mBio最新文献

{"title":"12-Lipoxygenase (12-LOX) plays a key role in the hyperinflammatory response caused by SARS-CoV-2.","authors":"Melinee D'silva, Karen Jackson, Matthew T Vaughan, David J Maloney, Sachin A Gupte, Jerry L Nadler, Chandra Shekhar Bakshi","doi":"10.1128/mbio.00738-26","DOIUrl":"https://doi.org/10.1128/mbio.00738-26","url":null,"abstract":"<p><p>The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant global morbidity and mortality. The severe disease outcomes are often associated with a hyperinflammatory response known as a \"cytokine storm.\" The mechanisms underlying this exaggerated immune response remain incompletely understood. This study aimed to investigate the molecular pathways contributing to the severe inflammatory damage and mortality associated with COVID-19. SARS-CoV-2 hijacks host lipid metabolism, particularly the phospholipase A2 (PLA2) pathway, leading to the production of bioactive lipid mediators, including 12-lipoxygenase (12-LOX)-derived lipid mediators in platelets, and in lung and vascular cells. We hypothesized that 12-LOX drives the hyperinflammatory response and disease severity, and that its inhibition could reduce inflammation and improve outcomes. Analysis of autopsy lung samples from COVID-19 decedents and SARS-CoV-2-infected K18-hACE2 transgenic mice revealed increased 12-LOX expression. We evaluated VLX-1005, a selective small-molecule 12-LOX inhibitor, in infected mice. Treatment initiated 48 h post-infection significantly improved survival, reduced body weight loss, and decreased lung inflammation compared to controls. Notably, male mice showed higher survival rates than females. VLX-1005 treatment also suppressed key chemokines and cytokines associated with the cytokine storm, and reduced lung damage. These findings identify 12-LOX as a critical mediator of the hyperinflammatory response in severe COVID-19 and support its inhibition as a promising therapeutic strategy to mitigate inflammatory damage and reduce mortality.</p><p><strong>Importance: </strong>This study provides critical insights into the mechanisms underlying severe COVID-19, identifying 12-lipoxygenase (12-LOX) as a key driver of the hyperinflammatory response that contributes to disease severity and mortality. By demonstrating that SARS-CoV-2 hijacks host-lipid metabolism to elevate proinflammatory lipid mediators, the research uncovers a novel pathogenic pathway that exacerbates lung inflammation. The use of VLX-1005, a selective 12-LOX inhibitor, significantly improved survival and reduced inflammatory damage in a mouse model, highlighting its therapeutic potential. These findings not only deepen our understanding of COVID-19 pathogenesis but also position 12-LOX as a promising intervention target, offering a new avenue to mitigate the effects of cytokine storms in severe cases.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0073826"},"PeriodicalIF":4.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-utilization of viral polymerase: parainfluenza virus hijacks the RdRp of porcine sapelovirus to facilitate its replication during co-infection.","authors":"Jianing Chen, Shengyu Lin, Jiao Tang, Mengling Gao, Qianzi Liu, Jiawei Du, Chen Tan, Zhenli Gong, Libin Liang, Ting Zhu, Guangliang Liu","doi":"10.1128/mbio.03817-25","DOIUrl":"https://doi.org/10.1128/mbio.03817-25","url":null,"abstract":"<p><p>Parainfluenza virus is a significant respiratory pathogen affecting both humans and animals, capable of causing acute respiratory tract infections in infants and immunocompromised individuals. Recently, parainfluenza virus 5 (PIV5) has been frequently detected in swine diarrheal samples. However, experimental infections revealed that PIV5 alone induces only mild clinical symptoms. Further analysis suggested that co-infection with porcine sapelovirus (PSV) may underlie the observed disease severity. This hypothesis was confirmed through animal studies. Co-infection was shown to occur intracellularly, where PSV significantly enhanced PIV5 replication. Mechanistically, this effect was primarily mediated by PSV 3D, an RNA-dependent RNA polymerase (RdRp). PSV 3D directly interacted with PIV5 nucleoprotein and genomic RNA. Mini-genome assays demonstrated that PSV 3D substantially increased PIV5 genomic activity. Using an infectious cDNA clone of PIV5 and a series of mutants, we further confirmed that PSV 3D promoted transcription of both plus- and minus-strand PIV5 RNAs. Notably, RdRp (3D) proteins from two other picornaviruses also enhanced PIV5 RNA synthesis, suggesting a conserved function across picornaviruses. In summary, this study provides the first evidence that PIV5 hijacks the RdRp of a co-infecting virus from a different viral family to support its own replication. These findings advance our understanding of virus-virus interactions and offer a novel perspective in virology.