Mac1 N40D in HEK293T and A549 cells and quantified changes in protein interactions by TMT-multiplexed tandem mass spectrometry. We identified interactions between Mac1 and ADP-ribosylated substrates involved in DNA damage response, cytoskeletal components, and cell cycle regulation. Additionally, several members of the TRiC complex involved in protein folding were selectively enriched with mutant Mac1 from A549 cells. These findings suggest a novel role of Mac1 in regulating host protein folding. Full article

This study examined alterations in serum redox biomarkers before and one month after administration of the coronavirus disease 2019 (COVID-19) booster (third) doses across four vaccine regimens. A longitudinal cohort of 410 adults was analyzed following homologous Pfizer-BioNTech, Sinopharm [Vero Cell]-Inactivated, Sputnik V, or heterologous Sinopharm/Pfizer vaccination. Serum total proteins, albumin, total thiols, nitrites, ferric-reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity were measured, with DPPH interpreted as an ex vivo surrogate of serum radical-scavenging capacity. Additional analyses included stratification by prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, multivariable regression, correlation analysis, effect-size estimation, and sensitivity testing. Booster vaccination was associated with modest but consistent decreases in DPPH activity, albumin, and total proteins, whereas FRAP, nitrite, and total thiol levels remained stable. This pattern supports a transient shift in antioxidant buffering capacity but, by itself, does not exclude oxidative stress, as direct oxidative damage markers were not assessed. The most pronounced changes were observed in Sinopharm-based regimens, particularly in the heterologous Sinopharm/Pfizer group. Prior SARS-CoV-2 infection did not materially alter the qualitative response pattern, whereas older age and comorbidities were associated with greater declines in DPPH activity and albumin. Overall, the findings indicate a modest, transient redox-associated response following booster-induced immune activation and suggest that host-related factors, such as age and comorbidity burden, may accentuate short-term changes in antioxidant buffering capacity. Full article

Why do pandemics keep emerging despite decades of surveillance and response? Paleopathology, the study of disease traces in ancient remains, has been revolutionized by ancient DNA (aDNA) analysis and next-generation sequencing (NGS). Reconstructing pathogen genomes from archaeological material enables the identification of extinct lineages, the refinement of disease chronologies, and the characterization of long-term host-pathogen co-evolution. This provides context for public health challenges, including the emergence of pandemics and antimicrobial resistance (AMR). Infectious diseases are increasingly understood as complex phenomena arising from biological, ecological, and sociopolitical forces. Integrating paleopathology, aDNA, and paleomicrobiology supports a deep-time syndemic framework, revealing how recurring biosocial drivers have structured infectious disease risk throughout history. Ancient resistome studies demonstrate that AMR predates modern antibiotic use, reframing resistance as an intrinsic ecological feature rather than solely a modern phenomenon. Coronavirus disease 2019 (COVID-19) reaffirmed how infection intersects with chronic disease, health system fragility, and social inequities. This review highlights how integrating evolutionary perspectives into One Health shifts surveillance from a reactive approach to upstream risk mitigation and spillover prevention. Full article

Background/Objectives: Maintenance hemodialysis patients are particularly vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to evaluate clinical outcomes and identify admission laboratory biomarkers associated with in-hospital mortality in hospitalized hemodialysis patients with coronavirus disease 2019 (COVID-19). Methods: We conducted a retrospective observational study including 130 adult hemodialysis patients with confirmed SARS-CoV-2 infection. Clinical characteristics and admission laboratory parameters were analyzed in relation to in-hospital outcomes using comparative, multivariable logistic regression, and receiver operating characteristic (ROC) curve analyses. Results: The overall in-hospital mortality rate was 34.6%. The median age of the cohort was 66 years, with 64.6% male patients. Non-survivors showed significantly higher levels of inflammatory and tissue-injury markers, including C-reactive protein (CRP) (p < 0.001) and lactate dehydrogenase (LDH) (p < 0.001), together with lower serum albumin (p < 0.001), platelet count (p < 0.001), and lymphocyte levels (p = 0.03). In multivariable analysis, cardiovascular disease, respiratory disease, dyspnea, and ambulatory origin were independently associated with mortality. ROC analysis identified platelet count as the best individual predictor (area under the curve [AUC] = 0.767). An exploratory composite risk score demonstrated excellent discriminative performance (AUC = 0.902). Conclusions: Admission inflammatory and hematological biomarkers are strongly associated with adverse outcomes in hospitalized hemodialysis patients with COVID-19. The integration of clinical and laboratory parameters into a composite risk score may improve early risk stratification and support clinical decision-making in this high-risk population. Full article

