mBio最新文献

{"title":"Higher proportions of circulating CXCR3+ CCR6- Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders.","authors":"Ruthu Nagaraju, Pruthvi S Gowda, Durai M Gunasekaran, Anita S Desai, Udaykumar Ranga, Ramesh N R Masthi, Manjunatha M Venkataswamy","doi":"10.1128/mbio.00575-25","DOIUrl":"https://doi.org/10.1128/mbio.00575-25","url":null,"abstract":"<p><p>Despite long-term suppressive antiretroviral therapy (ART), immune dysregulation due to impaired reconstitution of CD4+ T cells is a major hurdle for reducing morbidity and mortality in HIV-1-infected immunological non-responders (INRs, CD4+ T cells ≤350 cells/µL). To evaluate potential immunological factors associated with impaired CD4+ T-cell reconstitution, we performed comprehensive immunophenotyping of multiple subsets of CD4+ T cells among HIV-1-infected individuals with high (>350 cells/µL) and low (≤350 cells/µL) CD4+ T cells, either ART-naïve or ART-exposed (median, 10 years). In comparison to other groups, INRs showed exclusively elevated proportions of CXCR3+ CCR6- Th1-like circulatory T follicular helper (cTfh1) CD4+ T cells, correlating negatively with CD4+ T cells (<i>r</i> = -0.6769, <i>P</i> < 0.0001), suggesting a strong association with incomplete CD4+ T-cell recovery. In contrast, compared to INRs, higher proportions of CXCR3- CCR6+ Th17-like cTfh cells (cTfh17) in immunological responders (IRs, CD4+ T cells >350 cells/µL) showed no correlation with CD4+ T-cell counts, suggesting a lack of association with CD4+ T-cell recovery. Additionally, proportions of activated (CD4+ CD38+ HLA-DR+) and regulatory (CD4+ CD25+/hi CD127-/lo) CD4+ T cells were increased in INRs compared to IRs, as previously known. A negative correlation was also observed between the CD4+ T-cell counts and activated (<i>r</i> = -0.6726, <i>P</i> < 0.0001) or regulatory (<i>r</i> = -0.5627, <i>P</i> < 0.0001) CD4+ T-cell proportions among IRs and INRs. Our study highlights that immune dysregulation associated with skewing of cTfh cells toward CXCR3+ CCR6- Th1-like phenotype may be the leading cause of inefficient CD4+ T-cell recovery in INRs and can serve as a hallmark of impaired CD4+ T-cell reconstitution.IMPORTANCEThe altered proportions of CD4+ T-cell subsets in immunological non-responders (INRs) indicate their involvement in poor CD4+ T-cell reconstitution. Reversing these alterations may help prevent the loss of CD4+ T cells. Particularly, blocking cTfh-cell polarization toward CXCR3+ CCR6- cTfh-cell subset may help restore CD4+ T-cell counts in INRs, thereby preventing increased risk of morbidity and mortality.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0057525"},"PeriodicalIF":5.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700590","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":"Storage of the vital metal tungsten in a dominant SCFA-producing human gut microbe <i>Eubacterium limosum</i> and implications for other gut microbes.","authors":"Nana Shao, Dayong Zhou, Gerrit J Schut, Farris L Poole, Sydney B Coffey, Aaron P Donaghy, Saisuki Putumbaka, Michael P Thorgersen, Lirong Chen, John Rose, Bi-Cheng Wang, Michael W W Adams","doi":"10.1128/mbio.02605-24","DOIUrl":"https://doi.org/10.1128/mbio.02605-24","url":null,"abstract":"<p><p>Enzymes containing tungsten rather than the ubiquitous and analogous element molybdenum are prevalent in the human gut microbiome, especifically in microbes that contribute to overall gut health. <i>Eubacterium limosum</i> is a dominant human gut organism whose production of beneficial short-chain fatty acids (SCFAs) from lactate involves tungstoenzymes. Here, we characterized <i>E. limosum</i> Tub, a tungsten storage protein. Tub has a sub-nanomolar affinity for tungstate and contains a single TOBE domain first characterized in a molybdate storage protein. Crystal structures revealed Tub assembles as a hexamer composed of a trimer of dimers, capable of binding eight tungstate oxyanions at two distinct binding sites located at inter-subunit interfaces. Tungstate-saturated Tub exhibited unusually high thermal and chemical stability. Glucose-grown <i>E. limosum</i> accumulates tungsten in Tub and has low levels of two tungstoenzymes, termed WOR1 and FDH, which oxidize aldehydes and formate, respectively. Lactate-grown cells contain high concentrations of these two tungstoenzymes where WOR1 and FDH are involved in converting lactate to SCFAs. Glucose-grown cells appear to accumulate tungstate in Tub in preparation for