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Toll-like receptors (TLR) 7 and 8 (TLR7/8) are activators of innate and adaptive immunity contributing to lupus pathogenesis. In Cohort B of WILLOW, a phase 2, randomised, placebo-controlled, double-blind, basket, dose-finding study, enpatoran, an oral small molecule inhibitor of TLR7/8, was evaluated in participants with active systemic lupus erythematosus (SLE). Participants were eligible if they were aged 18-75 years with moderate-to-severe SLE, with or without cutaneous manifestations, had a disease duration of at least 6 months, and were receiving a stable dose of medication before the screening period. Participants were recruited from 132 centres in 22 countries. In Part 1, participants were randomly allocated in a 1:2 ratio to receive either placebo or 100 mg enpatoran, both twice-daily. Following the enrolment of 60 participants, Part 2 was activated and additional participants were randomly allocated in a 1:1:1:1 ratio to 25 mg, 50 mg, or 100 mg of enpatoran or placebo, all twice-daily, for 24 weeks. Random allocation was stratified by region, biomarker status, and hybrid Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index score. The primary objective was to evaluate the dose-response relationship of enpatoran, using British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate at week 24, based on multiple comparison procedure-modelling analysis. Study visits were scheduled from week 0 to week 24, followed by a 2-week safety follow-up period for participants who chose not to enter the long-term extension. From weeks 2 to 12, glucocorticoid doses were tapered to a prednisone-equivalent dose of no more than 5 mg/day, as clinically tolerated. Adverse events were monitored continuously throughout the study; safety parameters (including physical examination, vital signs, and routine chemistry and haematology) were assessed at all study visits. The trial was registered at ClinicalTrials.gov (NCT05162586) and a long-term extension study is ongoing. Between May 4, 2022, and Feb 6, 2024, participants were screened for eligibility for WILLOW cohorts A and B; 715 participants were screened and 354 were randomly allocated and included in the Cohort B safety population (95 to placebo, 71 to 25 mg enpatoran, 74 to 50 mg enpatoran, and 114 to 100 mg enpatoran). One patient allocated to the placebo group was found to be ineligible and was excluded from the full analysis set for the efficacy analyses. 335 (95%) of 353 participants were female, 18 (5%) were male, and median age was 41 years (IQR 33-51). At week 24, the study did not meet its primary objective of identifying a statistically significant dose-response relationship for enpatoran in BICLA response rate (p=0·14). BICLA response rates at week 24 were higher with all doses of enpatoran (25 mg: 41 [58%] of 71; odds ratio [OR] vs placebo 2·2 [95% CI 1·1-4·0], 50 mg: 36 [49%] of 74; OR 1·5 [95% CI 0·8-2·8], and 100 mg: 56 [49%] of 114; OR 1·6 [95% CI 0·9-2·8]) versus placebo (37 [39%] of 94). The most common treatment-emergent adverse event was diarrhoea, in four (6%) of 71, two (3%) of 74, and two (2%) of 114 participants in the 25 mg, 50 mg, and 100 mg enpatoran groups, respectively, and seven (7%) of 95 participants in the placebo group. Serious adverse events were reported in one (1%) of 71, three (4%) of 74, five (4%) of 114, and three (3%) of 95 participants treated with 25 mg, 50 mg, and 100 mg enpatoran and placebo, respectively. In this study of participants with moderate-to-severe SLE, enpatoran improved BICLA response rates versus placebo; however, the primary objective of a statistically significant dose-dependent effect on disease activity based on BICLA response was not met. Enpatoran was well tolerated across all dose groups. Merck Healthcare (Darmstadt, Germany).
Penetrance of breast cancer (BC) among women who carry pathogenic variants (PVs) in BRCA1 is incomplete, and the age at BC diagnosis varies considerably, even among carriers of the same PV, suggesting the involvement of genetic and non-genetic risk modifying factors. Polygenic Risk Score (PRS) models based on common sequence variants account for less than 10% of the total risk variability among BRCA1 PV carriers, indicating that further genetic modifiers remain to be identified. Here, for the first time, we applied whole-exome sequencing for this challenge, investigating a cohort of 321 Israeli women carrying the BRCA1 185delAG founder PV. In our cohort, we found that harbouring additional putatively damaging missense variants in genes involved in innate immunity was significantly associated with earlier BC onset. The HR for carrying a missense variant in genes annotated to the top-scoring immune-related gene set NATURAL_KILLER_CELL_ACTIVATION was 3.62 (95% CI 1.96 to 6.67; p=3.8×10-5). These findings highlight a potential role for innate immune pathways as modifiers of BRCA1 penetrance and support the development of more refined, personalised risk prediction models.
