mBio最新文献

{"title":"Molecular mechanisms of drug resistance and compensation in SARS-CoV-2 main protease: the interplay between E166 and L50.","authors":"Sarah N Zvornicanin, Ala M Shaqra, Julia Flynn, Heidi Carias Martinez, Weiping Jia, Stephanie Moquin, Dustin Dovala, Daniel N Bolon, Nese Kurt Yilmaz, Celia A Schiffer","doi":"10.1128/mbio.04068-24","DOIUrl":"10.1128/mbio.04068-24","url":null,"abstract":"<p><p>The SARS-CoV-2 main protease (M^pro) is essential for viral replication and is a primary target for COVID-19 antivirals. Direct-acting antivirals such as nirmatrelvir, the active component of Paxlovid, target the M^pro active site to block viral polyprotein cleavage and thus replication. However, drug resistance mutations at the active site residue Glu166 (E166) have emerged during <i>in vitro</i> selection studies, raising concerns about the durability of current antiviral strategies. Here, we investigate the molecular basis of drug resistance conferred by E166A and E166V mutations against nirmatrelvir and the related PF-00835231, individually and in combination with the distal mutation L50F. We found that E166 mutations reduce nirmatrelvir potency by up to 3,000-fold while preserving substrate cleavage, with catalytic efficiency reduced by only up to twofold. This loss of catalytic efficiency was compensated for by the addition of L50F in the double-mutant variants. We have determined three cocrystal structures of the E166 variants (E166A, E166V, and E166V/L50F) bound to PF-00835231. Comparison of these structures with wild-type enzyme demonstrated that E166 is crucial for dimerization and for shaping the substrate-binding S1 pocket. Our findings highlight the mutability of E166, a prime site for resistance for inhibitors that leverage direct interactions with this position, and the potential emergence of highly resistant and active variants in combination with the compensatory mutation L50F. These insights support the design of inhibitors that target conserved protease features and avoid E166 side-chain interactions to minimize susceptibility to resistance.</p><p><strong>Importance: </strong>Drug resistance remains a great challenge to modern medicine. This study investigates SARS-CoV-2 main protease variants E166A and E166V which confer nirmatrelvir resistance. These variants can retain considerable enzymatic activity through combination with the compensatory mutation L50F. For single- and double-mutant variant enzymes, we assessed catalytic efficiency, measured loss in potency for nirmatrelvir and its analog PF-00835231, and cocrystallized with inhibitors to investigate drug resistance caused by these mutations. Our results contribute toward understanding of molecular mechanisms of resistance and combinations of mutations, which pushes toward resistance-thwarting inhibitor design. These principles also apply broadly to many quickly evolving drug targets in infectious diseases.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0406824"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-colonizing <i>Pseudoalteromonas elyakovii</i> metabolically reprograms the tumor microenvironment and promotes breast ductal carcinoma.","authors":"Shuyan Liu, Youpeng Pan, Chaopeng Zheng, Qinghui Zheng, Yaoqiang Du, Yajuan Zheng, Hongchao Tang, Xiaozhen Liu, Jiancheng Mou, Xin Zeng, Zhuotao Yang, Wenjuan Gui, Yuning Tang, Mingxing Xu, Zhihao Ye, Haotian Su, Qiuran Xu, Xuli Meng","doi":"10.1128/mbio.03873-24","DOIUrl":"10.1128/mbio.03873-24","url":null,"abstract":"<p><p>The correlation between the microbiota found in tumors and tumor development is being progressively understood, specifically regarding its involvement in the initiation and advancement of tumors. We examined a total of 102 samples, examining the microbial composition at the species level in each person unveiled significant variations in both the microbial makeup and tumor proportions among individuals, examining the fluctuating alterations in the microbial profile during breast cancer advancement and progression. The levels of expression for <i>Pseudoalteromonas elyakovii</i> were notably elevated in the tumor groups when compared to the para-cancer normal group, aligning with the results obtained from qRT-PCR analysis. The relationship between tumor immunity and microorganisms within the tumor was