mBio最新文献

{"title":"Dual function of <i>Candida auris</i> mannosyltransferase, MNT5, in biofilm community protection from antifungal therapy and the host.","authors":"Robert Zarnowski, Mark V Horton, Chad J Johnson, Por Choua Vang, Jeremy Uram, Liyanage Devthilini Pasasum Fernando, Jiri Vlach, Christian Heiss, Parastoo Azadi, Jeniel E Nett, David R Andes","doi":"10.1128/mbio.00346-25","DOIUrl":"10.1128/mbio.00346-25","url":null,"abstract":"<p><p>Screen of mutants from a mannosyltransferase family identified the importance of <i>MNT5</i> for <i>C. auris</i> biofilm drug resistance and neutrophil evasion. Biochemical analysis of the <i>mnt5∆</i> mutant matrix and cell wall identified alterations in the mannan structures. Resistance and matrix for <i>mnt5∆</i> were restored with delivery of wild-type matrix via extracellular vesicles. Analysis of the <i>mnt5</i>∆ cell wall revealed a reduction in mannan and compensatory increase in cell surface glucan and chitin, suggesting a role for <i>MNT5</i> in mannan masking of pathogen-associated molecular patterns.</p><p><strong>Importance: </strong><i>C. auris</i> recalcitrance is linked to biofilm drug resistance and immune evasion. The mannosyltransferase encoded by <i>MNT5</i> is necessary for both phenotypes and may serve as a useful therapeutic target.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0034625"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492632","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":"Defense arsenal of the strict anaerobe <i>Clostridioides difficile</i> against reactive oxygen species encountered during its infection cycle.","authors":"Aurélie Lotoux, Léo Caulat, Catarina Martins Alves, Carolina Alves Feliciano, Claire Morvan, Filipe Folgosa, Isabelle Martin-Verstraete","doi":"10.1128/mbio.03753-24","DOIUrl":"10.1128/mbio.03753-24","url":null,"abstract":"<p><p><i>Clostridioides difficile</i>, a strict anaerobe, is the major cause of antibiotic-associated diarrhea. This enteropathogen must adapt to oxidative stress mediated by reactive oxygen species (ROS), notably those released by the neutrophils and macrophages recruited to the site of infection or those endogenously produced upon high oxygen (O₂) exposure. <i>C. difficile</i> uses a superoxide reductase, Sor, and several peroxidases to detoxify ROS. We showed that Sor has a superoxide reductase activity <i>in vitro</i> and protects the bacterium from exposure to menadione, a superoxide donor. After confirming the peroxidase activity of the rubrerythrin, Rbr, we showed that this enzyme together with the peroxiredoxin, Bcp, plays a central role in the detoxification of H₂O₂ and promotes the survival of <i>C. difficile</i> in the presence of not only H₂O₂ but also air or 4% O₂. Under high O₂ concentrations encountered in the gastrointestinal tract, the bacterium generated endogenous H₂O₂. The two O₂ reductases, RevRbr2 and FdpF, have also a peroxidase activity and participate in H₂O₂ resistance. The <i>CD0828</i> gene, which also contributes to H₂O₂ protection, forms an operon with <i>rbr</i>, <i>sor</i>, and <i>perR</i> encoding a H₂O₂-sensing repressor. The expression of the genes encoding the ROS reductases and the CD0828 protein was induced upon exposure to either H₂O₂ or air. We showed that the induction of the <i>rbr</i> operon is mediated not only by PerR but also by OseR, a recently identified O₂-responsive regulator of <i>C. difficile</i>, and indirectly by σ^B, the sigma factor of the stress response, whereas the expression of <i>bcp</i> is only controlled by σ^B.</p><p><strong>Importance: </strong>ROS plays a fundamental role in intestinal homeostasis, limiting the proliferation of pathogenic bacteria. <i>Clostridioides difficile</i> is an important enteropathogen that induces an intense immune response, characterized by the massive recruitment of immune cells responsible for secreting ROS, mainly H₂O₂ and superoxide. We showed in this work that ROS exposure leads to the production of an armada of enzymes involved in ROS detoxification. This includes a superoxide reductase and four peroxidases, Rbr, Bcp, revRbr2, and FdpF. These enzymes likely contribute to the survival of vegetative cells of <i>C. difficile</i> in the colon during the host immune response. Distinct regulations are also observed for the genes encoding the ROS detoxification enzymes allowing a fine tuning of the adaptive response to ROS exposure. Understanding the mechanisms of ROS protection during infection could shed light on how <i>C. difficile</i> survives under conditions of an exacerbated inflammatory response.