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At least 19 recordsLinked to original sources
PubMed2026

Glycaemic burden disrupts innate immunity in TB by modulating CD206 expression and macrophage antimicrobial responses.

Tuberculosis (TB) and diabetes mellitus (DM) represent a growing dual global health burden, with chronic hyperglycaemia recognized as a major modifier of host immunity against Mycobacterium tuberculosis (Mtb). Macrophages, central to pathogen recognition, phagocytosis, antigen presentation, and intracellular killing, may be particularly vulnerable to diabetic metabolic dysregulation. This study evaluated phenotypic and functional macrophage alterations in individuals with pulmonary TB, type 2 DM, TB-DM comorbidity, and healthy controls. Surface receptor expression was analysed by multicolour flow cytometry, while phagocytosis and intracellular bacterial clearance were assessed using FITC-labelled Mtb assays and colony-forming unit enumeration. Hyperglycaemia was associated with reduced CD11b, MARCO, and TLR2 expression alongside upregulation of the mannose receptor CD206, which correlated positively with HbA1c levels, indicating a shift toward a permissive M2-like phenotype. Phagocytic uptake of Mtb was significantly impaired and inversely correlated with HbA1c. Antigen-presenting capacity was selectively compromised, with reduced CD80 and CD86 expression in DM and TB-DM groups, while HLA-DR remained unchanged. Intracellular Mtb killing was markedly diminished in diabetic macrophages. These findings demonstrate that chronic hyperglycaemia profoundly disrupts macrophage innate immunity, contributing to increased TB susceptibility and poor infection control in diabetic populations.

Humans↗
PubMed2026

Upper airway microbiome interacts with GSDMB and ORMDL3 asthma risk SNPs to influence early-life wheeze risk.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the chromosome 17q12-q21 region and, independently, early-life nasal microbiota dominated by Moraxella, Streptococcus, or Haemophilus (MSH) increase risk of chronic wheeze and asthma development. OBJECTIVE: We sought to determine whether 17q12-q21 risk SNPs and nasal microbiota interact to modulate childhood wheeze risk. METHODS: Nasal wash samples from 12-month-old infants in 2 birth cohorts, COAST (Childhood Origins of Asthma; n = 180) and URECA (Urban Environment and Childhood Asthma; n = 139), underwent 16S ribosomal RNA variable region 4 sequencing. Nasal microbiota dominated by MSH or Corynebacterium, Dolosigranulum, Staphylococcus, or Bacillus (CDSB) were assessed. Paired blood was genotyped for 9 17q12-q21 risk SNPs. Logistic regression tested interactions between 17q12-q21 SNPs and MSH or CDSB on wheeze risk in the first 3 years of life. A549 lung epithelial cells, CRISPR-edited to encode the rs7216389 risk genotype (rs7216389TT) were compared to the heterozygous (rs7216389CT) line using bulk RNA sequencing. RESULTS: SNPs, particularly those in the ORMDL3 (rs8076131; odds ratio [OR]: 1.72; 95% CI: 1.09-2.71; Pint = .031) and GSDMB (rs2305480; OR: 1.72; 95% CI: 1.09-2.71; Pint = 0.042; and rs7216389; OR: 1.73; 95% CI: 1.09-2.70; Pint = .047) genes, interact with MSH microbiota to increase early-life wheeze risk (false discovery rate Pint = .016 for all), while interactions with CDSB reduce risk. A549 airway epithelial cells homozygous for rs7216389TT exhibited decreased expression of genes involved in antimicrobial responses and neutrophil recruitment and evidence increased microbial adherence compared with the heterozygous cell line. CONCLUSION: Airway microbiota interact with SNPs at the 17q12-q21 locus in genes involved in sphingolipid metabolism and intracellular antimicrobial responses, to modulate wheeze risk.

Humans↗
PubMed2026

Intestinal plasmacytoid dendritic cells preferentially produce interferon lambda, contributing to localized innate immune responses.