lactate availability in the human gut. Tub and other TOBE-containing proteins are widespread in the human gut microbiome, and gene co-occurrence analysis predicts that there are comparable numbers of TOBE-containing proteins involved in the storage of tungstate as there are that bind molybdate. The results with <i>E. limosum</i> represent an important step for understanding tungsten storage mechanisms for tungstoenzymes within human gut microbes in general.IMPORTANCETungsten metabolism was found to be prevalent in the human gut microbiome, which is involved in the detoxification of food and antimicrobial aldehydes, as well as in the production of beneficial SCFAs. In this study, we characterized a protein in the human gut microbe, <i>Eubacterium limosum</i>, that stores tungstate in preparation for its use in enzymes involved in SCFA generation. This revealed several families of tungstate binding proteins that are also involved in tungstate transport and tungstate-dependent regulation and are widely distributed in the human gut microbiome. Elucidating how tungsten is stored and transported in the human gut microbes contributes to our understanding of the human gut microbiome and its impact on human health.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0260524"},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692701","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":"EV68-228-N monoclonal antibody treatment halts progression of paralysis in a mouse model of EV-D68 induced acute flaccid myelitis.","authors":"Michael J Rudy, Courtney J Wilson, Brendan Hinckley, Danielle C Baker, Joshua M Royal, Marshall P Hoke, Miles B Brennan, Matthew R Vogt, Penny Clarke, Kenneth L Tyler","doi":"10.1128/mbio.03906-24","DOIUrl":"10.1128/mbio.03906-24","url":null,"abstract":"<p><p>In 2014, 2016, and 2018, infection with enterovirus D68 (EV-D68) was associated with outbreaks of a poliomyelitis-like paralytic syndrome, called acute flaccid myelitis (AFM). While only a small fraction of patients infected with EV-D68 developed AFM, this subgroup of patients does not typically seek treatment until after the onset of neurological symptoms. There are currently no approved human monoclonal antibody therapies or vaccines available for EV-D68. Here, we show that a monoclonal antibody, EV68-228-N, can quickly stop the progression of paralysis in a mouse model of AFM, even when treatment is initiated after the onset of paralysis. We found that EV68-228-N effectively halted the progression of paralysis when tested against both 2014 and 2016 EV-D68 isolates in an immunocompetent mouse model of AFM. All animal experiments were conducted in a blinded fashion. The IC₅₀ of EV68-228-N against 2014 and 2016 EV-D68 isolates was confirmed <i>in vitro</i> to be less than 330 ng/mL, and EV68-228-N was found to be equally effective at neutralizing 2018 and 2022 viral isolates without any evidence of emerging resistance. We further show that, following infection with EV-D68, mice treated with EV68-228-N have more surviving motor neurons in the spinal cord's lumbar enlargement than control treated animals. Taken together, this work suggests that EV68-228-N treatment has the potential to halt the progression of paralysis in AFM patients who present at the clinic with neurologic symptoms and that EV68-228-N will retain neutralization potential against emerging EV-D68 isolates.</p><p><strong>Importance: </strong>Enterovirus D-68 (EV-D68) associated acute flaccid myelitis (AFM) is an emergent poliomyelitis-like illness occurring predominantly in children. There are currently no proven effective therapies. We describe the use of a human monoclonal antibody (EV68-228-N) in a murine model of EV-D68 AFM in which therapy prevents progression of paralysis even when treatment is instituted after onset of weakness.</p><p><strong>Clinical trials: </strong>This study is registered with ClinicalTrials.gov as NCT06444048.