mSphere最新文献

{"title":"<i>Mycobacterium tuberculosis</i> bacillus induces pyroptosis in human lung fibroblasts.","authors":"Takemasa Takii, Hiroyuki Yamada, Chihiro Motozono, Sho Yamasaki, Jordi B Torrelles, Joanne Turner, Aoi Kimishima, Yukihiro Asami, Naoya Ohara, Shigeaki Hida, Hidetoshi Hayashi, Kikuo Onozaki","doi":"10.1128/msphere.00110-25","DOIUrl":"10.1128/msphere.00110-25","url":null,"abstract":"<p><p>We previously reported that live, but not dead, virulent <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) H37Rv bacilli induce cell death in human lung fibroblast cell lines, MRC-5, MRC-9, and TIG-1. Here, using two distinct <i>Mtb</i> strains from two different lineages (HN878 lineage 2 and H37Rv lineage 4), we confirmed cell death at day 2 after infection with a device that measures cell growth/cytotoxicity in real time (Maestro-Z [AXION]). <i>Mtb</i> bacilli uptake by the fibroblast was confirmed with a transmission electron microscope on day 2. Expressions of inflammatory cytokines and interleukin (IL)-1β, IL-6, and IL-8 were observed when exposed to live, but not dead bacteria. The cell death of fibroblasts induced by both <i>Mtb</i> strains tested was prevented by caspase-1/4 and NLRP3 inflammasome inhibitors, but not by caspase-3 and caspase-9 inhibitors. Therefore, we classified the fibroblast cell death by <i>Mtb</i> infection as pyroptosis. To investigate the biological and pathological relevance of fibroblast cell death by <i>Mtb</i> infection, we performed dual RNA-Seq analysis on <i>Mtb</i> within fibroblasts and <i>Mtb</i>-infected fibroblasts at day 2. In <i>Mtb</i> bacilli <i>tcrR</i>, <i>secE2</i>, <i>ahpD</i>, and <i>mazF8</i> genes were highly induced during infection. These genes play roles in survival in a hypoxic environment, production of a calcium-binding protein-inducing cytokine, and regulation of transcription in a toxin-antitoxin system. The gene expressions of IL-1β, IL-6, and IL-8, caspase-4, and NLRP3, but not of caspase-3 and caspase-9, were augmented in <i>Mtb</i> bacilli-infected fibroblasts. Taken together, our study suggests that <i>Mtb</i> bacilli attempt to survive in lung fibroblasts and that pyroptosis of the host fibroblasts activates the immune system against the infection.</p><p><strong>Importance: </strong>The role of \"non-classical immune cells,\" that is, fibroblasts, epithelial cells, adipocytes, etc., except for the \"classical immune cells,\" that is, macrophages and lymphoid cells, is not well known in the infection of Mtb bacilli. We have previously found that live, but not dead, Mtb bacilli induce cell death in human lung fibroblasts, except in human macrophages and monocytes. The present study reveals that fibroblasts ingest Mtb bacilli the same as macrophages and that <i>in vivo</i> Mtb bacilli within fibroblasts attempt to survive in the host cells, and pyroptosis, including the production of inflammatory cytokines, is induced in the Mtb-infected fibroblasts. Our results suggest that pyroptosis of the host fibroblasts activates the immune system against the infection.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0011025"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple perinatal characteristics affect the association between maternal diabetes status and early neonatal gut microbiota.","authors":"Cheng Liu, Wei Zheng, Jia Wang, Xianxian Yuan, Yuan Zhang, Yuanyuan Wang, Xu Ma, Guanghui Li","doi":"10.1128/msphere.00914-24","DOIUrl":"10.1128/msphere.00914-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Increasing evidence has suggested that maternal gestational diabetes mellitus (GDM) can influence the neonatal gut microbiota. However, the initial microbial colonization of neonates is still unclear. The discrepancy in results between studies may be due to many other prenatal characteristics. This study aimed to investigate whether perinatal characteristics affect the association between maternal GDM status and early neonatal gut microbiota. This nested case-control study was based on a cohort of mothers and children (2016YFC1000304). Meconium samples were collected from neonates of mothers with (&lt;i&gt;n&lt;/i&gt; = 114) and without GDM (&lt;i&gt;n&lt;/i&gt; = 133) within 24 h after birth, and then assessed via 16S rRNA gene amplicon sequencing. Differences in the diversity and composition of the neonatal gut microbiota were compared according to maternal GDM status and other perinatal characteristics. The gut microbiota of neonates born to mothers with GDM presented lower alpha diversity with the Chao1 index (&lt;i&gt;P&lt;/i&gt; = 0.0235). Principal coordinate analysis revealed that the meconium samples were clustered by maternal GDM status only with unweighted UniFrac distances (&lt;i&gt;R&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt; = 0.011, &lt;i&gt;P&lt;/i&gt; = 0.003). In other groups, such as maternal age ≥ 35 years old and maternal prepregnancy BMI ≥ 24 kg/m&lt;sup&gt;2&lt;/sup&gt;, meconium was not clustered by maternal GDM status. Linear discriminant analysis revealed that 81 taxa were significantly different between the GDM group and the control group. Based on delivery mode, there were 226 representative taxa in the control group, whereas in the GDM group, there were no representative taxa. In addition, based on neonatal sex, there were 79 representative taxa in the GDM group and seven in the control group. Other perinatal characteristics, such as maternal prepregnancy BMI, age, gestational weight gain, and birth weight also influenced the differential taxa of the neonatal gut microbiota between the two groups. In our cohort, newborns from mothers with GDM and without GDM had similar composition but different abundances of the gut microbiota. Maternal prepregnancy BMI, age, gestational weight gain, and neonatal delivery mode, sex, and birth weight had different influences on the diversity and differential taxa of the neonatal gut microbiota. The results of this study suggest that when studying the association between GDM and neonatal gut microbiota, it is necessary to consider the concomitant perinatal characteristics.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;This study uses 16S rRNA gene amplicon sequencing to analyze 247 meconium samples with or without maternal gestational diabetes mellitus (GDM) and make a multi-group comparison. We found that newborns from mothers with GDM and normoglycemic mothers had similar compositions but different abundances of the gut microbiota. Other than the maternal diabetes status, maternal body mass index, age, gestational weight gain, and neonatal delivery mode, gender and birth weight a","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0091424"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ceftazidime retains <i>in vivo</i> efficacy against strains of <i>Stenotrophomonas maltophilia</i> for which traditional testing predicts resistance.","authors":"Matthew C Phillips, Bosul Lee, Sarah L Miller, Jun Yan, Kristine Goy, Marlène Maeusli, Tina Lam, Catherine Spellberg, Michael Spellberg, Rosemary She, Brad Spellberg, Brian Luna","doi":"10.1128/msphere.00840-24","DOIUrl":"10.1128/msphere.00840-24","url":null,"abstract":"<p><p><i>Stenotrophomonas maltophilia</i> is responsible for a growing number of nosocomial infections and is difficult to treat owing to limited antibiotic susceptibilities. However, there are numerous recently published examples where traditional susceptibility testing methodology fails to accurately predict <i>in vivo</i> efficacy. We sought to determine if there were efficacious antibiotics against <i>S. maltophilia</i> that have been overlooked due to specious <i>in vivo</i> resistance determined by traditional <i>in vitro</i> methods. Antibiotic resistance testing was performed utilizing conventional and nutrient-limited media. Antibiotics with discordant minimum inhibitory concentrations (MICs) between the two media were selected for further experimentation. Metal ions were supplemented back into the nutrient-limited media to establish possible mechanisms. <i>In vivo</i> corroborations of <i>in vitro</i> MICs were done utilizing two infection models, <i>Galleria mellonella</i> and a neutropenic mouse oral aspiration pneumonia model. <i>S. maltophilia</i> MICs were significantly lower for ceftazidime in nutritionally deficient media that better corresponds to the <i>in vivo</i> environment than conventional rich media, resulting in a high percentage of strains determined resistant in traditional media being determined susceptible in nutritionally deficient media. The addition of zinc and manganese to the deficient media abrogated this difference, which was dependent on the L1 metallo-β-lactamase (MBL). Ceftazidime protected both <i>G. mellonella</i> and neutropenic mice against lethal infection caused by <i>S. maltophilia</i> that was predicted to be resistant in traditional media but susceptible in nutrient-deficient media. Ceftazidime may remain a viable therapeutic option for patients with <i>S. maltophilia</i> infection caused by strains predicted to be resistant by traditional susceptibility testing. Sequestration