The healthy intestine maintains homeostasis in part via immune responses to microbiota, which includes basal production of interferon cytokines. Previous work showed that Type III Interferon (IFN-λ) stimulates localized pockets of interferon-stimulated genes (ISGs) in the adult mouse intestinal epithelium at homeostasis that provide preemptive protection from viral pathogens. Here, we demonstrate that a major source of homeostatic IFN-λ production in the intestine is a population of epithelium-associated plasmacytoid dendritic cells (pDC). Expansion of the pDC population increases epithelial ISG expression at homeostasis, suggesting the abundance of these cells is a limiting factor in IFN-λ responses. On the other hand, depletion of pDC or bone marrow reconstitution with IFN-λ-deficient pDC results in reduced expression of homeostatic ISGs in the intestinal epithelium. Notably, intestinal pDC preferentially produce homeostatic IFN-λ, whereas splenic pDC produce Type I IFNs. Comparison of intestinal and splenic pDC reveal tissue-specific changes in gene expression and genomic accessibility, including evidence of responses to transforming growth factor beta (TGF-β) in the intestine. Isolated gut pDC produce more IFN-λ than splenic pDC upon stimulation, and pretreatment of a human pDC cell line with TGF-β results in enhanced transcription of IFN-λ upon stimulation. This study demonstrates that pDC are a substantial source of homeostatic IFN-λ in the intestine and implicates the barrier cytokine TGF-β in regulating IFN types produced by pDC upon stimulation. Reprogramming of recruited pDC by tissue cytokines may have important implications for balancing effective antimicrobial responses with damaging inflammation at barrier tissues.

Animals↗
PubMed2025

Plasmacytoid dendritic cells in the intestine preferentially produce interferon lambda at homeostasis contributing to tonic localized innate immune responses.

The healthy intestine maintains homeostasis in part via immune responses to microbiota, which includes basal production of interferon cytokines. Previous work showed that Type III Interferon (IFN-λ) stimulates localized pockets of interferon-stimulated genes (ISGs) in the adult mouse intestinal epithelium at homeostasis that provide preemptive protection from viral pathogens. Here, we demonstrate that a major source of homeostatic IFN-λ production in the intestine is a population of epithelium-associated plasmacytoid dendritic cells (pDC). Depletion of bacterial microbiota in the intestine also reduces pDC abundance, and pDC depletion or bone marrow reconstitution with IFN-λ-deficient pDC results in reduced expression of homeostatic ISGs in the intestinal epithelium. Notably, intestinal pDC preferentially produce IFN-λ over Type I IFNs whereas splenic pDC produce more Type I IFNs. Comparison of intestinal and splenic pDC reveal tissue-specific changes in gene expression and genomic accessibility, including evidence of responses to transforming growth factor beta (TGF-β) in the intestine. Isolated gut pDC produce more IFN-λ than splenic pDC upon stimulation, and pre-treatment of a human pDC cell line with TGF-β results in enhanced production of IFN-λ upon stimulation. This study demonstrates that pDC are an important source of homeostatic IFN-λ in the intestine and defines the role of barrier cytokine TGF-β in regulating IFN types produced by pDC upon stimulation. Reprogramming of recruited pDC by tissue cytokines may have important implications for balancing effective antimicrobial responses with damaging inflammation at barrier tissues.

Journal Article↗
PubMed2026

Molecular Bases and Genetic Design of Rice Disease Resistance for Optimized Yield and Sustainable Agriculture.