Feline infectious peritonitis virus (FIPV) remains one of the most challenging viral diseases in veterinary medicine, largely owing to the absence of a consistently effective and safe vaccine. Despite widespread feline coronavirus infection, only a subset of infected cats progresses to feline infectious peritonitis, indicating that host immune responses are key determinants of disease outcomes. Accumulating evidence indicates that disease severity is driven not only by viral replication but also by macrophage- and monocyte-centered immune signaling, leading to excessive inflammation and systemic immunopathology in the host. Previous vaccine approaches against FIPV have failed to provide consistent protection and, in some cases, have been associated with enhanced disease. These outcomes suggest that vaccine-induced immune responses that recapitulate pathogenic signaling patterns may exacerbate disease rather than confer protection. In this review, we discuss the current knowledge of immune cell signaling pathways implicated in FIPV infection, including innate sensing through Toll-like receptors, downstream mitogen-activated protein kinases and NF-κB signaling, cytokine production profiles, Fc receptor-associated processes, and intracellular pathways such as autophagy, and how these mechanisms shape vaccine-induced immunity. By integrating insights from immune signaling kinetics, antibody functionality, adjuvant-driven pathway engagement, and platform-specific immune signatures, this review emphasizes the need to reframe FIPV vaccine development strategies that actively shape host immune responses. Rather than maximizing immunogenicity, successful vaccine design is likely to depend on limiting sustained macrophage activation and pro-inflammatory cytokine amplification while supporting antiviral immune functions, thereby reducing the risk of antibody-dependent enhancement and immunopathology. Beyond feline diseases, these considerations provide broader lessons for vaccine design in settings where immune-mediated pathology contributes to disease severity. Full article

Background and Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy has raised concerns regarding possible fetal consequences, including potential effects on auditory system development. Although the current literature suggests that overt congenital hearing loss is uncommon among newborns exposed in utero, subtle cochlear functional alterations may not be detectable through conventional threshold-based screening alone. The objective of this study is to investigate whether in utero exposure to maternal COVID-19 is associated with early cochlear functional changes in newborns, as assessed by frequency-specific transient evoked otoacoustic emission (TEOAE) amplitude ratios, and to determine whether such alterations are accompanied by differences in click-evoked auditory brainstem response (ABR) thresholds. Materials and Methods: This prospective cohort study was conducted between October 2021 and September 2022 and included 61 pregnant women: 30 with laboratory-confirmed SARS-CoV-2 infection during pregnancy (study group) and 31 without documented infection (control group). All newborns underwent standardized audiological evaluation shortly after birth, including otoscopy, TEOAE, click-evoked ABR, and tympanometry. Frequency-specific TEOAE amplitude ratios at 500, 1000, 1500, 2000, and 4000 Hz were compared between groups. A logistic regression analysis was performed to identify audiological predictors of newborn exposure to SARS-CoV-2 in utero. Results: No significant differences were observed in ABR thresholds or in TEOAE “pass/refer” outcomes between the control and study groups, indicating the absence of clinically overt HL. However, newborns exposed to SARS-CoV-2 in utero showed significantly reduced TEOAE amplitude ratios at 2000 Hz (p = 0.0077) and 4000 Hz (p = 0.020). Logistic regression identified the 4000 Hz amplitude ratio as an independent negative predictor of in utero exposure (OR = 0.75; p = 0.0352). No significant differences were detected at lower frequencies. Conclusions: Maternal COVID-19 during pregnancy was not associated with immediate neonatal HL but was linked to subtle high-frequency cochlear functional modulation. Longitudinal audiological follow-up is needed to clarify the clinical significance of these findings. Full article