</p><p><strong>Importance: </strong>The gastrointestinal tract harbors a vast and diverse community of microorganisms, making it an ideal environment for exploring microbial interactions. While virus-bacteria interactions have been widely studied, virus-virus interactions remain largely uncharacterized. In this study, we demonstrated that porcine sapelovirus (PSV) and parainfluenza virus 5 (PIV5) co-infect cells and directly interact within the host. Specifically, the RNA-dependent RNA polymerase protein (3D) of PSV significantly promoted PIV5 replication by interacting with key components of the PIV5 ribonucleoprotein complex and enhancing the synthesis of both plus- and minus-strand viral RNAs. Similar effects were observed with the 3D proteins from two additional picornaviruses, suggesting a shared mechanism among picornaviruses in facilitating co-infecting virus replication. This work uncovers a novel cross-family polymerase hijacking event and provides important insights into virus-virus interactions, highlighting new potential targets for the control and prevention of swine enteric diseases.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0381725"},"PeriodicalIF":4.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Injectisome assembly primes <i>Pseudomonas aeruginosa</i> for type III secretion.","authors":"Kristen Ramsey, Shoichi Tachiyama, Apolline Brossard, Zhao Hang, Jun Liu, Barbara I Kazmierczak","doi":"10.1128/mbio.00545-26","DOIUrl":"https://doi.org/10.1128/mbio.00545-26","url":null,"abstract":"<p><p>Many Gram-negative pathogens, including <i>Pseudomonas aeruginosa</i>, use a type III secretion system (T3SS) to intoxicate eukaryotic cells. The T3SS is an important virulence factor linked to increased morbidity and mortality in infections, yet its expression slows bacterial growth and activates innate immune receptors. T3SS genes are expressed heterogeneously, with T3SS-ON cells arising from \"primed\" bacteria that express the T3SS transcriptional activator ExsA and respond immediately to T3SS activating signals. However, the mechanistic basis for priming is not known. ExsA is part of a complex protein-sequestration network, positively regulating its own expression, as well as that of its anti-activator (ExsD), its anti-anti-activator (ExsC), and ExsC's binding partner (ExsE). These four proteins create a bistable regulatory network. We hypothesized that transcription from a cAMP-dependent promoter upstream of ExsA could drive cells into the primed state, and tested this at the single-cell level. Exogenous cAMP increased the proportion of primed, ExsA-expressing cells, with whole-cell cryo-electron tomography demonstrating the assembly of T3SS injectisomes under these conditions. Interstrain variation in endogenous cAMP levels correlated with strain-specific proportions of primed bacteria, while genetic manipulation of cAMP levels altered primed population size. This work demonstrates how endogenous and exogenous cAMP inputs into a bistable regulatory switch generate subpopulations of T3SS-primed cells poised to respond to activating signals.IMPORTANCEType III secretion systems (T3SS) are specialized protein secretion systems that allow bacteria to inject toxins into eukaryotic cells. T3SS are important virulence factors, but their expression carries a fitness cost: they slow bacterial growth and make bacteria vulnerable to detection by the innate immune system. Some pathogens, like <i>Pseudomonas aeruginosa,</i> balance the costs and benefits of T3SS expression by restricting T3SS expression to a subset of cells. T3SS-ON cells arise from \"primed\" bacteria that express the transcriptional activator ExsA and respond immediately to T3SS activating signals. However, the mechanistic basis for priming is unknown. In this study, we tested whether expression of ExsA from a cAMP-dependent promoter could drive cells into the primed state and found this to be true. Whole-cell cryo-electron tomography demonstrated that primed bacteria assembled T3SS injectisomes. This work demonstrates how cAMP inputs into a bistable regulatory switch generate subpopulations of T3SS-primed cells.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0054526"},"PeriodicalIF":4.