of trace metals in the host environment may prevent <i>S. maltophilia</i> MBL activity against ceftazidime.IMPORTANCEBreakpoint interpretation criteria for ceftazidime against <i>S. maltophilia</i> were recently removed by CLSI and the FDA. It was noted that clinical data were insufficient to validate the current breakpoints. Clinical data were mixed, with some studies reporting treatment success, but others reporting treatment failure. We believe that antimicrobial testing is suboptimal, and improved testing strategies, such as the use of zinc-limited media for culture, will better model the activity of ceftazidime <i>in vitro</i>. Improved susceptibility testing strategies may better discriminate against those isolates that are truly resistant from those that were previously falsely identified as being resistant using conventional testing methods.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0084024"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of a high-resolution melt assay for monitoring SARS-CoV-2 variants in Burkina Faso and Kenya.","authors":"Caitlin Greenland-Bews, Sonal Shah, Morine Achieng, Emilie S Badoum, Yaya Bah, Hellen C Barsosio, Helena Brazal-Monzó, Jennifer Canizales, Anna Drabko, Alice J Fraser, Luke Hannan, Sheikh Jarju, Jean-Moise Kaboré, Mariama A Kujabi, Cristina Leggio, Maia Lesosky, Jarra Manneh, Tegwen Marlais, Julian Matthewman, Issa Nebié, Eric Onyango, Alphonse Ouedraogo, Kephas Otieno, Samuel S Serme, Sodiomon Sirima, Ben Soulama, Brian Tangara, Alfred Tiono, William Wu, Emily R Adams, Abdul Karim Sesay, Chris Drakeley, Feiko O Ter Kuile, Issiaka Soulama, Simon Kariuki, David J Allen, Thomas Edwards","doi":"10.1128/msphere.00027-25","DOIUrl":"10.1128/msphere.00027-25","url":null,"abstract":"<p><p>The rapid emergence and global dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a need for robust, adaptable surveillance systems. However, financial and infrastructure requirements for whole-genome sequencing mean most surveillance data have come from higher-resource geographies, despite unprecedented investment in sequencing in low- and middle-income countries (LMICs). Consequently, the molecular epidemiology of SARS-CoV-2 in some LMICs is limited, and there is a need for more cost-accessible technologies to help close data gaps for surveillance of SARS-CoV-2 variants. To address this, we have developed two high-resolution melt (HRM) curve assays that target variant-defining mutations in the SARS-CoV-2 genome, which give unique signature profiles that define different SARS-CoV-2 variants of concern (VOCs). Extracted RNA from SARS-CoV-2-positive samples collected from 205 participants (112 in Burkina Faso, 93 in Kenya) enrolled in the MALCOV study (Malaria as a Risk Factor for COVID-19) between February 2021 and February 2022 were analyzed using our optimized HRM assays. With next-generation sequencing on Oxford Nanopore MinION as a reference, two HRM assays, HRM-VOC-1 and HRM-VOC-2, demonstrated sensitivity/specificity of 100%/99.29% and 92.86%/99.39%, respectively, for detecting Alpha, 90.08%/100% and 92.31%/100% for Delta, and 93.75%/100% and 100%/99.38% for Omicron BA.1. The assays described here provide a lower-cost approach to conducting molecular epidemiology, capable of high-throughput testing. We successfully scaled up the HRM-VOC-2 assay to screen a total of 506 samples from which we were able to show the replacement of Alpha with the introduction of Delta and the replacement of Delta by the Omicron variant in this community in Kisumu, Kenya.IMPORTANCEThe rapid evolution of the severe acute respiratory syndrome coronavirus 2 variants of concern (VOCs) demonstrated the need for accessible surveillance tools so all communities can conduct viral surveillance. Sequencing, the gold standard, is still a largely inaccessible methodology in low-resource settings. Here, we present a quick, low-cost tool to screen for the common VOCs, designed to support surveillance efforts in low-resource settings. This tool was used to screen samples from Burkina Faso and Western Kenya throughout the pandemic. We show through comparison to sequencing that our assay can generate highly similar data on the different variants circulating in a population, therefore showing the effectiveness of our tool. While not a replacement for sequencing, we present a method of screening and prioritizing samples for further investigation and reduce overburdening sequencing capacity. Our findings provide insight into one potential tool that could be further applied to pathogen screening in the absence of robust sequencing infrastructure.