The surface spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key target for the development of Coronavirus Disease 2019 (COVID-19) vaccines. Nevertheless, the mutations in the S protein, particularly in its receptor-binding domain region, have resulted in a reduced or complete loss of immunogenicity and/or protective efficacy in early vaccines against the Omicron variant and subvariants. Accordingly, continuous efforts are required to develop effective vaccines against multiple Omicron subvariants to reduce current and future threats. In this study, we designed an mRNA vaccine targeting the S protein of a recent Omicron-XEC subvariant (XEC-S-mRNA) and assessed its immunogenicity, including its broad neutralizing activity, and its protective efficacy against multiple Omicron subvariants. Our results demonstrated that the lipid nanoparticle-formulated mRNA vaccine formed an appropriate particle size with strong stability and successful antigen expression. It elicited durable cellular immune responses and broad neutralizing antibodies against multiple early and recent Omicron subvariants, thereby cross-protecting transgenic mice from challenge with a heterologous Omicron strain (KP.3). Moreover, the vaccine-induced neutralizing antibodies alone were sufficient to prevent Omicron-KP.3 infection. Overall, this study shows promise for further development of the candidate vaccine against current and future Omicron infections. Full article

In early 2020, a respiratory virus swept across the world. The World Health Organization (WHO) confirmed pandemic status and the virus was identified as a coronavirus with superlative transmission properties. Using work from the 1950s, the WHO declared that the virus was transmitted through respiratory ‘droplets’, which were expelled by infected persons through coughing/sneezing. These would fall to the ground within 1–2 m. Scientists investigating viral transmission questioned this premise because recent work had shown that viruses populate the smallest respiratory particles, remaining airborne for much longer than larger ‘droplets’ and capable of spreading throughout the indoor environment. Advice such as handwashing, surface disinfection and social distancing was not as important as face masks and adequate indoor ventilation. People needed to know that poor ventilation constituted the highest risk for contracting the virus. Instead, homes and surfaces were disinfected and social distancing was maintained in community settings. The scientists formed a consortium named Group 36 in order to contest the WHO over airborne transmission but they could not present definitive evidence in the short term to reverse initial guidance. This account details the evolution of understanding of COVID-19 transmission and the role of Group 36 and others in challenging WHO-based policies based on dated physical science. Full article

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through the interaction between the spike protein receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (hACE2) receptor, which is expressed on epithelial cells in various tissues, including the respiratory tract. Therefore, mucosal immunity in the respiratory tract plays a key role in protection against viral infection. Previously, we demonstrated that intranasal administration of antigens (Ags) conjugated with the M cell-targeting peptide Co4B enhances both mucosal and systemic immune responses. That conjugation with human β-defensin 2 (HBD2) increases neutralizing antibody (Ab) responses. Methods: A recombinant antigen conjugate incorporating both Co4B and HBD2 was designed to enhance immunogenicity. Its immunogenicity was evaluated in mice following intranasal immunization. Antigen-specific antibody responses were measured in serum and bronchoalveolar lavage fluid. T-cell responses were evaluated in lungs and spleens. Protective efficacy was assessed using SARS-CoV-2-susceptible hACE2 knock-in mice. Results: Ag-specific Ab levels increased in both serum and bronchoalveolar lavage fluid of mice immunized intranasally with the conjugate. Especially, T-cell responses were significantly enhanced in the lungs and spleens of immunized hACE2 knock-in mice. In challenge experiments, intranasal administration of the conjugate reduced viral load. Moreover, Siglec F was identified as a potential receptor for Co4B, a previously uncharacterized M cell-targeting ligand. Conclusions: A recombinant viral Ag containing Co4B and HBD2 induces virus-specific humoral and cellular immune responses. Although further optimization of the vaccine formulation and administration strategy is needed, this conjugate shows potential as a platform for improving mucosal and systemic immunity. Full article