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mice on a high-fat diet have reduced immunopathology and an altered immune response during respiratory syncytial virus infection.","authors":"Kendall T Whitt, Dorothea R Morris, Pamela H Brigleb, Lauren Rowland, Heather Sheppard, Stacey Schultz-Cherry","doi":"10.1128/mbio.00689-26","DOIUrl":"https://doi.org/10.1128/mbio.00689-26","url":null,"abstract":"<p><p>Obesity has been identified as an independent risk factor for increased morbidity and mortality during pandemic H1N1 influenza and SARS-CoV-2 infections. Various studies have determined that obese hosts have dysregulated antiviral responses driven by systemic low-grade inflammation, resulting in prolonged viral replication, induction of proinflammatory cytokines during the disease resolution phase, and profound lung parenchymal damage. However, the impact of obesity on disease outcomes in the context of other viral respiratory infections remains unclear. In this study, we sought to understand how obesity affects disease progression during respiratory syncytial virus (RSV) infection using an obese mouse model in which male C57BL/6 mice were fed a high-fat diet (HFD). Mice fed a standard chow diet served as controls. We found that HFD mice exhibited reduced weight loss, illness scores, and histopathological changes after intranasal inoculation with RSV A2. Investigation of potential mechanisms underlying this reduction in severity revealed reduced viral load in obese mice, along with altered innate and adaptive immune responses. Specifically, HFD mice had reduced proinflammatory cytokines in the lungs early in infection and increased CD4⁺ T cells late in infection. HFD mice also had reduced M2 macrophages in the lungs at 7 days post-infection. Notably, HFD mice infected with RSV did not exhibit aberrant proinflammatory cytokine secretion late in infection, as seen with influenza, likely due to effective viral control. In conclusion, HFD mice exhibited reduced disease severity during RSV infection, associated with decreased viral load and an attenuated but sufficient antiviral response.</p><p><strong>Importance: </strong>Obesity has been shown to induce dysregulated antiviral responses during influenza infections, resulting in extensive morbidity and mortality. No studies to date have investigated how obesity-induced immune dysregulation affects respiratory syncytial virus (RSV) disease progression. RSV has a high global burden, inflicting millions of infections and tens of thousands of deaths yearly, most notably among the very young, the elderly, and those with comorbidities. It is essential to understand how risk factors, such as obesity, affect disease progression to ensure appropriate protection and care for patients. Here, we demonstrate that male C57BL/6 mice fed a high-fat diet had lower viral loads and attenuated inflammatory responses during RSV infection, resulting in reduced morbidity and immunopathology. This pilot study advances our understanding of how obesity affects pulmonary antiviral immunity to RSV and, concurrently, further elucidates RSV pathogenesis.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0068926"},"PeriodicalIF":4.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired envelope integrity in the absence of SanA is linked to increased lipid II availability and an imbalance of septal peptidoglycan synthesis.","authors":"Joseph F Carr, Carolina Basurto De Santiago, Shivani A Bhut, Daniel J Warzecha, Sarah A Vastani, Robert Wei, Carmen M Herrera, M Stephen Trent, Beiyan Nan, Angela M Mitchell","doi":"10.1128/mbio.00635-26","DOIUrl":"10.1128/mbio.00635-26","url":null,"abstract":"<p><p>In gram-negative bacteria, the outer membrane (OM) acts in conjunction with the peptidoglycan (PG) cell wall as a barrier against physical, osmotic, and chemical environmental stressors, including antibiotics. SanA, an inner membrane protein in <i>Escherichia coli</i> K-12, is required for vancomycin resistance at high temperatures (>42°C) and impacts sodium dodecyl sulfate (SDS) resistance during the stationary phase reached from carbon limitation. However, its function remains unknown. Here, we show that Δ<i>sanA</i> has a synthetic genetic interaction with Δ<i>wecA</i>, a mutation that increases the availability of the isoprenoid carrier for PG synthesis. Specifically, the Δ<i>sanA</i> Δ<i>wecA</i> strain demonstrated heightened SDS-EDTA sensitivity, activation of the Rcs stress response, and increased cell length. Further investigation tied the SDS-EDTA sensitivity to increased lipid II available for PG synthesis. Spontaneous suppressor mutants of this phenotype harbored point mutations in <i>prc</i>, which encodes tail-specific protease, or <i>ftsI</i>, which encodes the cell division DD-transpeptidase, a target of Prc. We focused on the <i>ftsI</i> mutations and demonstrated that the <i>ftsI</i> mutations increased cell length but nevertheless enhanced PG incorporation at the septum compared to the Δ<i>sanA</i> mutant, returning PG incorporation to wild-type levels. Moreover, other mutations affecting septal PG synthesis, but not divisome assembly, also suppressed the SDS-EDTA sensitivity. These findings suggest that in the absence of SanA, increased lipid II availability perturbs the balance between septal PG synthesis, lateral PG elongation, and other envelope