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0002725"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging the lifecycle of <i>Microsporidia</i> sp. MB in <i>Anopheles coluzzii</i> from western Burkina Faso reveals octosporogony.","authors":"Ewan R S Parry, Roland Pevsner, Beth C Poulton, Deepak-Kumar Purusothaman, Abdelhakeem I Adam, Sare Issiaka, Thomas H Ant, Stephanie M Rainey, Etienne Bilgo, Abdoulaye Diabaté, Steven P Sinkins","doi":"10.1128/msphere.00851-24","DOIUrl":"10.1128/msphere.00851-24","url":null,"abstract":"<p><p>A newly discovered microsporidian, <i>Microsporidia</i> sp. MB (MB), was recently found to block <i>Plasmodium falciparum</i> transmission in <i>Anopheles arabiensis</i> mosquitoes from Kenya. Here, we describe the lifecycle of the first laboratory colony of <i>Anopheles coluzzii</i> with MB, originating from western Burkina Faso. The lifecycle of MB was explored using fluorescent <i>in situ</i> hybridization and confocal microscopy, facilitated by the development of optimized protocols to produce histological sections of whole adult, larval, and embryo tissues. As in <i>An. arabiensis</i>, transmission appears to be predominantly vertical, with MB highly localized to the ovaries across multiple lifecycle stages. MB was sparsely distributed within the majority of developing oocytes in the gravid female. After oviposition, in the majority of embryos, MB relocated to the developing gonad at the onset of tissue differentiation, suggesting a highly specialized adaptation to host tissues. Sporogony was identified for the first time in a proportion of developing oocytes and in embryos post-oviposition. Microsporidian spore characteristics were subsequently confirmed with electron microscopy. Identification of MB sporogony in eggs suggests there are alternative horizontal routes of transmission which could play an important role in developing MB as a malaria control strategy.</p><p><strong>Importance: </strong>Malaria in West Africa, caused by <i>Plasmodium falciparum</i> infection and spread by anopheline mosquitoes, is responsible for hundreds of thousands of deaths annually and resulted in over 120 million cases in 2022 . The transmission-blocking effect of <i>Microsporidia</i> sp. MB (MB) suggests its potential as an agent for combating the spread of malaria. Understanding the routes of transmission and their effect on MB in mosquito populations is crucial for its development as a control tool. The identification of MB spores reveals the potential for another avenue of transmission beyond the vertical transmission from female to offspring. Spores could also have the potential for alternative MB dissemination methods, alongside or instead of adult mosquito releases.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0085124"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome content reorganization in the non-model ciliate <i>Chilodonella uncinata</i>: insights into nuclear architecture, DNA content, and chromosome fragmentation during macronuclear development.","authors":"Ragib Ahsan, Xyrus X Maurer-Alcalá, Laura A Katz","doi":"10.1128/msphere.00075-25","DOIUrl":"10.1128/msphere.00075-25","url":null,"abstract":"<p><p>Ciliates are a model lineage for studies of genome architecture given their unusual genome structures. All ciliates have both somatic macronuclei (MAC) and germline micronuclei (MIC), both of which develop from a zygotic nucleus following sex (i.e., conjugation). Nuclear developmental stages are not well documented among non-model ciliates, including <i>Chilodonella uncinata</i> (class Phyllopharyngea), the focus of our work. Here, we characterize nuclear architecture and genome dynamics in <i>C. uncinata</i> by combining 4',6-diamidino-2-phenylindole (DAPI) staining and fluorescence <i>in situ</i> hybridization (FISH) techniques with confocal microscopy. We developed a telomere probe for staining, which alongside DAPI allows for the identification of fragmented somatic chromosomes among the total DNA in the nuclei. We quantify both total DNA and telomere-bound signals from more than 250 nuclei sampled from 116 individual cells, and analyze changes in DNA content and nuclear architecture across <i>Chilodonella</i>'s nuclear life cycle. Specifically, we find that MAC developmental stages in the ciliate <i>C. uncinata</i> are different from those reported from other ciliate species. These data provide insights into nuclear dynamics during development and enrich our understanding of genome evolution in non-model ciliates.