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0390624"},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692699","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":"https://doi.org/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":"2025-03-24","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":"Standard mouse diets lead to differences in severity in infectious and non-infectious colitis.","authors":"Joshua E Denny, Julia N Flores, Nontokozo V Mdluli, Michael C Abt","doi":"10.1128/mbio.03302-24","DOIUrl":"https://doi.org/10.1128/mbio.03302-24","url":null,"abstract":"<p><p><i>Clostridioides difficile</i> infects the large intestine and can result in debilitating and potentially fatal colitis. The intestinal microbiota is a major factor influencing the severity of disease following infection. Factors like diet that shape microbiota composition and function may modulate <i>C. difficile</i> colitis. Here, we report that mice fed two distinct standard mouse chows (LabDiet 5010 and LabDiet 5053) exhibited significantly different susceptibility to severe <i>C. difficile</i> infection. Both diets are grain-based with comparable profiles of macro and micronutrient composition. Diet 5010-fed mice had severe morbidity and mortality compared to Diet 5053-fed mice despite no differences in <i>C. difficile</i> colonization or toxin production. Furthermore, Diet 5053 protected mice from toxin-induced epithelial damage. This protection was microbiota-dependent as germ-free mice or mice harboring a reduced diversity microbiota fed Diet 5053 were not protected from severe infection. However, cohousing with mice harboring a complex microbiota restored the protective capacity of Diet 5053 but not Diet 5010. Metabolomic profiling revealed distinct metabolic capacities between Diet 5010- and Diet 5053-fed intestinal microbiotas. Diet 5053-mediated protection extended beyond <i>C. difficile</i> infection as Diet 5053-fed mice displayed less severe dextran sodium sulfate-induced colitis than Diet 5010-fed mice, highlighting a potentially broader capacity for Diet 5053 to limit colitis. These findings demonstrate that standard diet formulations in combination with the host microbiota can drive variability in severity of infectious and non-infectious murine colitis systems, and that diet holds therapeutic potential to limit the severity of <i>C. difficile</i> infection through modulating the functional capacity of the microbiota.IMPORTANCEDiet is a major modulator of the microbiota and intestinal health. This report finds that two different standard mouse diets starkly alter the severity of colitis observed in a pathogen-mediated (<i>Clostridioides difficile</i>) and non-infectious (dextran sodium sulfate) mouse colitis experimental systems. These findings in part explain study-to-study variability using these mouse systems to study disease. Since the gut microbiota plays a key role in intestinal homeostasis, diet-derived modulation of the microbiota is a promising avenue to control disease driven by intestinal inflammation and may represent a potential intervention strategy for at-risk patients.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0330224"},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692700","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":"Insights into the physiological and metabolic features of <i>Thalassobacterium</i>, a novel genus of <i>Verrucomicrobiota</i> with the potential to drive the carbon cycle.","authors":"Xin-Yun Tan, Xin-Jiang Liu, De-Chen Lu, Yu-Qi Ye, Xin-Yu Liu, Fan Yu, Hui Yang, Fan Li, Zong-Jun Du, Meng-Qi Ye","doi":"10.1128/mbio.00305-25","DOIUrl":"https://doi.org/10.1128/mbio.00305-25","url":null,"abstract":"<p><p><i>Verrucomicrobiota</i> are widely distributed across various habitats but are difficult to culture. Some previous multiomics analyses reported that <i>Verrucomicrobiota</i> have outstanding metabolic capacity for organic matter degradation and are able to degrade and synthesize polysaccharides, two activities that could contribute significantly to the Earth's carbon cycle. Here, we isolated from marine sediment two novel strains, <i>Thalassobacterium maritimum</i> SDUM461003^T and <i>Thalassobacterium sedimentorum</i> SDUM461004^T, that represent a new genus of the difficult-to-culture phylum <i>Verrucomicrobiota</i>. Genome analysis, functional annotation, and experimental verification revealed that these two strains degrade polysaccharides and antibiotics, including some complex sulfated polysaccharides (SPs), primarily fucoidan and chondroitin sulfate. Moreover, electron microscopy images revealed that these bacteria can synthesize and store large amounts of glycogen. These polysaccharide degradation and synthesis capacities also exist but differ under nitrogen-deficient conditions, indicating that <i>Verrucomicrobiota</i> may have the potential to maintain their normal metabolism by nitrogen fixation under aerobic conditions. Given that polysaccharides and their degradation products are particularly crucial carbon sources for marine microorganisms, <i>Verrucomicrobiota</i> are thought to be important contributors to biogeochemical cycling in the ocean.