Suppressor of cytokine signaling 1 (SOCS1) is a pivotal negative regulator of cytokine-mediated signaling in mammals, yet its role in teleost fish immunity remains poorly understood. In this study, we cloned and characterized the full-length SOCS1 cDNA from Japanese eel (Anguilla japonica), which encodes a 203-amino acid protein containing a conserved SH2 domain and SOCS box. Phylogenetic analysis placed AjSOCS1 within the teleost clade, showing high conservation with other vertebrate SOCS1 homologs. AjSOCS1 was ubiquitously expressed across tissues, with the highest levels in intestine and immune-related organs. Its transcription was significantly induced both in vivo (lipopolysaccharide [LPS], polyinosinic-polycytidylic acid [poly(I:C)], Aeromonas hydrophila) and in vitro (pathogen-associated molecular patterns [PAMPs] and bacterial infection), highlighting responsiveness to bacterial and viral stimuli. Subcellular localization analysis demonstrated that AjSOCS1 is cytoplasmic, consistent with its role in intracellular signaling regulation. Functional assays using a dual-luciferase reporter system revealed that AjSOCS1 strongly suppressed NF-κB activation under basal conditions, as well as during MyD88-, LPS-, and poly(I:C)-induced stimulation, and overexpression of AjSOCS1 resulted in coordinated downregulation of NF-κB subunits and downstream inflammatory and antimicrobial genes. Together, these findings provide the first functional evidence that SOCS1 in Japanese eel acts as a negative regulator of NF-κB signaling, thereby extending the known repertoire of SOCS1 activity in fish. This study not only enriches comparative immunology of SOCS proteins but also has potential implications for controlling excessive inflammation and improving disease resistance in aquaculture.
Neutrophil granulocytes actively contribute to tissue damage after ischemic stroke. The membrane protein CD (cluster of differentiation)177 is detectable on variable neutrophil numbers in most individuals (CD177 wild-type [CD177WT] genotype), whereas ≈5% of the general population completely lack CD177 (CD177-deficient [CD177null] genotype). Despite its known relevance in vasculitis, the role of ischemic stroke remains unknown. In 2 prospective cohorts of patients with first-ever ischemic stroke (PROSCIS-B [Prospective Cohort With Incident Stroke Berlin], NOFF-S [Neutrophils: Origin, Fate & Function Stroke]), we assessed the effect of CD177null and CD177WT status on stroke severity and outcome (National Institutes of Health Stroke Scale and modified Rankin Scale) over 1 year or 3 months poststroke, respectively. By flow cytometry, we stratified CD177 expression level as CD177neg, CD177dim, and CD177high. The predictive value of the CD177 state was evaluated by multivariable regression and discrimination analyses. In PROSCIS-B (n=579; mean age, 68.1 years; 38.5% women) and NOFF-S (n=236, 68.4 years, 36.9% women), similar rates of patients were CD177null (n=26 [4.5%] and n=10 [4.2%], respectively). Patients with CD177null had a higher probability of unfavorable stroke outcome (modified Rankin Scale score 3-6) than patients with CD177WT (n=8 of 21 [38.1%] versus 90 of 462 [19.5%] with follow-up, P=0.05, in PROSCIS-B; n=8 of 10 [80.0%] versus n=23 of 142 [16.2%] with follow-up, P<0.0001, in NOFF-S). This association remained when adjusted for age, sex, initial stroke severity defined by National Institutes of Health Stroke Scale score, stroke subtype defined by TOAST (Trial of ORG 10172 in Acute Stroke Treatment), and reperfusion treatment (relative risk, 3.8 [95% CI, 2.0-7.1]; P<0.001, in NOFF-S). In NOFF-S, the proportion of CD177dim neutrophils at admission was negatively associated with stroke severity at admission, while that of CD177high neutrophils predicted a favorable clinical outcome after 3 months. CD177 expression level significantly improved the prediction of stroke outcome in addition to clinical adjustment variables in area under the curve, net reclassification improvement, and integrated discrimination improvement analyses (P=0.004, P=0.001, and P<0.001, respectively, for CD177high). CD177 expression at admission is an easy-to-measure biomarker for patient stratification. CD177 holds potential as a therapeutic target to modulate immune responses after stroke. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856. URL: https://drks.de/search/en/trial/Unique identifier: DRKS00030825.