</p><p><strong>Importance: </strong>Ciliates are a clade of diverse single-celled eukaryotic microorganisms that contain at least one somatic macronucleus (MAC) and germline micronucleus (MIC) within each cell/organism. Ciliates rely on complex genome rearrangements to generate somatic genomes from a zygotic nucleus. However, the development of somatic nuclei has only been documented for a few model ciliate genera, including <i>Paramecium</i>, <i>Tetrahymena</i>, and <i>Oxytricha</i>. Here, we study the MAC developmental process in the non-model ciliate, <i>C. uncinata</i>. We analyze both total DNA and the generation of gene-sized somatic chromosomes using a laser scanning confocal microscope to describe <i>C. uncinata</i>'s nuclear life cycle. We show that DNA content changes dramatically during their life cycle and in a manner that differs from previous studies on model ciliates. Our study expands knowledge of genome dynamics in ciliates and among eukaryotes more broadly.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0007525"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome mining identifies a diversity of natural product biosynthetic capacity in human respiratory <i>Corynebacterium</i> strains.","authors":"Ashley L Cunningham, Ilya Y Zhbannikov, Rachel Myers, Tommy H Tran, Wei Gao, Katherine P Lemon, Jhoanna N Aquino, Jillian H Hurst, Joon Won Yoon, Patrick C Seed, Matthew S Kelly","doi":"10.1128/msphere.00258-25","DOIUrl":"10.1128/msphere.00258-25","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;i&gt;Corynebacterium&lt;/i&gt; species, integral to the healthy human upper respiratory tract (URT) microbiota, remain underexplored in microbial genomics for their potential to promote respiratory health and exclude pathobionts. This genomic study investigated the diversity and capacity for natural product synthesis within these species, as indicated by their biosynthetic gene clusters (BGCs). We aimed to map and quantify the BGC diversity in a contemporary collection of &lt;i&gt;Corynebacterium&lt;/i&gt; strains, representative of their prevalence in the respiratory microbiota, and to elucidate intra- and interspecies variation in BGC content. The outcomes of this research could reveal key factors in maintaining the ecological balance of the upper respiratory tract and identify novel antimicrobial agents targeting respiratory pathobionts. Employing an &lt;i&gt;in silico&lt;/i&gt; approach, we analyzed the biosynthetic potential of respiratory strains of non-diphtheriae &lt;i&gt;Corynebacterium&lt;/i&gt; species and their reference genomes through genome sequencing and antiSMASH6 analysis. Among 161 genomes, we identified 672 BGCs, 495 of which were unique, including polyketide synthase, non-ribosomal peptide synthetase, ribosomally synthesized and post-translationally modified peptide, and siderophore families. To understand how this biosynthetic capacity compared to other respiratory bacteria, we then downloaded genomes from eight species that are associated with the URT and conducted BGC searches. We found that despite their compact genomes, &lt;i&gt;Corynebacterium&lt;/i&gt; species possess a multitude of predicted BGCs, exceeding the diversity of natural product BGCs identified in multiple other respiratory bacteria. This research lays the foundation for future functional genomics studies on the role of &lt;i&gt;Corynebacterium&lt;/i&gt; species in the respiratory microbiome and the discovery of novel therapeutics derived from this bacterial genus.IMPORTANCEBacterial secondary metabolites, produced by enzymes encoded by biosynthetic gene clusters, are ecologically important for bacterial communication and competition in nutrient-scarce environments and are a historically rich source of antibiotics and other medications. Human-associated &lt;i&gt;Corynebacterium&lt;/i&gt; species, abundant in the healthy upper respiratory tract, are understudied despite evidence of their roles in promoting human health and preventing pathobiont colonization. Through genome mining of a large collection of &lt;i&gt;Corynebacterium&lt;/i&gt; strains isolated from the human respiratory tract and publicly available genomes of other respiratory bacteria, our study suggests that &lt;i&gt;Corynebacterium&lt;/i&gt; species have a high biosynthetic capacity and are predicted to harbor a wide range of biosynthetic gene cluster families. These findings substantially expand current knowledge regarding the production of secondary metabolites by human-associated &lt;i&gt;Corynebacterium&lt;/i&gt; species. Our