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0375324"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663933","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 novel plasmid-encoded transposon-derived small RNA reveals the mechanism of sRNA-regulated bacterial persistence.","authors":"Shu-Ling Lin, Qi-Chang Nie, Carmen Oi-Kwan Law, Hoa-Quynh Pham, Ho-Fai Chau, Terrence Chi-Kong Lau","doi":"10.1128/mbio.03814-24","DOIUrl":"10.1128/mbio.03814-24","url":null,"abstract":"<p><p>Small regulatory RNAs (sRNAs) in bacteria are crucial for controlling various cellular functions and provide immediate response to the environmental stresses. Antibiotic persistence is a phenomenon that a small subpopulation of bacteria survives under the exposure of a lethal concentration of antibiotics, potentially leading to the development of drug resistance in bacteria. Here, we reported a novel transposon-derived sRNA called stnpA, which can modulate fosfomycin persistence of the bacteria. The stnpA sRNA located in the transposon with its own promoter is highly conserved among the prevalent multidrug resistance (MDR) plasmids in various pathogenic bacteria and expressed in response to the fosfomycin stress. It can directly bind to the ABC transporter, YadG, whereas this protein-RNA interaction modulated the export of fosfomycin and led to the enhancement of bacterial persistence. According to our knowledge, stnpA is the first identified transposon-derived sRNA, which controlled antibiotic persistence of bacteria, and our work demonstrated that nonresistance genes on MDR plasmids such as plasmid-encoded sRNA can provide additional survival advantages to the bacterial host against the antibiotics. In addition, the stnpA sRNA can be potentially utilized as the druggable target for the development of novel therapeutic strategies to overcome bacterial persistence.</p><p><strong>Importance: </strong>This study unveils a groundbreaking discovery in the realm of bacterial antibiotic persistence, highlighting the pivotal role of a newly identified small RNA (sRNA) called stnpA, which is a multidrug resistance plasmid-encoded transposon-derived sRNA that interacts directly with ABC transporter YadG to modulate the efflux of fosfomycin. Our findings elucidate a novel mechanism of small RNA-regulated fosfomycin persistence in bacteria that provides the potential pathway for the emergence of drug resistance in bacteria upon antibiotic treatment. Importantly, this study provides the first example of linking sRNA regulation to antibiotic persistence, presenting stnpA sRNA as a potential therapeutic target. This study underscores the critical role of noncoding RNAs in bacterial adaptation and offers valuable insights for developing new strategies to combat antibiotic persistence.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0381424"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492378","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 long noncoding RNA APR attenuates PPRV infection-induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replication.","authors":"Bo Wen, Wenchi Chang, Lulu Yang, Daiyue Lv, Lizhen Wang, Lei Wang, Yanzhao Xu, Jianhe Hu, Ke Ding, Qinghong Xue, Xuefeng Qi, Bo Yang, Jingyu Wang","doi":"10.1128/mbio.00127-25","DOIUrl":"10.1128/mbio.00127-25","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Peste des petits ruminants virus (PPRV) is an important pathogen that has long been a significant threat to small ruminant productivity worldwide. Iron metabolism is vital to the host and the pathogen. However, the mechanism underlying host-PPRV interactions from the perspective of iron metabolism and iron-mediated membrane lipid peroxidation has not been reported thus far. In this study, we identified a novel host long-noncoding RNA (lncRNA), APR, that impairs PPRV infectivity by sponging miR-3955-5p, a negative microRNA (miRNA) that directly targets the gene encoding the ferritin-heavy chain 1 (FTH1) protein. Importantly, we demonstrated that PPRV infection causes aberrant cellular iron accumulation by increasing transferrin receptor (TFRC) expression and that iron accumulation induces reticulophagy and ferroptosis, which benefits PPRV replication. Moreover, PPRV infection enhanced the localization of cellular iron on the endoplasmic reticulum (ER) and caused ER membrane damage by promoting excess lipid peroxidation to induce reticulophagy. Interestingly, APR decreased PPRV infection-induced accumulation of intracellular Fe&lt;sup&gt;2+&lt;/sup&gt; via miR-3955-5p/FTH1 axis and ultimately inhibited reticulophagy and ferroptosis. Additionally, our results indicate that interferon regulatory factor 1 promotes APR transcription by positively regulating APR promoter activity after PPRV infection. Taken together, our findings revealed a new pattern of PPRV-host interactions, involving noncoding RNA regulation, iron metabolism, and iron-related membrane lipid peroxidation, which is critical for understanding the host defense against PPRV infection and the pathogenesis of PPRV.IMPORTANCEMany viruses have been demonstrated to engage in iron metabolism to facilitate their replication and pathogenesis. However, the mechanism by which PPRV interacts with host cells from the perspective of iron metabolism, or iron-mediated membrane lipid peroxidation, has not yet been reported. Our data provide the first direct evidence that PPRV infection induces aberrant iron accumulation to promote viral replication and reveal a novel host lncRNA, APR, as a regulator of iron accumulation by promoting FTH1 protein expression. In this study, PPRV infection increased cellular iron accumulation by increasing TFRC expression, and more importantly, iron overload increased viral infectivity as well as promoted ER membrane lipid peroxidation by enhancing the localization of cellular iron on the ER and ultimately induced ferroptosis and reticulophagy. Furthermore, a host factor, the lncRNA APR, was found to decrease cellular iron accumulation by sponging miR-3955-5p, which