Search Results (92)

Sepsis is a life-threatening condition caused by a dysregulated immune response to infection, characterized by an initial hyperinflammatory phase frequently followed by compensatory immunosuppression (CARS). Regulatory T cells (Tregs) play a critical, biphasic role: inadequate suppression during early hyperinflammation fails to control cytokine storms, while excessive/persistent activity in late-phase immunosuppression drives immune paralysis and secondary infection susceptibility. This review explores advances in targeting Treg immunoregulation across bacterial, viral, and fungal sepsis, where pathogenic type critically influenced the types of immunoresponses, shaping Treg heterogeneity in terms of phenotype, survival, and function. Understanding this multifaceted Treg biology offers novel therapeutic avenues, highlighting the need to decipher functional heterogeneity and develop precisely timed, pathogen-tailored immunomodulation to safely harness beneficial Treg roles while mitigating detrimental immunosuppression. Full article

Guillain-Barre syndrome is an autoimmune disease that provokes neural illness causing acute paralysis neuropathy. This syndrome appears after some bacterial infections produced by Campylobacter jejuni, Streptococcus pyogenes, S. pneumoniae, Haemophilus influenciae, E. coli and current studies showed the appears of this syndrome after SARS-CoV-2 infection. In this study, a in silico analysis was carry out in which to determinate bacterial epitopes than produce the molecule mimicry phenomena and that can produce the immune system activation against this epitope. A conserved amino acid sequence has been encountered with the highest probability to activate the immune system against this bacterial epitope, human gliomedin and ryanodine 3 type receptor. More studies needed to demonstrate in vivo the molecular mimicry in Guillain-Barre syndrome patients. Full article

The detection of “silent” poliovirus (PV) circulation among clinically healthy populations is an important component of supplementary surveillance for poliomyelitis. Migrants from countries or regions where polio is endemic, affected by outbreaks, or at risk may contribute to the introduction of PVs of epidemic significance: wild poliovirus type 1, vaccine-derived polioviruses (VDPVs), or poliovirus type 2 into polio-free countries. Migrant children, refugees under 5 years of age, are considered a “risk group” in Russia and are subject to testing for PVs. During 2014–2023, guided by the algorithm of virological and molecular investigation of acute flaccid paralysis cases recommended by the WHO, 51,548 migrant children, arriving from 40 countries, were examined. Among 4% of children excreting various cytopathogenic viruses, polio excretors accounted for 20.8%. Among the PVs, PV3 was predominant (41.7%), and PV types 2, 1, and a mixture of PVs accounted for, respectively, 28.2%, 18.8%, and 11.3%. All isolates of PVs 1 and 3 were identified as Sabin-like. The detection of five children excreting epidemically significant PV2 (four VDPV2 and one Sabin-like) required an assessment of the risk of dissemination and additional immunization activities. Among 580 identified isolates of NPEV, the most abundant was the E. betacoxsakie species at 73.8% (CVB1–6, E11, E6, E13, E7). Information on NPEVs expands our knowledge of the spectrum of NPEVs circulating among healthy children worldwide, but its prognostic significance is still unclear. The detection of PVs in children from the “risk group” allows targeted anti-epidemic measures and is a significant advantage of this type of supplementary surveillance for polio. Full article

