Infection and Immunity最新文献

{"title":"Outer membrane vesicles secreted by <i>Bacteroides fragilis</i> inhibit CFTR chloride secretion by human colon organoids.","authors":"Roxanna Barnaby, Amanda Nymon, Paige Salerno, Carolyn T Roche, Young Ah Goo, Byoung-Kyu Cho, Timothy B Gardner, Zdenek Svindrych, Douglas J Taatjes, Thomas H Hampton, Benjamin Ross, Bruce A Stanton","doi":"10.1128/iai.00129-26","DOIUrl":"10.1128/iai.00129-26","url":null,"abstract":"<p><p>The goals of this study were to develop a model to study host-pathogen interactions in primary human colon organoids and to test the hypothesis that <i>Bacteroides fragilis</i> toxin (BFT-2) secreted in outer membrane vesicles (OMVs) modulates mucosal immunity and CFTR Cl⁻ secretion. Since <i>Bacteroides</i> species reside in mucus, OMVs are likely to represent a mechanism of communication between <i>Bacteroides</i> and the host. Two strains of <i>Bacteroides</i> were studied: enterotoxigenic <i>Bacteroides fragilis</i> (ETBF), which produces BFT-2, and the non-toxigenic <i>Bacteroides fragilis</i> strain NCTC 9343 (NTBF), which does not produce BFT-2. We also utilized two additional strains of <i>Bacteroides fragilis</i>: one in which <i>bft</i>-2 was knocked out (ETBF Δ<i>bft</i>) and one that was engineered to contain <i>bft-2</i> (NTBF+<i>bft</i>). We report that <i>Bacteroides fragilis</i> OMVs reduced CFTR Cl⁻ secretion, but had no effect on tight junction or cell adhesion proteins, transepithelial resistance (TER), or cytokine secretion by primary human colon organoids. NTBF OMVs containing BFT-2 were more effective in reducing CFTR Cl<i>^-</i> secretion than NTBF lacking BFT-2. By contrast, deletion of <i>bft</i> in ETBF did not have a significant effect on CFTR Cl⁻ secretion compared to ETBF. We conclude that OMVs secreted by <i>Bacteroides</i> can be an important mechanism of host-pathogen interactions in the colon by reducing CFTR Cl⁻ secretion, and that the effect of BFT-2 on CFTR Cl⁻ secretion is dependent on the strain of <i>Bacteroides fragilis</i>.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0012926"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated multi-omics analysis uncovers cervicovaginal ecological networks and their association with <i>Chlamydia trachomatis</i> load.","authors":"Caleb M Ardizzone, John W Lammons, Renny S Lan, Jacob H Elnaggar, Rebecca A Lillis, Evelyn Toh, Lindsay M Pack, Patricia D Mott, Clayton D Jacobs, Laxmi Yeruva, Christopher M Taylor, Alison J Quayle","doi":"10.1128/iai.00681-25","DOIUrl":"10.1128/iai.00681-25","url":null,"abstract":"<p><p><i>Chlamydia trachomatis</i> (Ct) is a causal agent of upper reproductive tract pathology. There is a broad spectrum of cervical Ct load in infected women, and upper tract infection is associated with higher cervical Ct load. Recent studies indicate that bacterial vaginosis (BV) can modulate host-Ct outcomes. To identify features associated with BV status and Ct load, we performed an integrated multi-omics analysis of the cervicovaginal microbiome, tryptophan metabolome, and cytokines. Samples were analyzed using 16S rRNA gene sequencing, targeted UPLC-MS/MS quantification of tryptophan metabolites, and multiplex cytokine profiling. Ordination analyses showed that BV status was separated by the microbiome, metabolome, and cytokines, whereas Ct load was separated only by cytokines. K-means clustering of tryptophan metabolites defined three metabolome state types (MSTs). MST I, associated primarily with <i>Lactobacillus crispatus</i>-dominated community state type (CST) I, exhibited high tryptophan availability, indole-3-lactic acid, and complete kynurenine-pathway activity. Both MST II and MST III were associated with BV-associated CST IV and showed marked tryptophan depletion. MST II was broadly depleted of most tryptophan metabolites, while MST III was enriched in downstream microbially derived indole pathway metabolites and kynurenic acid. Hierarchical all-against-all association testing revealed coordinated relationships linking clusters of bacterial taxa, metabolites, and cytokines. Importantly, multi-omics network analyses identified integrated microbial-metabolic-immune modules that predicted high versus low Ct load, highlighting CXCL9, CXCL10, IL-17, BV-associated taxa, and indole pathway metabolites as key discriminative features. Results demonstrate that cervical Ct load reflects coordinated microbial-metabolic-immune ecological states rather than microbiome composition alone and refine current models of Ct-BV interactions.