Pseudomonas aeruginosa is a significant pathogen associated with acute and chronic infections, particularly in immunocompromised individuals. Its capacity for biofilm formation, combined with antibiotic resistance, plays a critical role in the persistence of these infections. Peptidyl-arginine deiminases (PADs), including PAD2 and PAD4 isoforms, are involved in neutrophil phagocytic killing of P. aeruginosa. This study aimed to investigate the impact of PAD enzymes on biofilm development and virulence factor production in P. aeruginosa, with focus on the multidrug resistant strain, PGO2330. Biofilm formation was assessed using crystal violet assays and confocal scanning laser microscopy. Quorum sensing (QS) gene expression and QS-related virulence factor production were quantified using qPCR and virulence factor assays. Exposure to 20 n<sc>m</sc> of PAD2 or PAD4 reduced PGO2330 surface attachment (p < 0.0001) and biofilm formation to 67.9 ± 5.6% (p < 0.0001) and 68.2 ± 4.2% (p = 0.0004), respectively. Moreover, rPAD2 and rPAD4 citrullinated multiple protein substrates of P. aeruginosa, yet citrullination activity was not required by rPADs to reduce P. aeruginosa biofilm formation. PGO2330 exposed to PAD2 and PAD4 showed reduced lasR, lasI, rhlR, rhlI, and mvfR gene expression and reduced levels of extracellular DNA, rhamnolipids, pyocyanin, and protease activity. These results demonstrate that PADs inhibit P. aeruginosa biofilm formation and decrease the production of QS-related virulence factors, highlighting their potential as novel antimicrobials and supporting further research into the development of PAD-based therapeutics.
Cystitis is a bacterial infection of the bladder that occurs in about half of women at least once in their lifetime. Antibiotics such as nitrofurantoin are used to treat cystitis, but antibiotic resistance is a concern, especially for recurrent infections. Here we report an open-label, randomized, single-centre, phase 2 study to analyse the acute and long-term safety and efficacy of the IL-1 receptor antagonist anakinra, compared with nitrofurantoin, in recurrent cystitis. A total of 30 adult female patients with a documented history of recurrent cystitis and a current acute cystitis episode were randomized in a 2:1 ratio to treatment with anakinra (n = 20) or nitrofurantoin (n = 10) for 5 days. Primary and secondary efficacy end-points were reached, defined as the reduction in typical symptoms, measured by the acute cystitis symptom score (day 5), longitudinal symptom scores, recurrence rates, quality of life, gene expression analysis and microbiology at follow-up on days 15 and 30 and at 6 months. Symptom scores were decreased in the anakinra (P < 0.001) and nitrofurantoin (P < 0.001) arms after 5 days and remained low after 15 days, 30 days and 6 months. Recurrences were less frequent after 6 months in both treatment groups compared with the 6-month pre-enrolment history (P < 0.001 for anakinra and P = 0.004 for nitrofurantoin), and the quality of life was increased, without adverse effects. Immune gene expression was rapidly inhibited in the anakinra-treated patients but not in the nitrofurantoin group. Targeted innate immune inhibition therapy shows non-inferiority to nitrofurantoin in patients with recurrent acute cystitis. German Clinical Trials Register ID: DRKS00025964 .