Sepsis and cancer, though distinct in their clinical manifestations, share profound pathophysiological overlaps that underscore their interconnectedness in disease progression and outcomes. Here we discuss the intricate biological mechanisms linking these two conditions, focusing on the roles of inflammation, immune dysregulation, and metabolic alterations. In sepsis, an uncontrolled immune response to infection leads to a cytokine storm, tissue damage, and immune paralysis, while cancer exploits chronic inflammation and immunosuppressive pathways to promote tumor growth and metastasis. Both conditions exhibit metabolic reprogramming, such as the Warburg effect in cancer and glycolysis-driven immune cell activation in sepsis, which fuels disease progression and complicates treatment. Sepsis can exacerbate cancer progression by inducing genomic instability, epigenetic modifications, and a pro-tumorigenic microenvironment, while cancer increases susceptibility to sepsis through immunosuppression and treatment-related complications. The shared pathways between sepsis and cancer present unique opportunities for therapeutic intervention, including anti-inflammatory agents, immune checkpoint inhibitors, and metabolic modulators. Anti-inflammatory therapies, such as IL-6 and TNF-α inhibitors, show promise in mitigating inflammation, while immune checkpoint inhibitors like anti-PD-1 and anti-CTLA-4 antibodies are being explored to restore immune function in sepsis and enhance antitumor immunity in cancer. Metabolic modulators, including glycolysis and glutaminolysis inhibitors, target the metabolic reprogramming common to both conditions, though their dual roles in normal and pathological processes necessitate careful consideration. Additionally, antimicrobial peptides (AMPs) represent a versatile therapeutic option with their dual antimicrobial and antitumor properties. In this review, we also highlight the critical need for integrated approaches to understanding and managing the complex interactions between sepsis and cancer. By bridging the gap between sepsis and cancer research, this work aims to inspire interdisciplinary collaboration and advance the development of targeted therapies that address the shared mechanisms driving these devastating diseases. Ultimately, these insights may pave the way for novel diagnostic tools and therapeutic strategies to improve outcomes for patients affected by both conditions. Full article

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by high morbidity and mortality rates. Bacterial infection is a frequent precipitating factor and complication in ACLF patients, significantly worsening patient outcomes. Elucidating the mechanisms underlying bacterial infections and their impact on ACLF pathophysiology is crucial for developing effective therapies to reduce infection rates and mortality. Current research highlights that immune suppression in ACLF increases susceptibility to bacterial infections, which in turn exacerbate immune dysfunction. However, a comprehensive review summarizing the emerging mechanisms underlying this immunosuppression is currently lacking. This review aims to provide an overview of the latest research, focusing on alterations in the immune responses of innate immune cells—including monocytes, macrophages, and neutrophils—as well as adaptive immune cells such as T and B lymphocytes during the onset and progression of bacterial infections in ACLF. In addition, recent advances in immunomodulatory therapies, including stem cell-based interventions, will also be discussed. Full article

Pediatric sepsis presents a unique clinical challenge due to the distinct characteristics of the developing immune system. The immune response in children differs significantly from that in adults, exhibiting a unique combination of resistance, disease tolerance, and resilience. These factors influence the clinical presentation and prognosis of pediatric patients with sepsis. Over the past few years, various studies have explored the role of immunomodulatory therapies in managing sepsis, including the use of immunoglobulins, corticosteroids, monoclonal antibodies, and immunostimulatory treatments. However, the heterogeneity of the clinical presentations and individual responses makes it difficult to identify universally effective treatments. Recent research has highlighted the importance of a personalized approach based on specific biomarkers and patient phenotyping. Extracorporeal blood purification techniques have emerged as promising strategies for the modulation of hyperinflammation. However, strong evidence supporting their routine use in pediatric sepsis is lacking. This review provides a comprehensive overview of the current knowledge of the immune response in pediatric sepsis and discusses the main immunomodulatory strategies and future perspectives for personalized therapy. A deeper understanding of the immunological differences between children and adults could improve the prognosis and treatment efficacy, paving the way for new approaches to pediatric sepsis management. Full article