In 2023, Cyprus experienced a large-scale epizootic of feline infectious peritonitis (FIP) temporally associated with the emergence of a novel feline coronavirus, FCoV-23. While molecular investigations have elucidated the recombinant origin of FCoV-23, field-based clinical and other epidemiological data from FIP cases reported during the epizootic period were needed to characterize the outbreak better. A prospective study was conducted using a structured 31-item questionnaire embedded in veterinary management software to characterize FIP cases diagnosed during the epizootic period (late 2022–2025). Data were voluntarily submitted by registered veterinarians across Cyprus. Cases were included based on a clinical diagnosis of FIP; virological confirmation of FCoV-23 infection was not required for inclusion. Data from 68 FIP cases reported by 22 clinics (response rate 21.0%) were analyzed. Affected cats were older than typically reported for FIP (mean age 3.9 years; median 3.0; range 0.4–12.9 years; SD 3.41). Most cases were documented in Limassol (51.5%) and Nicosia (25.0%). The most frequently reported clinical signs were non-specific, like anorexia (60.3%) and weight loss (54.4%), while a variety of neurological and mental manifestations were documented in 35.3% of cases. An albumin-to-globulin ratio < 0.8 was observed in 86.8% of tested cats. Antiviral therapy (GS-441524 or molnupiravir) was administered in 92.2% of cases, with reported clinical improvement of 88.9%. These findings demonstrate the value of questionnaire-based surveillance in documenting outbreak-associated FIP patterns. Although individual cases were not uniformly confirmed as FCoV-23 infections, the increased proportion of neurological presentations among FIP cases reported during the epizootic period supports previous molecular evidence suggesting that neurological involvement was associated with FCoV-23 circulation. Full article

Coronavirus Disease 2019 (COVID-19) and other lower respiratory tract diseases (LRTDs), including bacterial pneumonia and acute respiratory distress syndrome, share overlapping clinical features but arise from distinct pathophysiological mechanisms. The molecular signatures that distinguish these diseases remain insufficiently characterized in African populations, where genetic background, endemic infections, and environmental exposures may substantially shape immune responses. We integrated spatially resolved single-cell transcriptomic profiles from lung autopsy specimens of 30 Malawian patients, including 10 with COVID-19, 12 with other LRTDs, and 8 non-LRTD controls. In total, 61,391 cells representing 15 cell types and 36,602 gene expression features were analyzed. Using an integrated machine learning framework that combined nine feature-ranking algorithms with incremental feature selection, we identified potential molecular signatures that could discriminate among disease states within this cohort. The optimal classification models achieved weighted F1 scores greater than 0.94, demonstrating a robust capacity to differentiate COVID-19 from other LRTDs in our dataset. Notably, the macrophage-associated state in COVID-19 was dominated by an IFN-γ response with upregulation of CD163 and HLA-DQA2, contrasting sharply with the type I/III interferon signature reported in European cohorts. In addition, we observed cell-type-specific COVID-19 signatures, including downregulation of CAV1 in AT1 cells, consistent with epithelial damage; dysregulation of SFTPC in AT2 cells, suggesting surfactant dysfunction; and upregulation of NFKBIA in neutrophils, indicating altered inflammatory regulation. Gene Ontology enrichment further revealed universal disruption of protein synthesis machinery, along with cell-type-specific alterations in immune activation, epithelial repair, and inflammatory signaling pathways. Full article