Rice diseases continue to undermine yield stability and threaten the sustainability of rice production. The central challenge is therefore not simply to maximize immune activation, but to identify genetic interventions that remain effective across diverse pathogen races and environmental conditions without imposing excessive penalties on growth or yield. Here, we synthesize the molecular basis of rice immunity from a design-oriented perspective. We first examine cell-surface pattern-recognition receptors and intracellular nucleotide-binding leucine-rich repeat receptors, and then assess the shared signaling hubs and defence outputs that connect pathogen perception to antimicrobial responses. Rather than treating these components as equivalent breeding targets, we compare their translational potential according to resistance spectrum, anticipated durability, tunability, pleiotropic risk, and the strength of field evidence. We further discuss breeding strategies based on receptor engineering, editing of susceptibility genes and cis-regulatory elements, post-translational motif engineering, pathogen-inducible and upstream open reading frame-mediated regulation, resistance-gene stacking and artificial intelligence-assisted prediction. We argue that rational resistance design in rice should move beyond constitutive immune activation toward allele-specific, quantitative, spatially restricted and infection-responsive regulation. Integrating mechanistic insights with precision genome editing, accelerated breeding and responsible deployment offers a practical route to durable, yield-compatible disease resistance while reducing dependence on chemical control.

breeding strategy↗
PubMed2025

Panduratin A Induces Autophagy Through AMPK Activation Independent of mTOR Inhibition and Restricts Mycobacterium tuberculosis in Host Macrophages.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health burden, especially with the increasing prevalence of drug-resistant strains. There is an urgent need for new therapeutics that act via alternative mechanisms. Autophagy, a vital cell-autonomous defense process, allows macrophages to degrade intracellular pathogens such as Mtb and has gained attention as a potential target for host-directed therapy. In this study, we conducted a high-content imaging screen of herb-derived compounds to identify autophagy inducers in RAW264.7 macrophages. Panduratin A (NPA), a natural compound from Boesenbergia rotunda, was found to potently induce autophagy. NPA promoted autophagic vacuole formation in a dose-dependent fashion at low micromolar levels. Its autophagy-inducing effect was validated using RFP-GFP-LC3 dual fluorescence assays and immunoblotting in the presence of bafilomycin A1. Further mechanistic analysis revealed that NPA activates autophagy through AMPK activation, independent of mTOR inhibition. Importantly, NPA significantly promoted intracellular Mtb clearance and increased colocalization of Mtb with autophagosomes and lysosomes, in a manner dependent on Beclin-1. These findings highlight NPA as a potent enhancer of macrophage antimicrobial responses via autophagy, supporting its potential as a candidate for host-directed adjunctive therapy against TB.

Autophagy↗
PubMed1979

Effect of a Salmonella group H1 R factor on virulence and response of infections to antimicrobial therapy.

A group H1 R factor encoding resistance to chloramphenicol, streptomycin, sulfonamide, and tetracycline was transferred into Salmonella typhimurium LT-2. The virulence of LT-2 for mice, as assessed by intraperitoneal 50% lethal dose and the number of organisms in the spleen, was not affected by the R factor. On the other hand, the R factor conferred resistance in mouse infections to therapy with chloramphenicol and trimethoprim plus sulfamethoxazole.

Animals↗
PubMed1979

Limulus lysate assay for early detection of certain Gram-negative corneal infections.

The limulus endotoxin assay has been previously demonstrated to be the most sensitive method available for detection of bacterial endotoxin. A commercially available form of limulus amoebocyte lysate was used in this study for detection of Gram-negative corneal infections in both experimental animals and in a group of nine patients. The limulus assay enabled rapid detection of Gram-negative infections in both the experimentally induced ulcers in rabbits and in the patients studied. False-positive reactions did not occur in corneal infections due to either Gram-positive bacteria, fungi, or herpes simplex keratitis. The limulus test proved to be more sensitive than examination of Gram-stained smears of corneal scrapings and became positive earlier than bacterial cultures. The limulus test was helpful in the diagnosis of partially antibiotic-treated corneal infections but could not be used to assess the response to antimicrobial therapy, since endotoxin persisted in the corneal scrapings for some time after initiation of therapy.

Animals↗
PubMed2026

TRIM21 induces selective autophagy of viruses and bacteria.