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0068125"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148224739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expansion of CD101⁻ neutrophils drives susceptibility to hyperyersiniabactin-producing <i>Yersinia</i> infection in hereditary hemochromatotic hosts.","authors":"Shreya Das, Saugata Majumder, Mohd Saqib, McKenzie Van der Veer, Bossardi Ramos Ramon, Akaki Tsilosani, Wenzheng Zhang, Qi Yang, Sridar V Chittur, Wei Sun","doi":"10.1128/iai.00691-25","DOIUrl":"10.1128/iai.00691-25","url":null,"abstract":"<p><p>Hereditary hemochromatosis (HH) increases susceptibility to bacterial infections. In our previous study, an oral <i>Yersinia pseudotuberculosis</i> Δ<i>fur</i> mutant (Δ<i>fur</i>) infection led to intestinal barrier disruption and acute mortality in HH (<i>Hfe^-/-</i>) mice. However, the systemic features of this fulminant infection are incompletely characterized. Here, HH mice infected with a hyperyersiniabactin-producing Δ<i>fur</i> rapidly develop sepsis symptoms, marked by an influx of immature CD101^- neutrophils with impaired bactericidal capacity and heightened inflammation, whereas infected wild-type mice harbor functional mature CD101⁺ neutrophils. This phenotype is partially recapitulated by the hyperyersiniabactin-producing clinical isolate, <i>Y. enterocolitica</i> WA strain. We further show that type I interferon (IFN-I) signaling impairs neutrophil bactericidal capacity, increasing bacterial burden, disrupting barrier disruption, and promoting emergency granulopoiesis, resulting in massive recruitment of CD101^- neutrophils in Δ<i>fur</i>-infected HH mice. Blocking IFN-I signaling restores neutrophil function, reduces bacterial loads, limits neutrophil recruitment, promotes a shift toward CD101⁺ neutrophils, preserves barrier integrity, mitigates hyperinflammation, and improves survival. These findings reveal that in HH mice infected with high-yersiniabactin producing <i>Yersinia</i> species, immature CD101^- neutrophils act as key mediators of sepsis, with IFN-I signaling as an essential regulator of this pathogenic response.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0069125"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148224701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of an isogenic <i>bimA</i> mutant in the ATS2021 strain of <i>Burkholderia pseudomallei</i>.","authors":"Christopher K Cote, Sherry Mou, Michael L Davies, Kevin D Mlynek, Christopher P Klimko, Sergei S Biryukov, Nathaniel O Rill, Jennifer L Dankmeyer, Taloria K Wheeler, Carlos I Rodriguez, Brian A Smith, Melissa Hunter, Elsie I Martinez, Christina E Douglas, Cheryl Taylor-Howell, Taalin S Hoj, Christopher P Stefan, Ju Qiu, Xiankun Zeng, Joel A Bozue, Nancy A Twenhafel, Charles J Shoemaker, David DeShazer","doi":"10.1128/iai.00727-25","DOIUrl":"10.1128/iai.00727-25","url":null,"abstract":"<p><p>Encephalomyelitis is uncommon but is associated with <i>Burkholderia pseudomallei</i> strains whose <i>bimA</i> gene, encoding an actin-based motility protein, resembles <i>bimA</i> from <i>Burkholderia mallei</i> (designated <i>bimA_Bm</i>). We previously characterized the virulence of <i>B. pseudomallei</i> wild-type ATS2021 (<i>bimA_Bm</i>). In a mouse model of ATS2021 aerosol exposure, lesions and inflammatory cytokines in the brain were seen early post-exposure and reached the central nervous system (CNS) through the olfactory nerve. In the current study, the <i>bimA</i> allele in the wild-type ATS2021 was replaced with the <i>bimA_Bp</i>, and virulence was assessed by estimations of LD₅₀, histopathological analyses, and bacterial dissemination. ATS2021 <i>bimA_Bp</i> reached the CNS but was significantly attenuated, with higher LD₅₀ estimates, altered bacterial dissemination, and reduced neuroinflammation. The immune response in lungs, spleens, and brains from mice exposed to aerosols indicated either strain induced shared and divergent immune patterns. Finally, the evaluation of the host response in brains via NanoString transcriptomic platform analyses suggested that the wild-type ATS2021 induced substantial changes in astrocyte and microglial activation, oligodendrocyte function, and overall inflammatory signaling, compared to the mutant <i>bimA_Bp</i> bacteria. These results support a direct role of the <i>bimA_Bm</i> gene product for bacterial dissemination after inhalation.