biogenesis pathways, leading to increased OM permeability.IMPORTANCEThe gram-negative cell envelope is a barrier that protects the cell from environmental stress. Therefore, the synthesis of each layer of this envelope needs to be closely coordinated throughout growth and division. Here, we investigated SanA, a protein in <i>Escherichia coli</i> K-12 that affects envelope permeability under cellular stress, including nutrient limitation and high temperature. We found that SanA plays a key role in maintaining the permeability barrier when precursor levels for peptidoglycan (PG) synthesis are elevated, linking envelope integrity to balanced septal PG production during cell division. Our results suggest that SanA modulates substrate availability to preserve envelope function, and that in its absence, imbalanced substrate flux to septal PG synthesis disrupts septum formation and compromises barrier integrity.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0063526"},"PeriodicalIF":4.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Guild Model of CF Airway Microbial Ecology.","authors":"Sage J B Dunham, Gregory A Willkeen, Ben Darby, Jodi M Corley, Andrea Hahn, Isaac Klapper, Heather D Bean, Lindsay J Caverly, Christina S Thornton, Christian Martin, Robert A Quinn, Stefanie Widder, Barbara A Bailey, Brandie D Wagner, Neha Garg, Paul J Planet, Ryan C Hunter, John J LiPuma, Forest Rohwer, Katrine L Whiteson","doi":"10.1128/mbio.03668-25","DOIUrl":"10.1128/mbio.03668-25","url":null,"abstract":"<p><p>Ecological guilds are groups of organisms that utilize the same class of resources and occupy similar niches, regardless of their taxonomic identities. Here we propose the Guild Model for Cystic Fibrosis Airway Microbial Ecology, which considers the ecological function and wider role of each microbe in the ecosystem. This model consists of four functional guilds: (i) \"Brewers\" metabolize host-derived substrates (e.g., mucins) and produce fermentation products; (ii) \"Drunkards\" exploit the metabolic niche built by Brewers, consuming fermentation products and secreting exopolysaccharides to build biofilms; (iii) \"Putrifiers\" produce toxic compounds causing inflammation and tissue necrosis; and (iv) \"Nihilists\" are specialist pathogens characterized by intracellular or lytic life cycles and cytotoxin production. By focusing on microbial function and the broader community context, this model offers a refined framework for interpreting cystic fibrosis airway ecology. Although developed for CF, the Guild Model is adaptable to other diseases influenced by microbial ecology.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0366825"},"PeriodicalIF":4.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plant litter chemistry and associated changes in microbial decomposition under drought.","authors":"Brian Chung, Shi Wang, Zhao Hao, Steven D Allison, Ashish A Malik","doi":"10.1128/mbio.00438-26","DOIUrl":"https://doi.org/10.1128/mbio.00438-26","url":null,"abstract":"<p><p>Drought has consequences for microbial decomposition rates, including indirect effects through changes in plant litter chemistry. Here, we studied the impact of a decade-long drought on plant litter chemistry and microbial decomposition traits in a semi-arid ecosystem during an 18-month litter bag experiment. We investigated litter sourced from four conditions: grass and shrub vegetation under ambient and reduced precipitation. We hypothesized that litter chemistry drives microbial decomposition capabilities and enzyme activity due to vegetation differences and drought effects on litter chemistry. We found that carbohydrate-rich grass litter had a higher abundance of decomposition genes detected using metagenomics and enzyme activity than more recalcitrant shrub litter, which was richer in lignin and lipids; these patterns were related to substrate supply. Drought decreased some carbohydrate fractions in grass litter but did not change the lignin fraction in grass and shrub litter, suggesting that drought does not make litter more recalcitrant. Most decomposition genes and enzyme activities were not significantly affected by drought, thereby maintaining decomposition rates. Microbial community succession patterns-decreasing fungal abundance and increasing bacterial abundance with time-corresponded with decreasing chitin gene abundance and increasing peptidoglycan gene abundance over time, indicating microbial necromass recycling. We demonstrate minimal litter chemistry-mediated effects of drought but show significant changes in community composition and their decomposition capabilities over time, highlighting that complex microbial-chemical interactions under climate change can influence ecosystem-scale processes.