investigated using double immunofluorescence staining combined with SweAMI probe <i>in situ</i> hybridization and scRNA-seq, allowing for an in-depth analysis of intratumoral microorganisms. Experiments have demonstrated that the supernatant derived from <i>P. elyakovii</i> displayed a significant ability to promote tumor growth and stimulation. In summary, we describe the characteristics of the intratumoral microbiota and the tumor-promoting effects of <i>P. elyakovii</i> supernatant within a small dose range in ductal carcinoma of the breast and characterize the potential clinical application value of intratumoural microorganisms in the progression of cancer and immunotherapy.</p><p><strong>Importance: </strong>Despite the existing studies, the specific microbial factors that influence the occurrence and progression of breast cancer still remain unclear. Researchers have clarified the distinctive microbial profile related to ductal carcinoma, a common histological type of breast cancer, in order to identify tumor-specific microbes and their roles in tumorigenesis. With the tumor microbiome as the focus, the enrichment of <i>Pseudoalteromonas elyakovii</i> features accelerates the disease progression in patients with ductal carcinoma of the breast. This study reveals the initial role relationship and innovative findings between <i>Pseudoalteromonas elyakovii</i> and ductal carcinoma in the breast.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0387324"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional control of <i>C. albicans</i> white-opaque switching and modulation by environmental cues and strain background.","authors":"Anupam Sharma, Ameen Homayoon, Michael Weyler, Corey Frazer, Bernardo Ramírez-Zavala, Joachim Morschhäuser, Richard J Bennett","doi":"10.1128/mbio.00581-25","DOIUrl":"10.1128/mbio.00581-25","url":null,"abstract":"<p><p>The opportunistic fungal pathogen <i>Candida albicans</i> can undergo cellular transitions in response to environmental cues that impact its lifestyle and its interactions with the human host. This is exemplified by the white-opaque switch, which is a heritable transition between two phenotypic states that is regulated by a highly interconnected network of transcription factors (TFs). To obtain greater understanding of the transcriptional regulation of the switch, we generated a genome-wide, tetracycline-inducible TF library in the WO-1 strain background and identified those TFs whose forced expression induces white cells to switch to the opaque state. This set of opaque-inducing TFs was also evaluated for their ability to induce switching in a second strain background, that of the standard reference strain SC5314, as well as during growth on different laboratory media. These experiments identify 14 TFs that can drive white-to-opaque switching when overexpressed but that do so in a highly strain- and media-specific manner. In particular, changes in pH, amino acids, and zinc concentrations had marked effects on the ability of TFs to drive phenotypic switching. These results provide insights into the complex transcriptional regulation of switching in <i>C. albicans</i> and reveal that an interplay between genetic and environmental factors determines TF function and cell fate.IMPORTANCEThe white-opaque switch in <i>Candida albicans</i> represents a model system for understanding an epigenetic switch in a eukaryotic pathogen. Here, we generated an inducible library of the set of transcription factors (TFs) present in <i>C. albicans</i> and identify 14 TFs that can drive the white-to-opaque transition when ectopically expressed. We demonstrate that several of these TFs induce the switch in a highly strain- and media-specific manner. This highlights that both strain background and changes in experimental conditions (including different water sources) can profoundly impact the phenotypic consequences of TF overexpression. Moreover, the inducible TF library provides an invaluable tool for the further analysis of TF function in this important human pathogen.