In Tenebrio molitor, the inhibitor of apoptosis protein 2 (TmIAP2) regulates immune responses; however, the role of TmIAP2 in the induction of antimicrobial peptides (AMPs) remains unexplored. Therefore, this study aimed to dissect the immunomodulatory function of TmIAP2 using RNAi-mediated silencing across whole body and five immune-relevant tissues following infection with Escherichia coli, Staphylococcus aureus, Candida albicans, and Listeria monocytogenes. Transcriptomic profiling revealed pathogen- and tissue-specific upregulation of AMP-related genes coupled with robust activation of NF-κB transcription factors (TmRelish, TmKayak, TmDorX1/2), particularly in response to fungal and Gram-negative challenges. Hemocytes, the gut, and Malpighian tubules emerged as key immunological hotspots. Intriguingly, Gram-positive bacteria elicited muted AMP responses, highlighting differential pathway engagement. Our study identified TmIAP2 as a central immune rheostat, which fine-tunes NF-κB-driven AMP expression to ensure compartmentalized, microbe-specific defense. These findings reveal a conserved IAP-NF-κB axis in insect immunity and provide mechanistic insights into an apoptosis-immune crosstalk pathway that is relevant to pest immunobiology.
Inhibitors of apoptosis proteins (IAPs) are endogenous apoptosis regulators conserved in many species. We used bioinformatics approaches, identified six members of the IAP gene family (named PtIAP-01 to PtIAP-06) in the genome of Portunus trituberculatus. We phylogenetically classified these PtIAPs into four distinct subfamilies, namely BIRC5, BIRC6, BIRC7-A, and BIRC7-B. All identified PtIAPs contained the characteristic baculoviral IAP repeat (BIR) domain. In addition, some PtIAP members were found to possess additional functional domains, including RING finger or UBC. The expression levels of the PtIAPs were tissue-specific. PtIAP-01 was highly expressed in immune-related tissues (intestine and hepatopancreas), PtIAP-05 dominated in muscle, while PtIAP-02, -03, -04, and -06 showed preferential expression in the eyestalk. Following Vibrio parahaemolyticus injection, the expression levels of PtIAP-01, -02 and -05 were significantly upregulated, reaching 1.64-, 3.48-, and 4.18-fold of the control group, respectively, indicating their potential involvement in anti-pathogen immunity. Fluorescence in situ hybridization (FISH), RNA interference (RNAi) and terminal deoxynucleotidyl transferase nick-end-labeling (TUNEL) apoptosis assays validated their function. FISH confirmed that PtIAP-01, -02, and -05 were in both the nucleus and cytoplasm of hepatopancreatic cells. Their fluorescence signals got stronger after V. parahaemolyticus infection (PtIAP-05 strongest). RNAi and TUNEL demonstrated that knockdown of PtIAP-01, -02, and -05 significantly increased the mortality and apoptosis rates of P. trituberculatus after V. parahaemolyticus challenge, and significant upregulation of downstream apoptotic effector genes (PtCaspase-1, -3, -8). These findings offer new insights into the innate immune mechanisms of crustaceans and lay a foundation for breeding disease-resistant strains.
BACKGROUND: Over the years, lung cancer incidence in never-smokers has been rising. Air pollution is a non-smoking-related factor that promotes lung cancer progression. Particulate matter 2.5 (PM2.5) is a component of air pollution that is associated with a type 2 immune response mediated by group 2 innate lymphoid cells (ILC2) and T helper 2 (Th2) cells. Furthermore, PM2.5 can activate fibroblasts, induce the secretion of collagen, and contribute to the development of lung fibrosis. Although type 2 immune response and lung fibrosis are described as pro-tumorigenic in lung cancer, whether PM2.5-driven type 2 immune response and/or lung fibrosis promote lung cancer tumorigenesis in mouse models of lung cancer remains unclear. This study investigated the impact of PM2.5 on the type 2 immune response, lung fibrosis, and lung cancer tumorigenesis in vivo. METHODS: We treated EGFR and KRAS/Trp53 mouse models of LUAD intranasally with PM2.5, analyzed lung tumor burden and lung fibrosis by histology, and changes in type 2 immune cell (ILC2, Th2) and CAF markers by flow cytometry. Different durations of PM2.5 treatment (3-week short-term vs. 6-week long-term), experimental time points (10 weeks vs. 15 weeks), and intervals between the onset of EGFR and KRAS/Trp53 mutations and first exposure to PM2.5 (3 days vs. 4 weeks delayed) were assessed. Unpaired t-test and One-way ANOVA statistical tests were utilized. RESULTS: We found that PM2.5 did not significantly impact lung tumor burden in EGFR and KRAS/Trp53 mouse models of LUAD. Notably, PM2.5 did not significantly affect the type 2 immune response mediated by ILC2 and Th2 cells. However, long-term exposure to PM2.5 or delayed treatment with PM2.5 significantly increased the abundance of CD90.2+ CAFs in lung cancer without impacting lung cancer burden. CONCLUSIONS: In summary, while PM2.5 did not significantly impact EGFR and KRAS/Trp53 lung tumor burden or the type 2 immune response, long-term or delayed exposure to PM2.5 promoted CD90.2+ CAFs in vivo. This study demonstrates that preclinical modeling of PM2.5-driven LUAD requires further validation and consideration of confounding variables to reflect air pollution-associated LUAD observed in humans.