</p><p><strong>Importance: </strong><i>Verrucomicrobiota</i> are widely distributed and able to utilize a variety of difficult-to-biodegrade polysaccharides, which have a significant impact on the marine carbon cycle. However, there are not enough pure culture strains of <i>Verrucomicrobiota</i>, as hard-to-cultivate bacteria, for us to study. Here, our study reports a new genus in the phylum <i>Verrucomicrobiota</i> and investigates their ability to degrade and synthesize a variety of polysaccharides as well as the mechanism of utilizing difficult-to-degrade polysaccharides. We also explored their special performance on carbon utilization in marine nitrogen-deficient environments. This contributes to deepening our understanding of the involvement of marine microorganisms in the marine carbon cycle.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0030525"},"PeriodicalIF":5.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663937","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":"Temporal expression classes and functions of vaccinia virus and mpox (monkeypox) virus genes.","authors":"Yining Deng, Santiago Navarro-Forero, Zhilong Yang","doi":"10.1128/mbio.03809-24","DOIUrl":"10.1128/mbio.03809-24","url":null,"abstract":"<p><p>Poxviruses comprise pathogens that are highly pathogenic to humans and animals, causing diseases such as smallpox and mpox (formerly monkeypox). The family also contains members developed as vaccine vectors and oncolytic agents to fight other diseases. Vaccinia virus is the prototype poxvirus and the vaccine used to eradicate smallpox. Poxvirus genes follow a cascade temporal expression pattern, categorized into early, intermediate, and late stages using distinct transcription factors. This review comprehensively summarized the temporal expression classification of over 200 vaccinia virus genes. The relationships between expression classes and functions, as well as different branches of immune responses, were discussed. Based on the vaccinia virus orthologs, we classified the temporal expression classes of all the mpox virus genes, including a few that were not previously annotated with orthologs in vaccinia viruses. Additionally, we reviewed the functions of all vaccinia virus genes based on the up-to-date published papers. This review provides a readily usable resource for researchers working on poxvirus biology, medical countermeasures, and poxvirus utility development.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0380924"},"PeriodicalIF":5.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663874","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":"Lactate dehydrogenase is the Achilles' heel of Lyme disease bacterium <i>Borreliella burgdorferi</i>.","authors":"Ching Wooen Sze, Michael J Lynch, Kai Zhang, David B Neau, Steven E Ealick, Brian R Crane, Chunhao Li","doi":"10.1128/mbio.03728-24","DOIUrl":"10.1128/mbio.03728-24","url":null,"abstract":"<p><p>As a zoonotic pathogen, the Lyme disease bacterium <i>Borreliella burgdorferi</i> has evolved unique metabolic pathways, some of which are specific and essential for its survival and thus present as ideal targets for developing new therapeutics. <i>B. burgdorferi</i> dispenses with the use of thiamin as a cofactor and relies on lactate dehydrogenase (BbLDH) to convert pyruvate to lactate for balancing NADH/NAD⁺ ratios. This report first demonstrates that BbLDH is a canonical LDH with some unique biochemical and structural features. A loss-of-function study then reveals that BbLDH is essential for <i>B. burgdorferi</i> survival and infectivity, highlighting its therapeutic potential. Drug screening identifies four previously unknown LDH inhibitors with minimal cytotoxicity, two of which inhibit <i>B. burgdorferi</i> growth. This study provides mechanistic insights into the function of BbLDH in the pathophysiology of <i>B. burgdorferi</i> and lays the groundwork for developing genus-specific metabolic inhibitors against <i>B. burgdorferi</i> and potentially other tick-borne pathogens as well.