study also lays the foundations for understanding how &lt;i&gt;Corynebacterium","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0025825"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sudapyridine (WX-081) inhibits <i>Mycobacterium tuberculosis</i> by targeting ATP synthase and upregulating host innate immunity.","authors":"Xinda Li, Xiaoyi Luo, Bin Wang, Lei Fu, Xi Chen, Yu Lu","doi":"10.1128/msphere.00149-25","DOIUrl":"10.1128/msphere.00149-25","url":null,"abstract":"<p><p>Drug-resistant tuberculosis (DR-TB) urgently requires safer, more accessible alternatives to bedaquiline (BDQ), which faces critical flaws like cardiotoxicity, high costs, and emerging resistance. WX-081, a promising BDQ alternative, has demonstrated superior anti-TB activity and improved safety in clinical studies. However, its mechanism of action remains unexplored, underscoring the need for further research to optimize its potential in advancing global TB elimination efforts. This study reveals WX-081's dual mechanisms: targeting <i>atpE</i> to disrupt ATP synthase and proton motive force via resistance screening, gene sequencing, and functional assays while enhancing host immunity through macrophage transcriptomics. Molecular docking confirmed <i>atpE</i> binding sites, and immune activation pathways (NF-κB/MAPK) were identified, positioning WX-081 as a potent, safe anti-DR-TB candidate despite unresolved mechanistic details.IMPORTANCEBedaquiline, a key drug for drug-resistant tuberculosis, is restricted by safety issues impacting its clinical utility. Its next-generation alternative, WX-081, has advanced to Phase III trials but lacks in-depth studies on its mechanism and host immune-modulatory effects, necessitating further research before broad clinical adoption.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0014925"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An extremely poor nutritional condition enables efficient white cell mating in <i>Candida albicans</i>.","authors":"Chaoran Zhong, Shuyun Guan, Ming Xu, Mingyang Ma, Chao Li, Li Tao, Guanghua Huang, Ming Guan","doi":"10.1128/msphere.00291-25","DOIUrl":"10.1128/msphere.00291-25","url":null,"abstract":"<p><p>Pathogenic fungi employ diverse strategies to undergo sexual reproduction. It was previously believed that the major human fungal pathogen <i>Candida albicans</i> must switch from the \"sterile\" white state to the mating-competent opaque state to mate. We recently reported that glucose depletion could induce <i>C. albicans</i> white cell mating at a moderate frequency. In this study, we demonstrate that white cells can undergo efficient mating when incubated on agar medium (water and agar, without additional nutritional components). Cell survival assays revealed that a subpopulation of white cells underwent cell death, releasing nutritional components that supported surviving cells in undergoing morphological changes and efficient mating. Inactivation of <i>CST20</i>, <i>MAC1</i>, <i>MCU1</i>, and <i>IDP2</i>-genes required for cell death and reactive oxygen species generation in <i>C. albicans</i>-resulted in a significant reduction in mating frequency under nutrient-depleted conditions. Taken together, our findings suggest that extremely poor nutritional conditions are able to promote epigenetic switch-independent mating in <i>C. albicans</i>.<b>IMPORTANCE</b>By demonstrating that white cells can mate under nutrient-depleted conditions, the research uncovers a novel mechanism of sexual reproduction in this pathogenic fungus. The findings suggest that cell death, through the release of nutritional components and the generation of reactive oxygen species, plays a crucial role in facilitating mating under nutrient-depleted conditions. This research not only provides novel insights into the reproductive strategies of <i>C. albicans</i> but also highlights potential avenues for exploring altruistic behaviors in other microorganisms. Understanding these mechanisms could have significant implications for the development of new therapeutic strategies to combat fungal infections, particularly in environments where nutrient limitations are common.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0029125"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Final reflections.","authors":"Michael J Imperiale","doi":"10.1128/msphere.00345-25","DOIUrl":"10.1128/msphere.00345-25","url":null,"abstract":"","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0034525"},"PeriodicalIF":3.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}