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0058125"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Ex vivo</i> and <i>in vivo</i> HIV-1 latency reversal by \"Mukungulu,\" a protein kinase C-activating African medicinal plant extract.","authors":"Khumoekae Richard, Zhe Yuan, Hsin-Yao Tang, Aaron R Goldman, Riza Kuthu, Boingotlo Raphane, Emery T Register, Paridhima Sharma, Brian N Ross, Jessicamarie Morris, David E Williams, Carol Cheney, Guoxin Wu, Karam Mounzer, Gregory M Laird, Paul Zuck, Raymond J Andersen, Sundana Simonambango, Kerstin Andrae-Marobela, Ian Tietjen, Luis J Montaner","doi":"10.1128/mbio.03816-24","DOIUrl":"10.1128/mbio.03816-24","url":null,"abstract":"<p><p>New HIV latency-reversing agents (LRAs) are needed that can reactivate and/or eliminate HIV reservoirs. \"Mukungulu,\" prepared from the plant <i>Croton megalobotrys</i> Müll Arg., is traditionally used for HIV/AIDS management in northern Botswana despite an abundance of protein kinase C-activating phorbol esters (\"namushens\"). Here, we show that Mukungulu is tolerated in mice at up to 12.5 mg/kg while robustly reversing latency in antiretroviral therapy (ART)-suppressed HIV-infected humanized mice at 5 mg/kg. In primary cells from ART-suppressed people living with HIV-1, 1 µg/mL Mukungulu reverses latency at levels similar to or superior to anti-CD3/CD28 positive control, based on HIV gag-p24 protein expression, while the magnitude of HIV reactivation in peripheral blood mononuclear cells corresponds to intact proviral burden in CD4+ T-cells. Bioassay-guided fractionation identifies five namushen phorbol esters that can reactivate HIV, but when combined, they do not match Mukungulu's activity, suggesting the presence of additional enhancing factors. Together, these results identify Mukungulu as a robust natural LRA that is already in use by humans and which may warrant inclusion in future HIV cure and ART-free remission efforts.IMPORTANCECurrent HIV therapies do not act on the latent viral reservoir, which is the major obstacle toward achieving a drug-free HIV remission and/or an HIV cure. \"Mukungulu,\" a bark preparation from <i>Croton megalobotrys</i> Müll Arg., has been documented for its traditional use for HIV/AIDS management in northern Botswana. Here, we show that Mukungulu activates viral reservoirs, a key step toward identifying and potentially eliminating these reservoirs, in both cells from people living with HIV as well as in HIV-infected humanized mice. The majority of this activity is due to the abundance of five phorbol esters (\"namushens\"). This reverse pharmacology-based approach has therefore identified a potent activator of viral reservoirs that is already traditionally used by humans, which in turn can inform and advance western HIV cure and drug-free remission efforts.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0381624"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A diverse set of solubilized natural fibers drives structure-dependent metabolism and modulation of the human gut microbiota.","authors":"Maria X Maldonado-Gomez, Katharine M Ng, Riley A Drexler, Alexandria M S Conner, Cory G Vierra, Nithya Krishnakumar, Hannah M Gerber, Zachary R Taylor, Jenna L Treon, Megan Ellis, Jada K A Garcia, James P Cerney, David G Chapin, Robnet T Kerns, Angela M Marcobal, Steven M Watkins, Matthew J Amicucci","doi":"10.1128/mbio.00470-25","DOIUrl":"10.1128/mbio.00470-25","url":null,"abstract":"<p><p>Growing evidence suggests that inadequate dietary fiber intake, termed the \"fiber gap,\" is linked to disease states through disruption of the gut microbiota. Despite this, our understanding of how various fiber structures influence the microbiota and health is limited by the lack of diverse commercially available fibers. Studies have primarily focused on a limited range of fibers, rather than the diverse array of fibers representative of those commonly found in our diets. In this study, we aimed to investigate how naturally derived fibers impact the human microbiota and their metabolic products. We performed a comprehensive structural characterization and functional evaluation of a unique and highly diverse set of new, highly soluble fibers with varied monosaccharide compositions, glycosidic linkages, and polymer lengths. Using an <i>ex vivo</i> high-throughput human microbiota platform coupled with metabolomic profiling, we demonstrate that these diverse fibers drive distinct and consistent microbial and metabolic profiles across cohorts of donors in a structure-dependent manner. These metabolic effects were