Introduction: Bell’s palsy is a common acute peripheral neurological disorder causing unilateral facial paralysis. Its exact etiology remains unknown, but it is linked to inflammation, immune responses, infections, and ischemia. This study explores the potential causal relationship between Bell’s palsy and peripheral blood inflammatory proteins, metabolites, and immune cell characteristics. Methods: Genetic data for Bell’s palsy were obtained from the Finnish database (version R10) and IEU OpenGWAS. A two-sample Mendelian randomization (MR) approach was applied, analyzing 4907 plasma proteins, 731 immune cell traits, 91 inflammatory proteins, and 1400 metabolites. The Finnish dataset served as the discovery cohort, while the IEU OpenGWAS dataset acted as the validation cohort. Bioinformatics analyses included protein–protein interaction (PPI) networks, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, colocalization, and Linkage Disequilibrium Score Regression (LDSC) to identify candidate proteins and explore potential therapeutic targets. Results: MR analysis identified 70 inflammatory proteins, 77 metabolites, and 26 immune cell traits as potentially causally associated with Bell’s palsy. After external validation, BLVRB, HMOX2, TNFRSF12A, DEFB128, ITM2A, VEGF-A, and DDX58 remained significantly associated (p < 0.05). PPI network analysis led to 31 candidate proteins, and six core proteins (JAK2, IL27RA, OSM, CCL19, SELL, VCAM-1) were identified. Conclusions: Our study identifies causal relationships between inflammatory proteins, metabolites, immune cells, and Bell’s palsy, highlighting that the JAK/STAT signaling pathway may be a potentially critical target for intervention in Bell’s palsy, and that its modulation may provide new directions and opportunities for therapeutic strategies and drug discovery for the disease. Full article

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons, leading to escalating muscle weakness, atrophy, and eventually paralysis. While neurons are the most visibly affected, emerging data highlight microglia—the brain’s resident immune cells—as key contributors to disease onset and progression. Rather than existing in a simple beneficial or harmful duality, microglia can adopt multiple functional states shaped by internal and external factors, including those in ALS. Collectively, these disease-specific forms are called disease-associated microglia (DAM). Research using rodent models, patient-derived cells, and human postmortem tissue shows that microglia can transition into DAM phenotypes, driving inflammation and neuronal injury. However, these cells can also fulfill protective roles under certain conditions, revealing their adaptable nature. This review explores recent discoveries regarding the multifaceted behavior of microglia in ALS, highlights important findings that link these immune cells to motor neuron deterioration, and discusses emerging therapies—some already used in clinical trials—that aim to recalibrate microglial functions and potentially slow disease progression. Full article

Spodoptera frugiperda is a major migratory agricultural pest that poses a significant threat to global crop safety. Metarhizium rileyi has emerged as an effective biocontrol agent against lepidopteran pests. In this study, we examined the immune responses of third-instar S. frugiperda larvae at various stages of an M. rileyi infection. Using RNA-seq and microscopic observation, we identified the immune-related pathways enriched at different infection stages, which were further validated by a qRT-PCR. Our findings revealed the following immune responses during infection: During the stage when M. rileyi penetrated the host cuticle (0–48 h), the genes related to energy metabolism, detoxification, and melanization were upregulated. Meanwhile, the TOLL and IMD signaling pathways were activated to counter the infection. During the stage of M. rileyi’s internal infection (48–96 h), which was the peak expression period of the immune-related genes, cellular immunity predominated. Hemocytes encapsulated and phagocytosed the hyphal bodies. Phagocytosis was enhanced through the upregulation of the genes related to ROS and the melanization-related genes, as well as the genes involved in insect hormone biosynthesis. During the stage when M. rileyi grew from the inside to the outside of the host (96–120 h), immune system paralysis resulted in host mortality. These findings deepen our understanding of the immune interactions between M. rileyi and S. frugiperda, support the potential of M. rileyi as an effective biocontrol agent, and provide a theoretical foundation for the development of targeted biopesticides for pests using biotechnological approaches. Full article

Background: Marek’s disease (MD) is a pathology affecting chickens caused by Marek’s disease virus (MDV), an acute transforming alphaherpesvirus of the genus Mardivirus. MD is characterized by paralysis, immune suppression, and the rapid formation of T-cell (primarily CD4+) lymphomas. Over the last 50 years, losses due to MDV infection have been controlled worldwide through vaccination; however, these live-attenuated vaccines are non-sterilizing and potentially contributed to the virulence evolution of MDV field strains. Mutations common to field strains that can overcome vaccine protection were identified in the C-terminal proline-rich repeats of the oncoprotein Meq (Marek’s EcoRI-Q-encoded protein). These mutations in meq have been found to be distinct to their region of origin, with high virulence strains obtained in Europe differing from those having evolved in the US. The present work reports on meq mutations identified in MDV field strains in Nigeria, arising at farms employing different vaccination practices. Materials and Methods: DNA was isolated from FTA cards obtained at 12 farms affected by increased MD in the Plateau State, Nigeria. These sequences included partial whole genomes as well as targeted sequences of the meq oncogenes from these strains. Several of the meq genes were cloned for expression and their localization ability to interact with the chicken NF-IL3 protein, a putative Meq dimerization partner, were assessed. Results: Sequence analysis of the meq genes from these Nigerian field strains revealed an RB1B-like lineage co-circulating with a European Polen5-like lineage, as well as recombinants harboring a combination of these mutations. In a number of these isolates, Meq mutations accumulated in both N-terminal and C-terminal domains. Discussion: Our data, suggest a direct effect of the vaccine strategy on the selection of Meq mutations. Moreover, we posit the evolution of the next higher level of virulence MDVs, a very virulent plus plus pathotype (vv++). Full article