The innate immune system requires the activity of interferon-stimulated genes (ISGs) to mount its protective response against viruses. However, the activity of ISGs against viruses varies widely and is orchestrated by the interplay of hundreds of ISGs. Utilizing a time-resolved, arrayed loss-of-function screen, we systematically investigate 285 ISGs for their virus-modulating activity against eight viruses. The quantitated data from the screen results do not necessarily result in similar quantitative biological effects of gene function but indicates virus specificity of many ISGs and pan-proviral activity of some ISGs, such as RNA 2',3'-cyclic phosphate and 5'-OH ligase (RTCB). Co-depletions of selected candidates identify ISGs with synergistic functions, highlighting particularly strong synergies between ISGs inhibiting entry pathways and ISGs involved in IFN signaling. Among unexplored ISGs, we identify BORCS8, which has a particularly prominent role in modulating SARS-CoV-2 infection. Mechanistically, BORCS8 mediates the acidification of early endosomes during viral entry, a process known to facilitate the degradation of virus particles. Collectively, this extensive resource reveals specificities of ISGs identified in this screening system and suggests potential strategies for antiviral treatment options.
The enzyme N-glycanase 1 (NGLY1) regulates autophagic processes and endoplasmic reticulum (ER)-associated proteasomal degradation by de-N-glycosylation of misfolded glycoproteins. Mutations of NGLY1 that result in a loss of protein function cause congenital disorder of deglycosylation 1 (CDDG1), also known as NGLY1 deficiency. NGLY1 deficiency is associated with severe dysregulation of mitochondria and proteasomal degradation, which primarily manifests as impairments in the nervous system. However, recent studies also linked NGLY1 function to cellular processes associated with immunity and autoimmune diseases, such as rheumatoid arthritis. NGLY1 plays a distinct role in mitochondrial homeostasis, thereby potentially regulating interferon responses, cellular stress responses and innate immunity. It also controls the stability of the programmed cell death protein-1 (PD-1) receptor on T lymphocytes and cancer cells, influencing tumor immune evasion. Importantly, NGLY1 was shown to process foreign peptides destined for presentation on major histocompatibility complex (MHC) molecules, a process that enables cytotoxic T lymphocytes to identify pathogens or mutated cells. Finally, altered levels of NGLY1 may impair B lymphocytes, especially the formation and function of antibody-secreting cells. In this review, we aim to compile findings from the last three decades and explore the connections between NGLY1-controlled processes and immune cell function. Understanding NGLY1-mediated mechanisms may provide new insights into the modulation of immune responses and the development of therapeutic strategies for immune-related disorders.