accompanied by both general and donor-specific changes in microbial taxa. Finally, we demonstrate that integrating detailed glycomic characterization with microbial and metabolomic data allowed for prediction of functional outcomes driven by a novel material, pineapple pulp fiber. This work highlights the potential for targeted dietary fiber interventions to modulate the microbiota and improve health outcomes, paving the way for the development of new fiber-rich products with specific health benefits.IMPORTANCEFiber deficiency is associated with numerous disease states, many of which are linked to disruption of the gut microbiota. This study encompasses the first systematic and comprehensive characterization of a diverse collection of naturally derived solubilized fibers and their impacts on the microbiota. The results expand our understanding of the beneficial effects of specific carbohydrate structures naturally found in the human diet, highlighting the potential for designing fiber-based health interventions. The high solubility of these fibers increases both the range of products they can be incorporated in as well as their assayability in experiments, enabling a widespread increase in fiber consumption and positive health impacts.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0047025"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eukfinder: a pipeline to retrieve microbial eukaryote genome sequences from metagenomic data.","authors":"Dandan Zhao, Dayana E Salas-Leiva, Shelby K Williams, Katherine A Dunn, Jason D Shao, Andrew J Roger","doi":"10.1128/mbio.00699-25","DOIUrl":"10.1128/mbio.00699-25","url":null,"abstract":"<p><p>Whole-genome shotgun (WGS) metagenomic sequencing of microbial communities enables the discovery of the functions, physiologies, and evolutionary histories of prokaryotic and eukaryotic microbes. However, metagenomic studies of microbial eukaryotes lag due to challenges in identifying and assembling high-quality genomes from WGS data. To address this problem, we developed Eukfinder, a bioinformatics pipeline that identifies potential eukaryotic sequences from WGS metagenomic data, with a complementary binning workflow for recovering nuclear and mitochondrial genomes. Eukfinder uses two specialized databases for read/contig classification, customizable to specific data sets or environments. We tested Eukfinder on simulated gut microbiome data sets which included varying numbers of reads from the protist <i>Blastocystis</i>, a human gut commensal. We also applied Eukfinder to previously published human gut microbiome WGS metagenomic data to recover new genomes of <i>Blastocystis</i>. Compared to other workflows, Eukfinder offers the potential to recover high-quality, near-complete genomes of diverse eukaryotes, including different <i>Blastocystis</i> subtypes, without relying on a reference genome. With sufficient sequencing depth, Eukfinder outperforms similar tools for recovering eukaryotic genomes from metagenomic data. Eukfinder is a valuable tool for reference-independent and cultivation-free studies of eukaryotic microbial genomes from environmental WGS metagenomic samples.</p><p><strong>Importance: </strong>Advancements in next-generation sequencing have made whole-genome shotgun (WGS) metagenomic sequencing an efficient method for <i>de novo</i> reconstruction of microbial genomes from various environments. Thousands of new prokaryotic genomes have been characterized; however, the large size and complexity of protistan genomes have hindered the use of WGS metagenomics to sample microbial eukaryotic diversity. Eukfinder enables the recovery of eukaryotic microbial genomes from environmental WGS metagenomic samples. Retrieval of high-quality protistan genomes from diverse metagenomic samples increases the number of reference genomes available. This aids future metagenomic investigations into the functions, physiologies, and evolutionary histories of eukaryotic microbes in the gut microbiome and other ecosystems.