</p><p><strong>Importance: </strong>Climate change is causing more severe and frequent droughts in semi-arid ecosystems, affecting soil microbes breaking down plant litter. Our research focuses on understanding the less studied pathway of drought impact on microbes via changes in plant litter chemistry. Drought can alter the plant litter chemistry by changing the composition and physiology of plants, which can alter microbial decomposition and ecosystem-level carbon cycling. We investigated litter decomposition traits of microbial communities in grass and shrub litter under long-term drought. There were significant changes in litter chemistry under drought but no increase in lignin fraction. Despite this, microbial communities maintained their decomposition capabilities under drought, highlighting the ability of microbes to adapt and continue functioning. We also demonstrate unique microbial community succession patterns and dead biomass recycling, which can have implications for carbon cycling rates in the ecosystem. This study sheds light on the complex microbial interactions that affect ecosystem functioning under climate change.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0043826"},"PeriodicalIF":4.7,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A protein-protein interaction inhibitor arrests the cell cycle in <i>Aspergillus fumigatus</i>.","authors":"I S R Storer, B P Thornton, A S Hackett, L Tabernero, M J Bromley","doi":"10.1128/mbio.03563-25","DOIUrl":"https://doi.org/10.1128/mbio.03563-25","url":null,"abstract":"<p><p>Invasive infections caused by <i>Aspergillus fumigatus</i> have high mortality rates, even when treated with the first-line agent voriconazole. The global emergence of azole resistance further increases treatment failure, underscoring the urgent need for antifungals with novel mechanisms of action. The fungal cell cycle is essential for viability and represents an attractive but underexplored target. In <i>A. fumigatus</i>, progression from G2 to M phase requires interaction between the phosphatase NimT and cyclin-dependent kinase NimX. Here, we characterize the role of this interaction and its inhibition by 2-fluoro-4-hydroxybenzonitrile (compound 1), a small molecule that targets the human Cdc25B-Cdk2 interface. Using mutagenesis, we show that NimT residues Arg438 and Arg442 are critical for NimT-NimX binding and confirm they are essential for viability. A co-immunoprecipitation assay demonstrates that compound 1 disrupts the interaction, while live-cell imaging shows that this inhibition arrests cell cycle progression. Our findings provide mechanistic insight into fungal mitosis and highlight cell cycle regulators as promising antifungal drug targets.IMPORTANCEInvasive aspergillosis has high mortality and limited treatment options, threatened by rising drug resistance. Targeting the fungal cell cycle represents an unexplored strategy for antifungal drug development. The dynamic interaction between NimT and NimX is critical to the fungal duplication cycle. Here, we show evidence that, unlike in <i>Schizosaccharomyces pombe</i>, relocation of NimT from the nucleus to the cytoplasm mid-interphase is the switching event that causes activation of NimX and allows the cell cycle to progress. We also show that disruption of the NimT-NimX interaction can be achieved using a reversible small-molecule inhibitor that arrests the fungal duplication cycle, highlighting mitotic regulators as promising antifungal drug targets.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0356325"},"PeriodicalIF":4.7,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vancomycin disrupts mitochondrial morphology and function and impairs macrophage fungal killing.","authors":"Ebrima Bojang, Lozan Sheriff, Emma Morris, Sophie Rouvray, Man Shun Fu, Chloe Wellings, Ketema Abdissa, Victoria Stavrou, Callum Clark, Andrew D Southam, Warwick B Dunn, David Bending, Jose R Hombrebueno, Ilse Jacobsen, Sarah Dimeloe, Rebecca A Hall, Rebecca A Drummond","doi":"10.1128/mbio.00580-26","DOIUrl":"https://doi.org/10.1128/mbio.00580-26","url":null,"abstract":"<p><p>Vancomycin is a widely prescribed antibiotic used in the treatment of gram-positive bacterial infections. We previously showed that this antibiotic disrupted protective antifungal immune responses via microbiome dysbiosis, enhancing susceptibility to invasive candidiasis. Antibiotics are an independent risk factor for developing this life-threatening fungal infection, but whether microbiota-independent mechanisms also drive this association is not clear. Here, we show that vancomycin directly impairs macrophage responses to <i>Candida albicans</i>, the main causative agent of invasive candidiasis. Vancomycin-treated macrophages were less able to kill <i>C. albicans</i> despite normal phagocytosis rates and were hyper-inflammatory and more likely to die during infection. Using