directly targets the gene encoding the FTH1 protein, thereby attenuating PPRV infection-induced ferroptosis and reticulophagy and inhibiting PPRV infection. Taken together, the results of the present study provide new insight into our understanding of host-PPRV interaction and pathogenesis from the perspective of ir","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0012725"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692702","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":"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":"https://doi.org/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":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of cellular membranes and the precore protein on hepatitis B virus core particle assembly and DNA replication.","authors":"Yu-Chen Chuang, Jing-Hsiung James Ou","doi":"10.1128/mbio.03972-24","DOIUrl":"10.1128/mbio.03972-24","url":null,"abstract":"<p><p>Hepatitis B virus (HBV) core particle is critical for the transport and replication of the viral DNA genome. By characterizing HBV core particles in different subcellular compartments, we found that when the HBV core protein was expressed by itself, it formed core particles with a uniform and fast mobility on a non-denaturing agarose gel. However, when the core protein was expressed from a replication-competent 1.3mer HBV genome, it formed particles with more heterogeneous structures. The presence of the precore protein, a protein related to the core protein, led to the formation of chimeric particles in the cytoplasm that consisted of both precore and core proteins. When the precore protein was expressed by itself, it could also form particulate structures in association with cellular RNAs in the nucleus. Our further analysis revealed that, in cells with replicating HBV, only the fast-migrating core particles on the gel contained the viral RNA and DNA, and the membrane-associated core particles contained more mature HBV DNA than the cytosolic core particles. In addition, the precore protein reduced the level of core particle-associated HBV DNA. Interestingly, the precore protein level in the cells could be increased by the degradative autophagy inhibitor bafilomycin A1 but not by the proteasome inhibitor MG132, suggesting that autophagy might regulate the biological activities of the precore protein. In conclusion, our results indicated that membranes and the precore protein could regulate HBV core particle assembly and DNA replication and suggested a role of autophagy in the regulation of HBV precore protein activities.</p><p><strong>Importance: </strong>Hepatitis B virus (HBV) is an important human pathogen that chronically infects 254 million people in the world. This virus contains a core particle, which plays an important role in the transport and replication of the viral DNA genome. The major protein constituent of this particle is the viral core protein. In this report, we examined how the subcellular compartments and the related precore protein might affect the core particle structure and viral DNA replication. We found that the subcellular localizations could affect the core particle assembly, and membranes and the precore protein could regulate HBV DNA replication. We also found that the inhibition of autophagic degradation increased the precore protein level, suggesting a role of autophagy in the regulation of precore protein activities. These findings provided important information for further understanding the HBV life cycle, which will aid in the development of novel drugs for the treatment of HBV patients.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0397224"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557316","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":"Two different sulfotransferases modify sugars of the N-linked tetrasaccharide decorating <i>Halobacterium salinarum</i> glycoproteins.","authors":"Marianna Zaretsky, Zlata Vershinin, Lihi Erez, Iris Grossman-Haham, Jerry Eichler","doi":"10.1128/mbio.03534-24","DOIUrl":"10.1128/mbio.03534-24","url":null,"abstract":"<p><p>Despite providing the first example of archaeal N-glycosylation almost 50 years ago, detailed insight into the pathway used by <i>Halobacterium salinarum</i> to assemble and attach an N-linked tetrasaccharide decorating glycoproteins in this haloarchaea has only recently appeared. Still, numerous components of this pathway remain to be identified, including sulfotransferase(s), which modify the third and fourth tetrasaccharide sugars. In the present report, a series of bioinformatics, genetic, biochemical, and structural approaches served to reveal how membrane-associated VNG1056C and soluble VNG1057C respectively sulfate the iduronic acid at tetrasaccharide position three and the terminal glucuronic acid, seemingly independent of each other. Deletion of <i>VNG1056C</i> but not of <i>VNG1057C</i> reduced cell motility to a minor degree and did not cause archaellum filament bundling. Finally, transcription of <i>VNG1056C</i> or <i>VNG1057C</i> was augmented upon deletion of the other when cells were grown in low but not high salinity conditions possibly in an attempt to compensate for the loss of sugar sulfation resulting from the deletion. This augmented transcription, however, had no effect on the extent of tetrasaccharide sulfation. With demonstrated roles in <i>Hbt. salinarum</i> N-glycosylation, VNG1056C and VNG1057C were respectively re-annotated as Agl30 and Agl31, employing the nomenclature used to define archaeal N-glycosylation pathway components.