Individuals with certain primary immunodeficiency disorders (PID) may be unable to clear poliovirus infection after exposure to oral poliovirus vaccine (OPV). Over time, vaccine-related strains can revert to immunodeficiency-associated vaccine-derived poliovirus (iVDPVs) that can cause paralysis in the patient and potentially spread in communities with low immunity. We reviewed the efforts for detection and management of PID patients with iVDPV infections and the epidemiology through an analysis of 184 cases reported to the World Health Organization (WHO) during 1962–2024 and a review of polio program and literature reports. Most iVDPV patients (79%) reported in the WHO Registry were residents in middle-income countries and almost half (48%) in the Eastern Mediterranean Region. Type 2 iVDPV was most frequently isolated (53%), but a sharp decline was observed after the switch to bivalent OPV in 2016, with only six cases reported during 2017–2024 compared to 63 during 2009–2016. Patients with common variable immunodeficiency have longer excretion of iVDPV than with other PID types. Implementation of sensitive sentinel surveillance to detect cases of iVDPV infection in high-risk countries and offer antiviral treatment to patients is challenged by competition with other health priorities and regulatory hurdles to the compassionate use of investigational antiviral drugs. Full article

Sepsis pathophysiology involves a dysregulated immune response to infection, excessive inflammation, and immune paralysis. This study explores the relationships between cell death biomarkers (serum-soluble levels of programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and interleukin-7 (IL-7)) and the percentages of various lymphocyte subsets in relation to the severity and progression of sepsis. This prospective, observational study included 87 critically ill patients. We monitored parameters on days 1 (sepsis was diagnosed according to the Sepsis-3 Consensus) and 5. We established an IL-7 cutoff value of 1.94 pg/mL by comparing levels between a healthy control group and patients with sepsis (p < 0.0001). Lymphopenia was observed in all patients, with negative correlations between helper T lymphocytes and cytotoxic and B lymphocytes, and positive correlations involving cytotoxic lymphocytes across all groups. We found correlations between PD-1/PD-L1 and lymphocyte subsets. IL-7 showed a statistical correlation with PD-1 in non-survivors. Assessing lymphocyte levels shows potential as a biomarker for evaluating the progression of sepsis. Monitoring IL-7 levels could help assess survival, as low levels are associated with higher mortality risk. Monitoring IL-7 levels could help assess survival, as low levels are associated with higher mortality risk. Elevated PD-1/PD-L1 expression impairs costimulatory signalling, reducing T cell responses and lymphopenia, which increases the risk of nosocomial infections. Full article