Mechanical forces are emerging physical cues that regulate biochemical signals of immune cells for antitumor immunity. Owing to the lack of precise tools to impose intracellular forces, little is known about whether and how organelle-level forces trigger mechanotransduction for antitumor immunity. Here, we developed a magneto-mechanical force-triggered lysosomal membrane permeabilization (MagLMP) strategy to induce durable macrophage repolarization for in vivo applications. Self-assembled magnetic nanomotors are driven by rotational magnetic fields, facilitating dynamic damage to the lysosomal membrane by a finely tuned torque-induced vortex. Intriguingly, galectin 9 (Gal9) was found to be critical for sensing cyclic MagLMP, which dynamically activated AMP-activated protein kinase (AMPK), enhanced activation of nuclear factor kappa B (NF-κB), and induced metabolic alterations for sustained M1-like macrophage repolarization, followed by mounting of antitumor immunity. Through single-cell RNA sequencing of tumor tissues, as well as macrophage depletion-reconstitution models involving intratumoral transfer of Gal9-KO bone marrow-derived macrophages (BMDMs) and AMPK shRNA-transduced Gal9-KO BMDMs, we confirmed the Gal9-AMPK-NF-κB axis as the essential pathway by which MagLMP functions in antitumor therapy. In a mouse model of lung adenocarcinoma in situ, overall survival was extended after intravenous administration of nanomotors followed by cyclic MagLMP, and one third of mice survived for more than 300 days. Together, these results demonstrate an intracellular mechanical strategy that can dynamically manipulate innate immune responses in vivo, providing a tool for durable immunotherapy through organelle mechanotransduction.
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical sensor in the innate immune response to intracellular pathogens, yet its therapeutic potential for augmenting macrophage-mediated control of Mycobacterium tuberculosis (Mtb) remains incompletely understood. This study investigated whether pharmacological activation of the STING pathway could enhance autophagy to promote Mtb clearance in human macrophages. Human THP-1 monocytes were differentiated into macrophages and infected with Mtb. The effects of the STING agonist MIW815 (ADU-S100) on Mtb phagocytosis, intracellular bacterial survival, and autophagic flux were assessed using a combination of molecular and cellular techniques, including quantitative real-time polymerase chain reaction, Western blotting, colony-forming unit (CFU) assays, and confocal immunofluorescence microscopy. The dependency on the cGAS-STING pathway was confirmed using small interfering RNA-mediated gene silencing. Pharmacological activation of STING with ADU-S100 significantly enhanced Mtb phagocytosis and subsequent intracellular clearance. This enhanced bactericidal activity was mechanistically linked to an increase in autophagic flux, as evidenced by elevated LC3-II protein levels and significantly increased colocalization of Mtb with lysosomal compartments. Importantly, treatment with the autophagy inhibitor hydroxychloroquine or silencing of cGAS significantly reversed these phenotypes, confirming the pivotal role of the STING-autophagy axis. Activating the STING pathway with ADU-S100 is a potent host-directed strategy to bolster macrophage autophagy and enhance the elimination of intracellular Mtb. This provides a strong rationale for exploring STING agonists as a novel therapeutic intervention for tuberculosis, addressing a significant and clinically relevant challenge in infectious disease.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by multiple factors, with diverse clinical manifestations leading to varying treatment outcomes. Dysbiosis of the respiratory microbiome is one of the key contributors to this variability. Due to differences in microbial detection technologies and sample collection methods, studies on the characteristics of respiratory prokaryotic microbiota and how these microbes influence host functions in COPD patients have yielded variable results. In this review, we conducted a comprehensive search of relevant literature from PubMed, ScienceDirect, and Elsevier, summarizing studies on the characteristics and functional analyses of prokaryotic microbiota under various technical approaches. The goal was to identify common patterns of microbiota changes in COPD across different disease states, as well as individual microbial influences on host functions. Compared with healthy adults, in stable-phase COPD patients, the relative abundance of Prevotella species in the Bacteroidetes phylum is significantly reduced. During acute exacerbations, the predominant microbiota is composed of Moraxella, Haemophilus, and Streptococcus species from the Proteobacteria and Firmicutes phyla. Clinical indicators in COPD patients are correlated with the abundance of Streptococcus (Firmicutes) and Prevotella (Bacteroidetes) species. Furthermore, the different phyla of respiratory prokaryotic microbiota are associated with innate immunity, metabolism, and inflammation factors related to COPD. This review summarizes evidence on dynamic changes in the airway prokaryotic microbiome during COPD progression. It highlights the dual role of these microbial changes as biomarkers of disease progression and modifiable targets for personalized care. Observed patterns-such as reduced Prevotella abundance in stable disease and the dominance of Moraxella, Haemophilus, and Streptococcus during acute exacerbations-provide a basis for stratifying patients and designing individualized treatment plans. Microbiome analysis may aid in early identification of high-risk patients for preventive strategies, guide pathogen-specific antimicrobial or immunomodulatory therapy, and allow treatment response to be monitored through microbial shifts. By linking distinct microbial profiles to host immune and inflammatory pathways, this approach supports the development of tailored interventions to restore microbial balance. These strategies could improve clinical outcomes and advance precision medicine in COPD management.