</p><p><strong>Importance: </strong>Like essentially all Archaea, the halophile <i>Halobacterium salinarum</i> performs N-glycosylation, namely, the covalent attachment of a glycan moiety to select asparagine residues in a target protein. Moreover, <i>Hbt. salinarum</i> represents one of the few current archaeal examples in which the pathway of N-glycosylation has been largely defined. Still, several components of this pathway remain to be defined, including the sulfotransferase(s) responsible for modifying the iduronic acid and glucuronic acid corresponding to the third and final sugars of the N-linked tetrasaccharide that decorates glycoproteins in this haloarchaeon. In the present report, a series of bioinformatics, genetic, biochemical, and structural approaches served to reveal how membrane-associated VNG1056C and soluble VNG1057C respectively sulfate the iduronic acid at tetrasaccharide position three and the terminal glucuronic acid, seemingly independent of each other. The need for two different enzymes reflects the sulfation of these sugars at distinct positions.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0353424"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492387","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":"Deployment of a <i>Vibrio cholerae</i> ordered transposon mutant library in a quorum-competent genetic background.","authors":"Nkrumah A Grant, Gracious Yoofi Donkor, Jordan Sontz, William Soto, Christopher M Waters","doi":"10.1128/mbio.00036-25","DOIUrl":"10.1128/mbio.00036-25","url":null,"abstract":"<p><p><i>Vibrio cholerae</i>, the causative agent of cholera, has sparked seven pandemics in recent centuries, with the current one being the most prolonged. <i>V. cholerae's</i> pathogenesis hinges on its ability to switch between low- and high-cell-density gene regulatory states, enabling transmission between the host and the environment. Previously, a transposon mutant library for <i>V. cholerae</i> was created to support investigations aimed toward uncovering the genetic determinants of its pathogenesis. However, subsequent sequencing uncovered a mutation in the gene <i>luxO</i> of the parent strain, rendering mutants unable to exhibit high-cell-density behaviors. In this study, we used chitin-independent natural transformation to move transposon insertions from these low-cell-density mutants into a wild-type genomic background. Library transfer was aided by a novel gDNA extraction method we developed using thymol, which also showed high lysis specificity for <i>Vibrio</i>. The resulting Grant Library comprises 3,102 unique transposon mutants, covering 79.8% of <i>V. cholerae's</i> open reading frames. Whole-genome sequencing of randomly selected mutants demonstrates 100% precision in transposon transfer to cognate genomic positions of the recipient strain in every strain analyzed. Notably, in no instance did the <i>luxO</i> mutation transfer into the wild-type background. Our research uncovered density-dependent epistasis in growth on inosine, an immunomodulatory metabolite secreted by gut bacteria that is implicated in enhancing gut barrier functions. Additionally, Grant Library mutants retain the plasmid that enables rapid, scarless genomic editing. In summary, the Grant Library reintroduces organismal-relevant genetic contexts absent in the low-cell-density-locked library equivalent.Ordered transposon mutant libraries are essential tools for catalyzing research by providing access to null mutants of all non-essential genes. Such a library was previously generated for <i>Vibrio cholerae</i>, but whole-genome sequencing revealed that this library was made using a parent strain that is unable to exhibit cell-cell communication known as quorum sensing. Here, we utilize natural competence combined with a novel, high-throughput genomic DNA extraction method to regenerate the signaling incompetent <i>V. cholerae</i> ordered transposon mutant library in quorum-sensing-competent strain. Our library provides researchers with a powerful tool to understand <i>V. cholerae</i> biology within a genetic context that influences how it transitions from an environmentally benign organism to a disease-causing pathogen.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0003625"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492531","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":"Endogenous nitric oxide promotes <i>Staphylococcus aureus</i> virulence by activating autophagy.","authors":"Nadira Nurxat, Qichen Wang, Na Zhao, Yanan Guo, Xilong Zhang, Yanan Wang, Ying Jian, Hua Wang, Shengbing Yang, Min Li, Qian Liu","doi":"10.1128/mbio.04006-24","DOIUrl":"10.1128/mbio.04006-24","url":null,"abstract":"<p><p>Endogenous nitric oxide (NO) is a small molecule that has been demonstrated to affect the physiology and survival of bacteria. The role of endogenous NO for <i>Staphylococcus aureus</i> survival inside host cells remains unclear. Here, we show that the production of endogenous NO by bacterial nitrate reductase (NR) is affected by molybdopterin biosynthesis protein