Oxidative stress and redox imbalance are central features of both age-related neurodegenerative disorders and the persistent neurological sequelae of coronavirus disease 2019. Increasing evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts neuronal redox homeostasis via mitochondrial dysfunction, iron dysregulation, inflammatory signaling, and the depletion of pyridine nucleotide pools. In that context, ferroptosis provides a unifying mechanistic framework linking lipid peroxidation to progressive neuronal injury. This review proposes that neuronal vulnerability might depend not only on the oxidative burden itself but also on the failure of membrane-localized antioxidant defenses. Particular emphasis is placed on the plasma membrane redox system (PMRS), a membrane-associated quinone-reducing network that can support coenzyme Q redox cycling and constrain lipid radical propagation at the plasma membrane. Unlike canonical ferroptosis defense systems that rely predominantly on NADPH, components of the PMRS, particularly cytochrome b5 reductase, can also use NADH, conferring partial metabolic flexibility in conditions of redox stress. We further discuss how SARS-CoV-2-induced NAD⁺ depletion might progressively destabilize this membrane-proximal defense architecture, potentially lowering the ferroptotic threshold of vulnerable neurons. Finally, we outline therapeutic strategies that might reinforce PMRS-dependent membrane redox control through NRF2 activation, NAD⁺ restoration, coenzyme Q-centered interventions, and modulation of iron-catalyzed lipid oxidation. Full article

Plant-derived products, particularly essential oils, represent a promising source of antiviral scaffolds. Although Populus balsamifera L. has been traditionally used to manage respiratory ailments and infections, the antiviral potential of its bud essential oil remains unexplored. In this study, we evaluated the in vitro antiviral cytoprotective activity of P. balsamifera bud essential oil and its major constituents against HCoV-OC43, a human betacoronavirus associated with seasonal respiratory infections, using a cell-based cytoprotection assay. The assay reliably detected the activity of reference antivirals, including chloroquine (EC₅₀ = 0.11 ± 0.01 µg/mL), molnupiravir, and fluvoxamine, supporting its suitability for antiviral screening. Under these conditions, P. balsamifera bud essential oil exhibited strong cytoprotective activity, with an EC₅₀ of 3.3 ± 0.5 µg/mL. Chemical analysis revealed a sesquiterpene-rich composition. Two major constituents, α-bisabolol and nerolidol, also showed marked cytoprotection, with EC₅₀ values of 2.7 ± 0.3 µg/mL and 2.6 ± 0.4 µg/mL, respectively, supporting their contribution to the overall activity of the oil. To our knowledge, this study provides the first experimental evidence of antiviral cytoprotective activity of P. balsamifera bud essential oil against a human coronavirus and identifies α-bisabolol and nerolidol as active compounds in this model. Full article

Background: Guillain–Barré syndrome (GBS) is an autoimmune peripheral neuropathy that can lead to paralysis and respiratory failure. In addition to infections, several drugs have been suggested as potential triggers of GBS. This study investigated drug-associated GBS using a spontaneous adverse event reporting database through disproportionality analysis for signal detection and time-to-onset analysis. Methods: The Japanese Adverse Drug Event Report (JADER) database was analyzed to assess more than 4000 drugs for potential associations with GBS. Signal detection was performed using reporting odds ratios, Fisher’s exact test, and total report counts. For vaccines and immune checkpoint inhibitors, time-to-onset patterns were further evaluated using Weibull distribution analysis. Results: Disproportionality signals suggesting potential associations with GBS were identified for 45 drugs, including vaccines, immune checkpoint inhibitors, tumor necrosis factor-α inhibitors, other anticancer drugs, antifungal agents, and interferons. Reports following vaccination were most frequently observed within 1–3 weeks after administration of coronavirus disease 2019 (COVID-19), influenza, and pneumococcal vaccines, and within 1–3 months after human papillomavirus 2-valent vaccination, with a gradual decrease thereafter. Reports following immune checkpoint inhibitor use were most frequently observed 1–3 months after nivolumab, ipilimumab, and pembrolizumab administration, whereas atezolizumab showed a peak in reporting within 1–3 weeks. In contrast to vaccine-related reports, no clear temporal trend in reporting was observed. Conclusions: Drugs that modulate immune function, including vaccines and immune checkpoint inhibitors, may be associated with reported GBS events. Vaccine-related reports showed an early concentration in time to onset, whereas immune checkpoint inhibitor-related reports did not demonstrate a clear temporal pattern. These findings should be interpreted as hypothesis-generating and warrant further investigation. Full article