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0072725"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic and genotypic analysis of <i>Candida albicans</i> vaginal isolates reveals that <i>ECE1</i> expression underpins pathogenicity.","authors":"Amirhossein Davari, Junyan Liu, Jabez P Fortwendel, Arturo Luna-Tapia, David J Lowes, Jian Miao, Hubertine M E Willems, Christian A DeJarnette, Tracy L Peters, Nasim Ahmadi, Surabhi Naik, Marc Swidergall, P David Rogers, Jack D Sobel, Glen E Palmer, Brian M Peters","doi":"10.1128/iai.00304-26","DOIUrl":"10.1128/iai.00304-26","url":null,"abstract":"<p><p><i>Candida albicans</i> is the leading cause of vulvovaginal candidiasis (VVC), yet the extent to which strain-level variation influences pathogenic mechanisms remains unclear. Candidalysin, a peptide toxin encoded by <i>ECE1</i>, is a key driver of epithelial damage and immunopathology, but its role has been largely defined in a limited number of laboratory strains. Here, we analyzed a panel of 27 vaginal clinical isolates obtained from asymptomatic, acute VVC, and recurrent VVC (RVVC) subjects and performed whole-genome sequencing and broad phenotypic profiling, including growth, biofilm formation, stressor and antifungal susceptibility, filamentation, and <i>ECE1</i> expression. To directly assess the role of candidalysin, <i>ece1</i>Δ/Δ mutant pairs were generated for each isolate and evaluated <i>in vitro</i> and in a murine model of VVC. Isolates exhibited substantial, context-dependent phenotypic heterogeneity, and pathogenic traits did not cluster according to clinical classification. Despite this diversity, deletion of <i>ECE1</i> universally reduced epithelial damage and inflammatory responses <i>in vitro</i> and attenuated immunopathological markers <i>in vivo</i>. Notably, the reference strain SC5314 displayed enhanced virulence compared to most clinical isolates, further demonstrating that it represents a hypervirulent outlier. Collectively, these findings demonstrate that the virulence determinant candidalysin operates across a highly heterogeneous population of vaginal clinical isolates, and its expression is positively correlated to pathogenicity. These studies further highlight the importance of delineating virulence attributes beyond the lens of SC5314.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0030426"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Staphylococcus aureus</i> pore-forming toxins differentially shape disease severity in experimental endophthalmitis.","authors":"Luis Longoria-Gonzalez, Van Le, Aaron C Parrot, Phillip S Coburn, Roger Astley, Michelle C Callegan","doi":"10.1128/iai.00168-26","DOIUrl":"10.1128/iai.00168-26","url":null,"abstract":"<p><p>Ocular infections caused by <i>Staphylococcus aureus</i> result in poor visual outcomes due to the expression of numerous virulence factors during infection. We hypothesized that pore-forming toxins (PFTs) contribute to the pathogenesis of <i>S. aureus</i> endophthalmitis, a severe intraocular infection that can result in blindness. We analyzed infection outcomes using wild-type (LAC), PFT-null (LAC ΔΔΔΔΔ), leukocidin-null (LAC Δ<i>leukocidin</i>), or alpha toxin-deficient (LAC Δ<i>hla</i>) mutants. These strains exhibited no differences in growth in brain heart infusion (BHI) and explanted rabbit vitreous. The expression of PFT genes was detected in both environments, but transcript levels were less in vitreous relative to that of BHI. Experimental endophthalmitis was induced in C57BL6/J mice by intravitreal injections of 5,000 colony-forming units (CFU) of <i>S. aureus</i> LAC or one of its three mutants. To quantify infection severity, eyes were analyzed for retinal function, intraocular CFU, inflammation via myeloperoxidase (MPO), cytokines and chemokines, neutrophil infiltration, alpha toxin production, and gross pathology via histology and slit-lamp imaging. Infections with LAC ΔΔΔΔΔ or LAC Δ<i>hla</i> resulted in improved retinal function, reduced intraocular CFUs, decreased ocular damage, and a trend toward decreased inflammation compared to infections with LAC. In contrast, infections with LAC Δ<i>leukocidin</i> progressed similarly as infections with LAC. Increasing concentrations of alpha toxin were detected over time in the eyes infected with LAC and LAC Δ<i>leukocidin</i>; 40%-60% of infiltrating neutrophils were ADAM10⁺, identifying these cells as potential targets for alpha toxin. Collectively, these results suggest that alpha toxin may be the main PFT driving the severity of <i>S. aureus</i> endophthalmitis.