A (MoeA), which is essential for molybdenum cofactor synthesis in <i>S. aureus</i>. During the infection, the production of endogenous NO promotes <i>S. aureus</i> survival inside macrophages by initiating cellular autophagy. Mechanistically, bacterial endogenous NO can modify the host regulatory protein thioredoxin vis S-nitrosylation, subsequently triggering the phosphorylation of the JNK-Bcl-2 pathway and promoting the initiation of autophagy through the release of Beclin1. Moreover, we confirmed the critical role of MoeA in bacterial survival <i>in vivo</i> by using bloodstream infection, pneumonia, and skin abscess model on both wild-type and autophagy-deficient mice. Interestingly, we observed the significantly increased production of NO and activation of cellular autophagy of sequence type (ST)5 compared with ST239, suggesting that the initiation of autophagy is involved in the clone shift of <i>S. aureus</i>. Our data offered new insights on the role of bacterial endogenous NO in regulating the host signal pathway during infection inside host cells.IMPORTANCEUnderstanding the mechanism underlying <i>Staphylococcus aureus</i> pathogenesis is essential for developing innovative strategies for the prevention and treatment of infection. In this study, we underscore the critical role of molybdopterin biosynthesis protein A and nitric oxide (NO) in inducing autophagy during <i>S. aureus</i> survival within macrophage and <i>in vivo</i> infection. We demonstrate that host regulatory protein can be modified by bacterial metabolites, which may influence cellular processes. Furthermore, our findings indicated that increased endogenous NO production may contribute to the stable prevalence of <i>S. aureus</i> ST5 in the healthcare-associated environment. These findings highlight the significance of bacterial metabolism in modulating the host immune system, thereby facilitating <i>S. aureus</i> survival and persistence.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0400624"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492647","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":"Nutrition-induced changes in the microbiota can cause dysbiosis and disease development.","authors":"Tim Lachnit, Laura Ulrich, Fiete M Willmer, Tim Hasenbein, Leon X Steiner, Maria Wolters, Eva M Herbst, Peter Deines","doi":"10.1128/mbio.03843-24","DOIUrl":"10.1128/mbio.03843-24","url":null,"abstract":"<p><p>Eukaryotic organisms are associated with complex microbial communities. Changes within these communities have been implicated in disease development. Nonetheless, it remains unclear whether these changes are a cause or a consequence of disease. Here, we report a causal link between environment-induced shifts in the microbiota and disease development. Using the model organism <i>Hydra</i>, we observed changes in microbial composition when transferring laboratory-grown <i>Hydra</i> to natural lake environments. These shifts were caused not only by new colonizers, through the process of community coalescence (merging of previously separate microbial communities), but also by lake water nutrients. Moreover, selective manipulation of the nutrient environment induced compound-specific shifts in the microbiota followed by disease development. Finally, L-arginine supplementation alone caused a transition in <i>Pseudomonas</i> from symbiotic to pathogenic, leading to an upregulation of immune response genes, tissue degradation, and host death. These findings challenge the notion that the host-associated microbiota is exclusively controlled by the host, highlighting the dynamic interplay between host epithelial environment, microbial colonizer pool, and nutrient conditions of the surrounding water. Furthermore, our results show that overfeeding of the microbiota allows for uncontrolled microbial growth and versatile interactions with the host. Environmental conditions may thus render symbionts a potential hazard to their hosts, blurring the divide between pathogenic and non-pathogenic microbes.IMPORTANCEThis study highlights the critical need to understand the dynamic interplay between host-associated microbiota and environmental factors to obtain a holistic view on organismal health. Our results demonstrate that ecosystem-wide microbial trafficking (community coalescence) and environmental nutrient conditions reshape microbial communities with profound implications for host health. By exploring nutrient-driven changes in microbial composition, our research finds experimental support for the \"overfeeding hypothesis,\" which states that overfeeding alters the functionality of the host microbiota such that an overabundance in nutrients can facilitate disease development, transforming non-pathogenic microbes into pathogens. These findings emphasize the critical role of metabolic interactions driving microbial pathogenicity. Furthermore, our research provides empirical evidence for the \"pathogenic potential\" concept, challenging traditional distinctions between pathogenic and non-pathogenic microbes and supporting the idea that any microbe can become pathogenic under certain conditions.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0384324"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492683","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}