The bursa of Fabricius (BF), a regressive lymphoid organ unique to avian species, plays a pivotal role in early immune defense post-hatching: it not only mediates innate immune responses but also provides a microenvironment necessary for B-cell maturation, thereby playing an indispensable role in the development and functional maturation of the avian adaptive immune system. Life history theory predicts energy allocation trade-offs in response to environmental challenges, which often suppresses costly processes like immunity to prioritize survival. This study investigated effects of long-term environmental heavy metal pollution on these trade-offs and BF development in the tree sparrow (Passer montanus). Contrary to the paradigm of stress-induced immunosuppression, we found that despite significant impairments in body condition and growth rate, nestlings from a polluted site exhibited enhanced BF development. This was demonstrated through three key phenotypic adaptations: (1) an increased BF coefficient, (2) accelerated follicular development and histological maturation, and (3) increased B-lymphocyte density and migration to the spleen. Nestlings from a polluted site also displayed enhanced innate immunity and antioxidant defenses. An Integrated Biological Response (IBR) model suggested a strategic energy reallocation where investment in growth was suppressed to prioritize immune organ development and function. These findings provide a novel perspective on adaptive life-history strategies, demonstrating that birds can prioritize immune resilience to persist in contaminated environments at a cost to somatic development.
This study aims to define a novel molecular subtype of LUAD by integrating multiple omics data. Additionally, we develop and validate an Artificial Intelligence Derived Prognostic Index (AIDPI) that predicts the prognosis of LUAD patients, identifies potential therapeutic targets. This study employed ten clustering algorithms from the R package "MOVICS" to integrate multi-omics data of LUAD sourced from TCGA database for molecular typing. Subsequently, an Artificial Intelligence Derived Prognostic Index (AIDPI) was constructed as the most effective indicator for predicting the overall survival rate of LUAD patients. The biological functions and mechanisms of NPC2 in lung adenocarcinoma were elucidated through both in vitro and in vivo experiments, which included CCK-8 assays, colony formation assays, flow cytometry, Transwell assays, and xenograft tumor models. Additionally, the impact of NPC2 on Ribociclib sensitivity was investigated through drug correlation analysis and molecular docking, while the predictive value of NPC2 regarding immunotherapy benefits was validated using the immune cell infiltration analysis. Through multi-omics clustering, we identified two subtypes of lung adenocarcinoma associated with prognosis, with the CS1 subtype exhibiting the most favorable prognostic outcomes. The low AIDPI group exhibited a more positive prognosis, accompanied by increased immune cell infiltration and activation of immune pathways. Meanwhile, NPC2 was recognized as a standalone risk factor for LUAD, with its high expression significantly improving the overall survival of LUAD patients. Functionally, the overexpression of NPC2 promotes tumorigenesis in LUAD both in vitro and in vivo. Mechanistically, the upregulation of NPC2 expression inhibits the progression of LUAD by suppressing the PI3K/AKT signaling pathway. Our study also demonstrated that high NPC2 expression is positively correlated with Ribociclib sensitivity, as confirmed by in vitro experiments. Furthermore, NPC2 expression is positively correlated with ImmuneScore, and may serve as a predictive indicator for the efficacy of immune checkpoint inhibitor (ICI) therapy. The comprehensive analysis of multiple omics data significantly enhances the molecular classification of lung adenocarcinoma. Furthermore, AIDPI is a potential biomarker that predicts the prognosis of LUAD patients. NPC2 inhibits the progression of LUAD by suppressing the PI3K/AKT signaling pathway and enhancing the chemotherapy sensitivity to Ribociclib.