TRIM21 is an exceptionally versatile ubiquitin ligase that can be directed by antibodies to target oligomeric protein scaffolds, viral capsids, and proteopathic aggregates for intracellular degradation. How the cell degrades these typically resistant substrates remains poorly understood. To address this, we used TRIM21 viral restriction to create a genome-wide phenotypic screen for antibody-dependent capsid degradation. We identify an antimicrobial selective macroautophagy pathway in mammalian cells, which we term "antibody-directed xenophagy" (ADX). We show that this mechanism restricts structurally diverse pathogens, including adenovirus and Salmonella. Using quantitative microscopy, we demonstrate that TRIM21 rapidly intercepts antibody-pathogen complexes, leading to ubiquitin ligase activation. Following this, selective autophagy adaptors are recruited, and viral cargoes are delivered to lysosomes. This process reduces Salmonella pathology and bacterial tissue invasion in mice. We propose that TRIM21 evolved through competition with pathogens to induce autophagy of diverse and complex substrates, potentially explaining its versatility for targeted protein degradation.

TRIM21 Protein↗
PubMed1975

Immunogenicity of an aerogenic BCG vaccine in T-cell-depleted and normal mice.

Aerogenic infection of adult thymectomized, lethally irradiated, bone marrow-reconstituted (THXB) C57B1 times C3H F1 hybrid mice with 1 to 3,000 viable BCG Montreal was followed by an extended period of logarithmic growth to a maximum population of 5 times 10-6 bacilli by day 35. The infection spread to the liver, spleen, and bone marrow with extensive multiplication in all test organs before the growth curves abruptly entered a stationary phase. Up to 30% of the THXB mice eventually died as a result of the ongoing BCG infection. There was no sign of an antimicrobial immune response in the THXB mice analogous to that seen in the control animals beginning about day 30. The THXB mice developed considerable immediate but no delayed hypersensitivity to PPD. Intravenous challenge of the BCG-vaccinated THXB mice with 105 virulent Mycobacterium tuberculosis Erdman indicated that they were as susceptible to the tuberculous challenge as a group of unvaccinated controls. Visible surface lesions developed on the lung 90 days postinfection in the T-cell-depleted host with a sharp rise in counts to 175 per lobe on day 120 followed by a plateau for the remainder of the study. Control mice developed visible lesions about day 50, with 225 lesions per lobe by day 70 and a sharp decline to undetectable levels by day 90. The histopathology of these changes was examined carefully, together with the rate of cellular proliferation (tritiated thymidine uptake) by lung and spleen cells as the BCG infection progressed in the THXB mice. Peak uptake by both organs was depressed during the early stages of the BCG infection in the T-cell-depleted mice, but later the incorporation rates were significantly elevated above control values as the infection progressed.

Animals↗
PubMed1978

Protective effect of metronidazole in experimental ulcerative colitis.

Administration of carrageenan to guinea pigs produces colonic lesions which are similar to those noted in idiopathic ulcerative colitis of human beings. This model was used to determine fecal flora changes and response to antimicrobial probes during the evolution of carrageenan-induced colitis. The results of fecal flora analysis showed that mean coliform concentrations increased from 10(2.7) to 10(7.4) per g during the initial stages of colonic ulceration. Pretreatment of carrageenan recipients with antimicrobials directed against coliforms reduced the concentrations of these organisms, but failed to attenuate the disease process. On the other hand, pretreatment with metronidazole, an antimicrobial primarily active against anaerobic bacteria, prevented carrageenan-induced colitis in a majority of animals. Delayed treatment with metronidazole until after colitis was established showed no salutory benefits. These results suggest that anaerobic bacteria play a role in the initial events of carrageenan-induced colitis in the guinea pig model.

Animals↗
PubMed1977

Clinical conditions associated with defective polymorphonuclear leukocyte chemotaxis.