a fluorescently labeled vancomycin, we observed vancomycin uptake by macrophages <i>in vivo</i> and within close proximity to the mitochondrial outer membrane. Vancomycin treatment led to a significant depolarization, reduced respiratory capacity, and a hyper-fragmented morphology of mitochondria, as well as increased cellular ROS production. Taken together, this work demonstrates direct effects of vancomycin on mammalian immune cells, helping us to understand the pro-inflammatory effects of this drug and how it promotes susceptibility to life-threatening fungal infection.IMPORTANCEAntibiotics are widely prescribed drugs used to treat bacterial infections; however, their use may increase the likelihood of developing life-threatening fungal infections in vulnerable patients. <i>Candida albicans</i> is a commensal fungus in humans but may cause serious disease in patients with defined risk factors, including antibiotic exposure. We find that the antibiotic vancomycin significantly impairs the ability of macrophages to kill <i>C. albicans</i> yeast. Vancomycin-induced defects in fungal killing were associated with changes to mitochondria in antibiotic-exposed macrophages, which also exhibited enhanced oxidative stress and reduced survival during fungal infection. This work identifies a direct mechanism by which antibiotics may impair antifungal immunity.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0058026"},"PeriodicalIF":4.7,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Akkermansia muciniphila</i> impacts group B <i>Streptococcus</i> vaginal colonization.","authors":"Stephanie M Marroquin, Shirli Cohen, Melody N Neely, Kelly S Doran","doi":"10.1128/mbio.02868-25","DOIUrl":"10.1128/mbio.02868-25","url":null,"abstract":"<p><p><i>Streptococcus agalactiae,</i> or group B <i>Streptococcus</i> (GBS), is an opportunistic pathogen that asymptomatically colonizes the vaginal tract of up to 30% of healthy individuals. However, during pregnancy, it is associated with adverse pregnancy outcomes, and GBS can be transmitted to the fetus <i>in utero</i> or the newborn during vaginal birth, resulting in invasive neonatal disease. Previously, we identified that <i>Akkermansia muciniphila</i> increases GBS vaginal persistence in a cohort of human vaginal microbiome samples collected throughout pregnancy and promotes GBS vaginal colonization in a murine model. However, the mechanisms responsible for these observations are unknown. Here, we analyze additional vaginal shotgun metagenomic data sets and show that across independent studies with diverse populations, <i>A. muciniphila</i>-positive samples had higher GBS abundance. We determined that <i>A. muciniphila</i> aggregates with human vaginal isolates of GBS across all serotypes and promotes GBS attachment to human vaginal epithelial cells (hVECs). RNA-sequencing analysis reveals that <i>A. muciniphila</i> changed the expression of 281 unique GBS genes during hVEC co-colonization, many of which are involved in cell wall/membrane/envelope biogenesis. We demonstrate the importance of the GBS capsule and pili for direct interaction with <i>A. muciniphila</i> and increased attachment to hVECs, respectively. Lastly, we found that <i>A. muciniphila</i> promoted GBS aggregation in the murine vaginal lumen and that continual treatment with <i>A. muciniphila</i> reduced GBS vaginal persistence. Our results provide mechanistic insights and further evidence of the impact of <i>A. muciniphila</i> on GBS vaginal colonization and also demonstrate a beneficial potential of <i>A. muciniphila</i> treatment in the vaginal environment.IMPORTANCEGroup B <i>Streptococcus</i> (GBS) is a frequent colonizer of the vaginal tract of healthy people; however, during pregnancy, maternal colonization is associated with adverse pregnancy outcomes. GBS is a leading cause of neonatal sepsis and meningitis, with transmission to neonates occurring either during vaginal delivery or through ascension into the uterus during pregnancy. The influence of the vaginal microbiota on GBS pathogenesis remains greatly underappreciated. We have found that GBS is associated with the mucin-degrading intestinal commensal <i>Akkermansia muciniphila</i>, a newly identified colonizer of the vaginal tract. Our research identifies the mechanistic impact of this commensal organism on GBS aggregation, cell adherence, and gene expression, as well as its therapeutic potential during GBS vaginal colonization. Unraveling relationships between GBS and the vaginal microbiota will improve maternal-fetal health and may facilitate the development of alternative methods to reduce GBS <i>in utero</i> complications and neonatal disease.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0286825"},"PeriodicalIF":4.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}