Innate immune activation is a major driver of unmodified in vitro-transcribed (IVT) mRNA degradation; however, how modified IVT mRNAs are degraded, and the related regulation mechanisms, remain poorly understood. Through a focused screen of viral- and host-derived immune suppressors, we identify 13 factors that enhance mRNA performance, with SOCS1 and the coronaviral membrane protein (M) emerging as the most potent. Multi-omics analyses reveal that pseudouridine-modified IVT mRNA undergoes rapid deadenylation and predominant 3'-5' decay, followed by bidirectional degradation, closely resembling endogenous mRNA decay kinetics, and is extensively associated with canonical mRNA decay machineries. Mechanistically, IVT mRNA activates IFN-β signaling, which promotes processing body (P-body) formation and XRN1-mediated 5'-3' degradation. Suppression of IFN signaling by SOCS1 or M markedly enhances mRNA expression across diverse cell types, organoid systems, and murine disease models. Together, these findings define a type I interferon-P-body-XRN1 axis that constrains modified IVT mRNA stability and provides a framework for enhancing mRNA therapeutics.
Neutrophils are essential components of host defense, traditionally recognized for their well-described antimicrobial functions in bacterial infections. Far from being merely short-lived and functionally limited, emerging evidence demonstrates that neutrophils are also key players in viral infections. Through mechanisms such as degranulation and formation of NETs, neutrophils play an important role in virus-induced inflammation and pathogenesis. However, their persistence and hyperactivated states also contribute to tissue damage and failed resolution of acute inflammation. Here, we summarize recent data regarding the role of neutrophils in respiratory and arboviral infections, from clinical evidence to mechanistic insights available from the last ten years. Finally, we discuss emerging therapeutic strategies that target neutrophil fate and function to promote the resolution of inflammation. Overall, although well characterized in some viral infections, for a few other viral diseases the role of neutrophils remains elusive. We highlight the importance of modulating neutrophils death in a timely and non-inflammatory manner, as some viruses influence apoptosis for their own benefit, favoring viral replication. For those infections, and also due to non-resolving inflammation provoked by these viruses, pro-resolving mediators certainly display a beneficial effect. Rather than broadly suppressing antiviral immunity, pro-resolving approaches aimed at recalibrating neutrophil activation, lifespan, and clearance may represent a promising and safer avenue for the treatment of viral diseases characterized by excessive and non-resolving inflammation.
Coronavirus disease 2019 (COVID-19) severity is closely associated with dysregulated inflammatory responses, with cytokines and chemokines emerging as key mediators and potential early biomarkers of adverse clinical outcomes. A retrospective study on 103 RT-PCR-confirmed COVID-19 patients during the first pandemic wave (January-May 2020) was performed to evaluate the prognostic value of a panel of cytokines and chemokines measured at hospital admission. Samples and clinical data were collected at the Department of Public Health and Infectious Diseases, Sapienza University of Rome, and sent to Istituto Superiore di Sanità for further characterization. Serum concentrations of IL-1β, IL-6, IL-8, IL-10, TNF-α, CCL3, and CXCL10 (IP-10) were quantified using multiplex ELISA. Associations with in-hospital mortality, intensive care unit (ICU) admission, and a composite outcome (death or ICU admission) were assessed using multivariable logistic regression. ICU admission occurred in 6.8% of patients and mortality in 11.7%. Among inflammatory mediators, CXCL10 emerged as the strongest predictor of adverse outcomes. In adjusted models, each 1,000 pg/mL increase in CXCL10 was associated with increased odds of death (OR 1.26; 95% CI 1.17-1.35), ICU admission (OR 1.13; 95% CI 1.06-1.21), and the composite outcome (OR 1.21; 95% CI 1.12-1.31). Elevated respiratory frequency and blood urea nitrogen were also independently associated with worse outcomes, while TNF-α tended to be associated with ICU admission. Conversely, IL-6 and other cytokines were not significant predictors in the multivariable models. These findings identify CXCL10 as a key early immunological predictor of COVID-19 severity, suggesting that its integration with clinical parameters may improve risk stratification and guide targeted management. CXCL10 may also represent a potential therapeutic target, warranting validation in larger prospective studies.