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0069925"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A mutualistic model bacterium is lethal to non-symbiotic hosts via the type VI secretion system.","authors":"Keegan E Gaddy, Alecia N Septer, Karen Mruk, Morgan E Milton","doi":"10.1128/mbio.00157-25","DOIUrl":"10.1128/mbio.00157-25","url":null,"abstract":"<p><p>What makes a bacterium pathogenic? Since the early days of germ theory, researchers have categorized bacteria as pathogens or non-pathogens, those that cause harm and those that do not, but this binary view is not always accurate. <i>Vibrio fischeri</i> is an exclusive mutualistic symbiont found within the light organs of Hawaiian bobtail squid. This symbiotic interaction requires <i>V. fischeri</i> to utilize a range of behaviors and produce molecules that are often associated with pathogenicity. This juxtaposition of employing \"pathogenic\" behaviors for a symbiotic relationship led the field to focus on how <i>V. fischeri</i> establishes a beneficial association with its host. In this study, we observe that <i>V. fischeri</i> induces mortality in zebrafish embryos and <i>Artemia</i> nauplii. Non-lethal doses of <i>V. fischeri</i> lead to zebrafish growth delays and phenotypes indicative of disease. Our data also provide evidence that the conserved type VI secretion system on chromosome I (T6SS1) plays a role in the <i>V. fischeri</i>-induced mortality of zebrafish embryos and <i>Artemia</i> nauplii. These results support the hypothesis that the <i>V. fischeri</i> T6SS1 is involved in eukaryotic cell interactions. Despite its traditional view as a beneficial symbiont, we provide evidence that <i>V. fischeri</i> is capable of harming aquatic organisms, indicating its potential to be pathogenic toward non-symbiotic hosts.IMPORTANCE<i>Vibrio fischeri</i> is best known for its beneficial partnership with the Hawaiian bobtail squid, where it uses molecular tools often associated with disease-causing bacteria. Our research shows that <i>V. fischeri</i> can also cause harm, killing zebrafish embryos and brine shrimp larvae. We pinpoint one of <i>V. fischeri</i>'s two type VI secretion systems (T6SS1) as a key factor in this pathogenicity. These findings reveal that <i>V. fischeri</i> is not strictly a mutualistic microbe but can act like a pathogen under certain conditions. This broadens our understanding of how <i>V. fischeri</i> could interact with different hosts and offers new insights into the dual roles bacteria can play in nature.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0015725"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-genomic comparison reveals complex population dynamics and parasitic adaptation of <i>Echinococcus granulosus sensu stricto</i>.","authors":"Yao-Dong Wu, Zirui Ren, Li Li, Wen-Hui Li, Nian-Zhang Zhang, Yan-Tao Wu, Guo-Dong Dai, Wei-Gang Chen, Wen-Jie Mu, Shuai Wang, Jiandong Li, Qin Yu, Xue-Peng Cai, Xin Jin, Bao-Quan Fu, Daxi Wang, Wan-Zhong Jia, Hong-Bin Yan","doi":"10.1128/mbio.03256-24","DOIUrl":"10.1128/mbio.03256-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Cystic echinococcosis (CE), caused by &lt;i&gt;Echinococcus granulosus sensu stricto&lt;/i&gt; (&lt;i&gt;s.s.&lt;/i&gt;), poses a substantial risk to both humans and domestic animals globally. Here, we compared the whole genomes of 111 &lt;i&gt;E. granulosus s.s.&lt;/i&gt; samples from China. Genomic variation data revealed frequent cross-fertilization in the hermaphroditic &lt;i&gt;E. granulosus&lt;/i&gt;. The G1 and G3 genotypes represent distinct mitochondrial lineages, while showing no differentiation in the nuclear genome, suggesting mito-nuclear discordance caused by historical geographic separation and subsequent fusion. Population structure, demographic history, and gene flow among populations reflected the transmission route of &lt;i&gt;E. granulosus s.s.&lt;/i&gt; from the Middle East to Qinghai-Xizang Plateau through the migration of nomadic people, followed by introgression during secondary contact. Genomic variations highlighted selection signatures within the genome prone to balancing selection, particularly impacting genes encoding membrane-related proteins, representing a potential evolutionary strategy for adaptation to parasitic life. Balancing selection pressure on the gene-coding sodium/bile acid cotransporter led to its high level of genetic stability, which may play a crucial role in the survival and development of &lt;i&gt;E. granulosus&lt;/i&gt; during the parasitic stage, making it a potential drug target for the treatment of CE. Meanwhile, other genomic regions under strong balancing selection may provide potential targets for protective immunity. These findings offer valuable insights into the complex dynamics and adaptive evolution of &lt;i&gt;E. granulosus s.s.