Impressive numbers of clinical conditions are associated with defective leukocyte chemotaxis. In many, this cellular dysfunction is associated with other abnormalities of the immune response, but in others abnormal chemotactic responsiveness of leukocytes is the only abnormality of function identified in the laboratory. Patients are usually selected for study because of unusually severe, recurrent infections or poor response to antimicrobial agents, and therefore a frequent association between abnormality of chemotaxis and infection would be expected. Many patients demonstrate abnormal chemotaxis during remissions as well as during infections, and there seems little doubt that abnormality of chemotaxis is related to susceptibility to infections. Partial classification of disorders of chemotaxis was attempted. Major abnormalities are found when there is a primary cellular disorder or cell-directed inhibitors of chemotaxis are found. Less marked abnormalities are found when chemotactic factors are deficient.

Bacterial Infections↗
PubMed2025

Applications and benefits of the British Society for Antimicrobial Chemotherapy Resistance Surveillance Project-legacy and future.

The BSAC Resistance Surveillance Project ran from 1999 to 2019, amassing an unrivalled collection of almost 100 000 bacterial isolates from bloodstream and lower respiratory tract infections in the UK and Ireland. It was initiated in response to increasing antimicrobial resistance and supplemented existing surveillance schemes, enhancing the understanding of resistance epidemiology by estimating species prevalence within collection groups together with levels of antibacterial resistance, presented in terms of MICs and percentage susceptibility for each species/antibiotic combination tested. Generated data were explored to monitor and identify factors shaping resistance trends, and to profile antibacterial resistance patterns in specific geographies, settings and patient populations. The release of data and/or bacterial isolates led to a rich repository of published peer-reviewed papers. Additionally, the promotion of the BSAC standardized susceptibility testing method resulted in greater uniformity of antimicrobial susceptibility testing in hospital microbiology laboratories. Over time, public health laboratories' surveillance systems became increasingly comprehensive, and the BSAC Project ceased in 2019. This invaluable collection is now housed in the University of Dundee, in collaboration with the University of St Andrews. We highlight the collection's unique timeliness, and how the BSAC Project contributed to key interventions for infection prevention and control, public health and antimicrobial stewardship. We demonstrate the utility and benefits of the Project outlining the collection's future applications as an important bioresource. It comprises well-defined bacterial isolates-many now sequenced-with MIC data and demographic information. This legacy is available to researchers via the Tayside Biorepository and custodian contacts.

Humans↗
PubMed1977

Antimicrobial activity of amine oxides: mode of action and structure-activity correlation.

The effect of N-alkyl derivatives of saturated heterocyclic amine oxides on the growth and metabolism of microorganisms has been studied. 4-Dodecylmorpholine-N-oxide inhibited the differentiation and growth of Bacillus cereus, of different species of filamentous fungi, and of the yeast Saccharomyces cerevisiae. For vegetative cells, the effect of 4-dodecylmorpholine-N-oxide was lethal. Cells of S. cerevisiae, after interaction with 4-dodecylmorpholine-N-oxide, released intracellular K(+) and were unable to oxidize or ferment glucose. The functions of isolated yeast mitochondria were also impaired. 4-Dodecylmorpholine-N-oxide at growth-inhibiting concentrations induced rapid lysis of osmotically stabilized yeast protoplasts, with the rate of lysis a function of temperature and of amine oxide concentration. A study of the relationships between structure, antimicrobial activity, and cytolytic activity was made with a group of structurally different amine oxides involving a series of homologous 4-alkylmorpholine-N-oxides, 1-alkylpiperidine-N-oxides, 1-dodecylpyrrolidine-N-oxide, 1-dodecylperhydroasepine-N-oxide, and N,N-dimethyldodecylamine oxide. Disorganization of the membrane structure after interaction of cells with the tested amine oxides was primarily responsible for the antimicrobial activity of the amine oxides. This activity was found to be dependent on the chain length of the hydrophobic alkyl group and was only moderately influenced by other substituents of the polarized N-oxide group.

Amines↗
PubMed1976

Effect of biotin deficiency on some properties of Staphylococcus aureus isolates from humans and other animals.