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0016826"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individual contributions of exotoxins S and T on internalized <i>P. aeruginosa</i>.","authors":"Zachary J Resko, Adam V Thota, Christopher J Corcoran, David G Glanville, Seby Edassery, Keith A Klein, Jonathan P Allen, Jonathan A Kirk, Andrew T Ulijasz, Abby R Kroken","doi":"10.1128/iai.00267-26","DOIUrl":"10.1128/iai.00267-26","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is a high-priority pathogen and significant burden to health care worldwide. Although often regarded as an extracellular pathogen, <i>P. aeruginosa</i> is also capable of existing intracellularly in multiple cell types, including epithelial cells, goblet cells, and macrophages. This designation is attributed to two of its type three secretion system (T3SS)-dependent exotoxins, ExoS and ExoT, which inactivate host proteins that facilitate phagocytosis. However, studies investigating intracellular bacteria show that ExoS can paradoxically facilitate survival and replication, seemingly overriding the anti-internalization properties of itself and ExoT through its ADP-ribosylation activity. Here, we set out to define the individual and combined contributions of ExoS and ExoT by examining how each of their two functional domain activities affects epithelial cell invasion. Through <i>in vitro</i> biochemical assays, we found that ExoS is capable of ADP-ribosylating ExoT and their shared human cofactor, 14-3-3. We also found that ExoT ADP-ribosylates itself, unexpectedly enhancing its GTPase-activating protein (GAP) activity. Using fluorescence microscopy, we found that GAP activity of either exotoxin does not block internalization events, but is instead associated with fewer internalized bacteria entering a phase of rapid cytoplasmic replication. We demonstrate that ExoS ADP-ribosyltransferase activity is positively associated with vacuolar exit and cytoplasmic replication, and delivery of ExoS from extracellular bacteria triggers the intracellular T3SS⁻ subpopulation to become T3SS⁺ and exit the vacuole. Overall, this study highlights the underappreciated ability of <i>P. aeruginosa</i> to become intracellular and delineates how the enzymatic domains of ExoS and ExoT dictate the intracellular localization of the pathogen.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0026726"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased low-molecular-weight mucins in muco-obstructive airway disease limit <i>Staphylococcus aureus</i> growth.","authors":"Caitlyn C Sebastian, RaNashia Boone, Susan E Birket, Megan R Kiedrowski","doi":"10.1128/iai.00693-25","DOIUrl":"10.1128/iai.00693-25","url":null,"abstract":"<p><p>Muco-obstructive airway diseases result in an increase in mucus accumulation and a decrease in mucus clearance. MUC5B is the most abundant secreted mucin in the human airways, and MUC5B mucin strands dimerize to create the mucus mesh network in the healthy respiratory tract. In muco-obstructive airway diseases like cystic fibrosis (CF), immune cells and bacteria release enzymes that degrade MUC5B into smaller fragments that become entangled and compacted, contributing to pathogenesis. We utilized synthetic cystic fibrosis sputum media (SCFM) to examine how mucin polymers can impact <i>Staphylococcus aureus</i>, a common CF pathogen that persists despite highly effective modulator therapies to correct CF disease. We found that low-molecular-weight (LMW) mucin negatively impacts <i>S. aureus</i> survival and biofilm biomass compared to high-molecular-weight (HMW) mucin. Adding extracellular DNA to SCFM with LMW mucin was not sufficient to restore growth. LMW mucin had a broad negative impact on <i>S. aureus</i> laboratory strains and CF clinical isolates. We next tested other CF pathogens, including <i>Pseudomonas aeruginosa</i> and nontypeable <i>Haemophilus influenzae</i>, and saw no significant differences in growth in HMW or LMW mucin. LMW mucin did not significantly impact <i>Staphylococcus epidermidis</i> growth, indicating that there may be specific interactions with <i>S. aureus</i>. Overall, this work highlights how interactions with pathogenic mucins may limit <i>S. aureus</i> growth in the diseased airways while supporting low-level persistence, and its ability to thrive in the presence of longer mucin strands may help explain why <i>S. aureus</i> is well adapted to survive in the healthy respiratory tract.