&lt;/i&gt; in China.IMPORTANCE&lt;i&gt;Echinococcus granulosus sensu stricto&lt;/i&gt; (&lt;i&gt;s.s.&lt;/i&gt;) is the primary cause of cystic echinococcosis (CE), a parasitic disease affecting humans and livestock with significant health and economic impacts. Previous studies on this parasite relied on mitochondrial DNA to classify its genotypes and understand its genetic diversity. However, these studies cannot capture the full complexity of its evolutionary dynamics and adaptation strategies. Our research employs comprehensive genome-wide sequencing, offering a more nuanced view of its genetic landscape. We discovered that cross-fertilization appears to be a prevalent reproductive strategy in the hermaphroditic &lt;i&gt;E. granulosus&lt;/i&gt;, underpinning the observed deep mitochondrial divergence between genotypes G1 and G3, as well as gene flow among populations. The transmission history of &lt;i&gt;E. granulosus s.s.&lt;/i&gt; in China and its widespread genetic mixing were likely facilitated by the migrations of nomadic peoples. Furthermore, we identified genes under balancing selection, including the gene involved in the uptake of host bile acids, which play a crucial role in the parasite's survival and development, potentially offering new targets for intervention. Our research advances the understanding of the genetic diversity and evolutionary strategies of &lt;i&gt;E. granulos","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0325624"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tandem inactivation of inositol pyrophosphatases Asp1, Siw14, and Aps1 illuminates functional redundancies in inositol pyrophosphate catabolism in fission yeast.","authors":"Beate Schwer, Isabel Prucker, Ana M Sanchez, Jill Babor, Henning J Jessen, Stewart Shuman","doi":"10.1128/mbio.00389-25","DOIUrl":"10.1128/mbio.00389-25","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Inositol pyrophosphates 5-IP&lt;sub&gt;7&lt;/sub&gt;, 1-IP&lt;sub&gt;7&lt;/sub&gt;, and 1,5-IP&lt;sub&gt;8&lt;/sub&gt; are eukaryal signaling molecules that influence cell physiology, especially phosphate homeostasis. In fission yeast, 1,5-IP&lt;sub&gt;8&lt;/sub&gt; and 1-IP&lt;sub&gt;7&lt;/sub&gt; impact gene expression by acting as agonists of RNA 3'-processing and transcription termination. 1,5-IP&lt;sub&gt;8&lt;/sub&gt; is synthesized by position-specific kinases Kcs1 and Asp1 that convert IP&lt;sub&gt;6&lt;/sub&gt; to 5-IP&lt;sub&gt;7&lt;/sub&gt; and 5-IP&lt;sub&gt;7&lt;/sub&gt; to 1,5-IP&lt;sub&gt;8&lt;/sub&gt;, respectively. Inositol pyrophosphatase enzymes Asp1 (a histidine acid phosphatase), Siw14 (a cysteinyl phosphatase), and Aps1 (a Nudix hydrolase) are agents of inositol pyrophosphate catabolism in fission yeast. Whereas Asp1, Siw14, and Aps1 are individually inessential, double pyrophosphatase mutants &lt;i&gt;asp1-H397A aps1&lt;/i&gt;∆ and &lt;i&gt;siw14&lt;/i&gt;∆ &lt;i&gt;aps1&lt;/i&gt;∆ display severe growth defects caused by overzealous 3'-processing/termination. By applying CE-ESI-MS to profile the inositol pyrophosphate content of fission yeast mutants in which inositol pyrophosphate toxicity is genetically suppressed, we elucidated the functional redundancies of the Asp1, Siw14, and Aps1 pyrophosphatases. Asp1, which exclusively cleaves the 1-β-phosphate, and Aps1, which prefers to cleave the 1-β-phosphate, play essential overlapping roles in guarding against the accumulation of toxic levels of 1-IP&lt;sub&gt;7&lt;/sub&gt;. Aps1 and Siw14 together catabolize the inositol-5-pyrophosphates, and their simultaneous inactivation results in overaccumulation of 5-IP&lt;sub&gt;7&lt;/sub&gt;. Cells lacking all three pyrophosphatases amass high levels of 1,5-IP&lt;sub&gt;8&lt;/sub&gt; and 1-IP&lt;sub&gt;7&lt;/sub&gt;, with concomitant depletion of IP&lt;sub&gt;6&lt;/sub&gt;. A genetic screen identified three missense mutations in the catalytic domain of Kcs1 kinase that suppressed inositol-1-pyrophosphate toxicosis. The screen also implicated the 3'-processing factor Swd22, the inositol pyrophosphate sensor Spx1, and the nuclear poly(A)-binding protein Nab2 as mediators