</p><p><strong>Importance: </strong>Lyme disease (LD) is the most commonly reported tick-borne illness in the U.S. and Europe, and its geographic distribution is continuously expanding worldwide. Though early LD can be treated with antibiotics, chronic LD is recalcitrant to antibiotic treatments and thus requires multiple courses of antibiotic therapy. Currently, there are no human vaccines nor prophylactic antibiotics to prevent LD. As the causative agent of LD, <i>Borreliella burgdorferi</i> has evolved unique metabolic pathways, some of which are specific and essential for its survival and thus present as ideal targets for developing new therapeutics. By using an approach of genetics, biochemistry, structural biology, drug screening, and animal models, this report provides evidence that lactate dehydrogenase can be a potential target for developing genus-specific metabolic inhibitors against <i>B. burgdorferi</i> and potentially other tick-borne pathogens as well.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0372824"},"PeriodicalIF":5.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663941","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":"https://doi.org/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":"2025-03-20","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":"Adaptive evolution of sesquiterpene deoxyphomenone in mycoparasitism by <i>Hansfordia pulvinata</i> associated with horizontal gene transfer from <i>Aspergillus</i> species.","authors":"Kazuya Maeda, Takuya Sumita, Oumi Nishi, Hirotoshi Sushida, Yumiko Higashi, Hiroyuki Nakagawa, Tomoko Suzuki, Eishin Iwao, Much Zaenal Fanani, Yoshiaki Nishiya, Yuichiro Iida","doi":"10.1128/mbio.04007-24","DOIUrl":"https://doi.org/10.1128/mbio.04007-24","url":null,"abstract":"<p><p>Leaf mold caused by the ascomycete fungus <i>Cladosporium fulvum</i> is a devastating disease of tomato plants. The mycoparasitic fungus <i>Hansfordia pulvinata</i> is an effective biocontrol agent that parasitizes <i>C. fulvum</i> hyphae on leaves and secretes 13-deoxyphomenone, an eremophilane-type sesquiterpene, which was also identified as a sporulation-inducing factor in <i>Aspergillus oryzae</i>. Here, we identified deoxyphomenone biosynthesis (<i>DPH</i>) gene clusters conserved in both <i>H. pulvinata</i> and <i>Aspergillus</i> section <i>Flavi</i>, including <i>A. oryzae</i> and <i>A. flavus</i>. Functional disruption of <i>DPH1</i> orthologous genes encoding sesquiterpene cyclase in <i>H. pulvinata</i>, <i>A. oryzae</i>, and its close relative <i>A. flavus</i> revealed that deoxyphomenone in <i>H. pulvinata</i> had exogenic antifungal activity against <i>C. fulvum</i> and controlled endogenic sporulation in <i>Aspergillus</i> species. Complete <i>DPH</i> clusters, highly similar to those in <i>H. pulvinata</i>, were exclusive to <i>Aspergillus</i> section <i>Flavi</i>, while species in other <i>Aspergillus</i> sections contained fragmented <i>DPH</i> clusters. A comparative genomics analysis revealed that these <i>DPH</i> gene clusters share a common origin and are horizontally transferred from an ancestor of <i>Aspergillus</i> to <i>H. pulvinata</i>. Our results suggest that after horizontal transfer, <i>H. pulvinata</i> maintained the <i>DPH</i> cluster as the inhibitory effect of deoxyphomenone on spore germination and mycelial growth contributed to its mycoparasitism on the host fungus <i>C. fulvum</i>.</p><p><strong>Importance: </strong>Tomato leaf mold disease caused by <i>C. fulvum</i> poses a significant economic threat to tomato production globally. Breeders have developed tomato cultivars with <i>Cf</i> resistance genes. <i>C. fulvum</i> frequently evolves new races that overcome these genetic defenses, complicating control efforts. Additionally, the pathogen has developed resistance to chemical fungicides, prompting the need for sustainable alternatives like biocontrol agents. The mycoparasitic fungus <i>H. pulvinata</i> is crucial as an effective agent against <i>C. fulvum</i>. Clarifying the mechanism of mycoparasitism is significant, as it enhances its application as a biocontrol agent against plant pathogens. This study revealed how <i>H. pulvinata</i> produces deoxyphomenone, an antifungal compound, through horizontal gene transfer from <i>Aspergillus</i> species. It is hypothesized that mycoparasitism could be one of the mechanisms that facilitated horizontal gene transfer between fungi. These insights facilitate the development of eco-friendly, sustainable agricultural practices by reducing dependence on chemical fungicides and promoting natural pathogen control methods.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0400724"},"PeriodicalIF":5.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663930","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}