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0069325"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148156020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C4BP occludes the non-opsonic interaction of <i>Neisseria gonorrhoeae</i> with human neutrophil CEACAMs.","authors":"Mary W Broden, Jutamas Shaughnessy, Frida Mohlin, Amaris J Cardenas, Anna M Blom, Sanjay Ram, Alison K Criss","doi":"10.1128/iai.00176-26","DOIUrl":"10.1128/iai.00176-26","url":null,"abstract":"<p><p><i>Neisseria gonorrhoeae</i> (Gc) causes the sexually transmitted infection gonorrhea, an urgent public health concern. Gc infection elicits a robust neutrophil response and serum leakage, but Gc has developed specialized defenses to evade both complement and neutrophils. We recently reported that the classical complement pathway inhibitor C4b-binding protein (C4BP) binds to Gc and reduces phagocytic killing by neutrophils in a complement-independent manner. Here, we used a Chinese hamster ovary (CHO) expression system and engineered C4BP constructs to define the underlying molecular mechanisms. C4BP inhibited interactions between opacity protein (Opa)-expressing Gc and carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), receptors that drive non-opsonic phagocytosis of Gc by neutrophils. The degree of C4BP-mediated inhibition varied among CEACAMs. By using wild-type and chimeric CEACAMs, we found that C4BP was more inhibitory toward the granulocyte-restricted CEACAM3 than the ubiquitously expressed CEACAM1, which we ascribed to CEACAM3's shorter extracellular domain. C4BP also inhibited the association between Opa-expressing Gc and the GPI-anchored CEACAM6. Molecules containing C4BP domains 1 and 2 fused to IgM (C4BP-IgM) or to a hexameric IgG Fc construct (C4BP-Hexa-IgG), proteins similar in diameter and degree of multimerization to native C4BP, inhibited the association of Opa-expressing Gc with CEACAM3-CHO cells to the same degree as C4BP, while Gc-binding C4BP domains fused to dimeric Fc (C4BP-IgG) did not. C4BP-IgM, but not C4BP-IgG bearing mutations to abrogate Fc gamma receptor interactions, blocked Opa-mediated phagocytosis by primary human neutrophils. These results support a model in which C4BP occludes Opa-CEACAM interactions, which protects Gc from phagocytic killing by neutrophils.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0017626"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148211094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the role of pyruvate dehydrogenase in <i>Listeria monocytogenes</i> virulence.","authors":"Matthew J Freeman, Noah J Eral, Abigail M Debrine, David M Stevenson, Daniel Amador-Noguez, John-Demian Sauer","doi":"10.1128/iai.00505-25","DOIUrl":"10.1128/iai.00505-25","url":null,"abstract":"<p><p>Bacterial pathogens must possess finely tuned physiological adaptations to adapt to their infectious niche. One such niche inhabited by <i>Listeria monocytogenes</i> (<i>L. monocytogenes</i>) is the host cell cytosol, a compartment characterized by significant barriers to entry, metabolic limitation, and immune surveillance. Previously, we identified <i>L. monocytogenes</i> transposon mutants defective for intracellular survival due to disruptions in key metabolic pathways, including cell wall biosynthesis, menaquinone production, and pyruvate metabolism. Here, we demonstrate that mutations in the pyruvate dehydrogenase (PDH) complex exhibit pronounced survival defects during infection, despite retaining robust growth and survival in nutrient-rich media. Metabolomic profiling of the PDH E2 subunit mutant revealed an altered respiro-fermentative metabolism with lower levels of both upper glycolytic intermediates and tricarboxylic acid cycle intermediates coupled with elevated levels of pyruvate and lactate. Additionally, we found that PDH mutants are unable to efficiently utilize phosphotransferase system (PTS)-dependent carbon sources, but their growth is indistinguishable from that of the wild type on non-PTS carbon sources such as hexose phosphates. A suppressor screen identified five suppressor mutants with restored ability to grow on the PTS substrate fructose, and each contained an independent mutation in the redox-sensing regulator <i>rex</i>. Loss of Rex function in PDH mutants partially restored intracellular growth, but not virulence <i>in vivo</i>. Together, these findings demonstrate that PDH is required for the import and metabolism of PTS-dependent carbon sources in the host cytosol and suggest that PDH-dependent redox balance and respiro-fermentative metabolism ultimately contribute to intracellular fitness and virulence.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0050525"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}