of inositol-1-pyrophosphate toxicity.IMPORTANCEInositol pyrophosphates are key effectors of eukaryal cellular phosphate homeostasis. They are synthesized by kinases that add a β-phosphate to the 5- or 1-phosphate groups of IP&lt;sub&gt;6&lt;/sub&gt; and catabolized by three classes of pyrophosphatases that hydrolyze the β-phosphates of 5-IP&lt;sub&gt;7&lt;/sub&gt;, 1-IP&lt;sub&gt;7&lt;/sub&gt;, or 1,5-IP&lt;sub&gt;8&lt;/sub&gt;. Whereas the fission yeast inositol pyrophosphatases-Asp1 (histidine acid phosphatase), Siw14 (cysteinyl phosphatase), and Aps1 (Nudix hydrolase)-are inessential for growth, Asp1/Aps1 and Aps1/Siw14 double mutations and Asp1/Siw14/Aps1 triple mutations elicit severe or lethal growth defects. By profiling the inositol pyrophosphate content of pyrophosphatase mutants in which this toxicity is genetically suppressed, we reveal the functional redundancies of the Asp1, Siw14, and Aps1 pyrophosphatases. Their synergies are manifested as excess accumulation of 1-IP&lt;sub&gt;7&lt;/sub&gt; upon dual inactivation of As","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0038925"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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-based assessment of antimicrobial resistance of <i>Escherichia coli</i> recovered from diseased swine in eastern China for a 12-year period.","authors":"Junxing Li, Jiang Chang, Jiangang Ma, Wei Zhou, Yue Yang, Jing Wu, Chunjiu Guan, Xiufang Yuan, Lihua Xu, Bin Yu, Fei Su, Shiyi Ye, Yijie Chen, Guoping Zhao, Biao Tang","doi":"10.1128/mbio.00651-25","DOIUrl":"10.1128/mbio.00651-25","url":null,"abstract":"<p><p>The global rise of antimicrobial resistance (AMR), driven by antibiotic use in healthcare and agriculture, poses a major public health threat. While AMR in clinical settings is well studied, there is a gap in understanding the resistance profiles of <i>Escherichia coli</i> from diseased livestock, particularly regarding zoonotic transmission. This study analyzes 114 <i>E. coli</i> isolates from diseased swine over 12 years, revealing that 99.12% were multidrug-resistant. Resistance was highest for ampicillin and amoxicillin/clavulanic acid (100%), followed by ciprofloxacin (96.49%) and tetracycline (94.74%). Furthermore, 21.05% of isolates were resistant to colistin, and 1.75% to tigecycline. A total of 76 antimicrobial resistance genes (ARGs) were identified, with <i>mcr-1</i> found in 18.42%, <i>mcr-3</i> in 4.39%, and <i>tet</i>(X4) in 1.75%. Significant co-occurrence of ARGs and plasmids suggests potential for co-selective dissemination. This study is the first to report enterotoxigenic <i>E. coli</i> (ETEC) strains carrying both <i>mcr-1</i> and <i>mcr-3</i> genes. After the 2017 colistin ban in China, <i>mcr-1</i> detection rates significantly decreased, while florfenicol resistance rates increased in 2018-2021 (94.29%) compared to 2010-2017 (79.55%). This work provides valuable insights into the AMR profiles of <i>E. coli</i> from diseased swine and highlights trends that can inform strategies for monitoring and controlling public health risks associated with zoonotic <i>E. coli</i> transmission.IMPORTANCEThis study highlights the critical role of diseased and deceased swine in the spread of antimicrobial resistance (AMR), providing new insights into the transmission of resistance genes in zoonotic contexts. By analyzing <i>E. coli</i> from diseased swine, we identify key resistance genes such as <i>mcr-1</i>, <i>mcr-3</i>, and <i>tet</i>(X4), which pose significant public health risks, especially regarding last-resort antibiotics like colistin. Moreover, the study identifies novel transmission patterns of <i>mcr</i> genes, including ETEC strains carrying the <i>mcr-3</i> gene and strains harboring both <i>mcr-1</i> and <i>mcr-3</i> genes. The role of plasmids in horizontal gene transfer is also revealed, facilitating rapid AMR spread across species. The long-term persistence of resistant strains highlights the challenges in controlling AMR in livestock. These findings underscore the need for enhanced surveillance and a One Health approach to mitigate AMR risks across animal, human, and environmental health.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 5","pages":"e0065125"},"PeriodicalIF":5.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}