Staphylococcus aureus isolates from humans and other animals were grown in biotin assay medium containing 12 mug of biotin per liter and compared to isolates from the same sources grown concurrently in medium containing adequate biotin. The two cultures were tested for production of coagulase, phosphatase, and fibrinolysin enzymes and for responses to various antimicrobial agents and bacteriophages. Organisms grown in biotin-deficient medium produced less phosphatase; coagulase and fibrinolytic activity was reduced, and they were more susceptible to antimicrobial agents than were normal organisms, but phage susceptibility was not greatly affected.

Animals↗
PubMed2026

Beyond antibiotics: artificial intelligence-enabled anti-infective ecosystems for next-generation precision therapeutics against antimicrobial resistance.

The rapid global expansion of antimicrobial resistance (AMR) threatens to undermine decades of progress in infectious disease management and highlights the limitations of conventional antibiotic-centered therapeutic strategies. Although emerging technologies-including antimicrobial peptides, bacteriophage therapy, CRISPR-based antimicrobials, microbiome therapeutics, anti-virulence approaches, nanotechnology-enabled drug delivery, and artificial intelligence (AI)-have individually demonstrated considerable promise, they are predominantly being developed as independent interventions rather than as coordinated components of an integrated therapeutic strategy. This Perspective proposes the Intelligent Anti-Infective Ecosystem (IAIE) as a conceptual systems-level framework that computationally integrates multimodal diagnostics, pathogen genomics, microbiome profiling, AI-assisted decision support, programmable precision therapeutics, ecological monitoring, and longitudinal clinical feedback within a continuously learning dynamically optimized workflow. Unlike existing paradigms that primarily optimize individual technologies or therapeutic decisions, IAIE emphasizes closed-loop coordination among complementary antimicrobial approaches to support precision-guided infection management while preserving microbiome integrity and mitigating resistance selection pressure. We further outline the core components, operational principles, translational challenges, and technology readiness of the major therapeutic platforms that could contribute to such an ecosystem, while distinguishing clinically established interventions from emerging experimental strategies. Importantly, IAIE should be interpreted as a prospective conceptual architecture rather than an existing clinical platform. Its proposed clinical value remains to be established through sequential computational, preclinical, and prospective clinical investigations using standardized microbiological, ecological, and patient-centered outcome measures. By framing antimicrobial innovation within an responsive systems perspective, IAIE provides a roadmap for future multidisciplinary research aimed at integrating artificial intelligence and systems microbiology to enable sustainable management of antimicrobial resistance.

Humans↗
PubMed2025

Two decades of resistance surveillance by the British Society for Antimicrobial Chemotherapy: design, development, delivery, deficiencies and future directions.

The British Society for Antimicrobial Chemotherapy Antimicrobial Surveillance Project was established in the United Kingdom (UK) and Ireland in response to dissatisfaction with existing antimicrobial surveillance which, in the 1990s, was fragmented and poorly informative for clinical and public heath purposes. The model developed into an integrated Project that was novel in its management and financing, being a true collaboration between a medical charity, pharmaceutical companies and the laboratories contracted to perform the testing. Separate 'Programmes' within an overall 'Project' collected and tested community- and hospital-acquired respiratory and bloodstream infection isolates. Cooperation with public sector bodies allowed data collection from the Project to be compared to routinely collected data from National Health Service laboratories. Between 1999 and 2019 the Project delivered test results on almost 100 000 isolates, from 17 bacterial genera to 44 antimicrobial agents. The results were made available annually on a specially constructed web site. In this supplement, we summarize the data collected in a series of papers relevant to the two programmes, discussing the Project's strengths and deficiencies. Support for the Project declined in the period after 2010, and collection ceased after 20 years, its demise related to changing priorities within the partner organizations. However, the bacterial collection remains and is to be maintained to assist in future work in combating antimicrobial resistance.

United Kingdom↗