Background: Multidrug-resistant Acinetobacter baumannii (CRAB) infections are a serious problem in critical care. This study aims to develop an early prognostic score for immune paralysis, using practical and cost-effective parameters, to predict ICU mortality in patients with CRAB infections being treated with Cefiderocol. Methods: We carried out an observational pilot study on consecutive patients hospitalized in the ICU with ensuing septic Acinetobacter baumannii infections treated with Cefiderocol monotherapy or Cefiderocol including combinations. We investigated the predictive power of lymphocyte counts, lymphocyte subpopulations, serum cholinesterase levels, and reactivation of herpes viruses. Results: Overall, 36 of 39 patients entered in our analysis: 20 survivors and 16 deceased. A total of 12 patients developed bacteremia, 19 patients had HAP/VAP, and 5 patients had a soft tissue infection. Univariate analyses of factors associated with unfavorable outcome revealed a significant association for age (OR: 1.5, CI: 1.11–2.02), SAPS II (OR: 1.05, CI: 1.01–1.1), SOFA score (OR: 1.37, CI: 1.06–1.76), lymphocytopenia (OR: 32.5, CI: 3.45–306.4), viral reactivation (OR: 9.75, CI: 1.72–55.4), and cholinesterase drop <1600 U/L (OR: 39.7, CI: 5.8–271.6). At variance, monotherapy or associations with Cefiderocol were not associated. In the final multivariable model, the only independent predictors of death were age (OR: 1.42, CI: 0.98–2.05), lymphocytopenia (OR: 18.2, CI: 0.87–371), and cholinesterase drop to below 1600 U/L (OR: 9.7, CI: 0.77–123.7). Conclusions: Age, lymphocytopenia, and serum cholinesterase drops, which were nearly significantly associated with an unfavorable outcome, may help pinpoint patients with acute immune paralysis during sepsis. Knowledge of such an immune state may in turn directly influence patients’ care. Full article

Background and Clinical Significance: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but may underlie diverse and potentially life-threatening immune-related adverse events (irAEs). They may cause various conditions leading to respiratory failure, including myasthenic syndromes and myositis. However, diaphragmatic paralysis (DP) has rarely been reported. To describe patients with diaphragmatic paralysis in a pharmacovigilance registry, we searched the prospective REISAMIC registry at the Gustave Roussy Cancer Center (Villejuif, France) for cases of diaphragmatic palsy (DP) occurring from September 2014 to December 2021. Case Presentation: We identified three patients, in whom DP was confirmed by diaphragmatic ultrasonography, pulmonary function tests, and/or diaphragmatic electroneuromyogram. Diaphragmatic palsy was life-threatening in all patients, as it caused respiratory failure requiring mechanical ventilation. In all cases, a pre-existing subclinical paraneoplastic syndrome was detected. Onconeural antibodies (anti-titin and anti-VGCC) were detected in these patients before and after the initiation of ICI therapy, suggesting a mixed paraneoplastic syndrome with features overlapping those of myasthenic syndrome (myasthenia gravis in one patient and Lambert–Eaton syndrome in another) and myositis. Conclusions: Diaphragmatic palsy is a severe irAE potentially resulting from different mechanisms, including myositis and neuromuscular junction involvement (myasthenia gravis, Lambert–Eaton). Antineuronal antibodies associated with such conditions were already present in our patients prior to immunotherapy initiation, suggesting ICIs could trigger flare-ups of pre-existing silent paraneoplastic autoimmune conditions. Full article

Snakebite envenoming (SBE) remains a severely neglected public health issue, particularly affecting tropical and subtropical regions, with Africa experiencing an estimated 435,000 to 580,000 snakebites annually, leading to high morbidity and mortality rates, especially across Africa and Asia. Recognized as a Neglected Tropical Disease, SBE management is further complicated by the inadequate efficacy of current antivenom treatments. Of particular concern are cobras (Naja sp.), whose neurotoxins can induce rapid fatal respiratory paralysis. In this study, we investigate the potential of nanobodies as a promising next-generation of immunotherapeutics against cobra venoms. Through a dual strategy of the characterization of venom toxic fractions from cobras captured for the first time in Algeria and Tunisia biotopes, coupled with in vitro assays to evaluate their interactions with acetylcholine receptors, and subsequent immunization of dromedaries to produce specific nanobodies, we identified two lethal fractions, F5 and F6, from each venom, and selected five nanobodies with significant binding and neutralizing of 3DL50 (0.74 mg/kg). The combination of these nanobodies demonstrated a synergistic effect, reaching 100% neutralizing efficacy of 2DL50 lethal venom fraction (0.88 mg/kg) doses in mice. Additionally, our findings highlighted the complex mechanism of cobra venom action through the lethal synergism among its major toxins. Full article