mBio最新文献

{"title":"The <i>ATO</i> gene family governs <i>Candida albicans</i> colonization in the dysbiotic gastrointestinal tract.","authors":"Rosana Alves, Faezeh Ghasemi, Wouter Van Genechten, Stefanie Wijnants, Odessa Van Goethem, Cláudia Barata-Antunes, Vitor Fernandes, Patrícia Ataíde, Alexandra Gomes-Gonçalves, Rudy Vergauwen, Qinxi Ma, Ricardo Duarte, Isabel Soares-Silva, Margarida Casal, Alistair J P Brown, Patrick Van Dijck, Sandra Paiva","doi":"10.1128/mbio.01644-25","DOIUrl":"10.1128/mbio.01644-25","url":null,"abstract":"<p><p>The fungal pathogen <i>Candida albicans</i> colonizes the human gut, where short-chain fatty acids (SCFAs) serve as a source of carbon. This fungus harbors one of the largest microbial families of <i>ATO</i> (acetate transporter ortholog) genes, which encode putative SCFA transport proteins. Here, we generate <i>C. albicans</i> null mutants lacking individual or all known putative SCFA transporter genes and compare their phenotypes <i>in vitro</i> and <i>in vivo</i>. We show that blocking <i>ATO</i> function in <i>C. albicans</i> impairs SCFA uptake and growth, particularly on acetate. The uptake of acetate is largely dependent on a functional Ato1 (also known as Frp3/Ato3), and it is effectively abolished upon deletion of all <i>ATO</i> genes. We further demonstrate that deletion of the entire <i>ATO</i> gene family, but not inactivation of <i>ATO1</i> alone, compromises the stable colonization of <i>C. albicans</i> in the murine gastrointestinal tract following bacterial disruption by broad-spectrum antibiotics. Our data suggest that the <i>ATO</i> gene family has expanded and diversified during the evolution of <i>C. albicans</i> to promote the fitness of this fungal commensal during gut colonization, in part through SCFA utilization.IMPORTANCEThe human gut is rich in microbial fermentation products such as short-chain fatty acids (SCFAs), which serve as key nutrients for both bacteria and fungi. <i>C. albicans</i>, a common fungal resident of the gut and a cause of opportunistic infections, carries an unusually large family of <i>ATO</i> (acetate transporter ortholog) genes. This study reveals that this <i>ATO</i> gene family is required for the efficient uptake of acetate, the most abundant SCFA in the gut, and for stable colonization of the gut. These findings uncover a new layer of metabolic adaptation in fungal commensals of humans and suggest that transporter gene expansion can shape microbial fitness in response to environmental nutrient signals.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0164425"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959503","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":"The siderophore-iron transporter BbMirB is required for the fungal pathogen <i>Beauveria bassiana</i> to repress insect immunity and promote proliferation during colonization of hemocoel.","authors":"Chenhua Zhu, Qi Liu, Yuhan Chen, Fangfang Tian, Dekun Kong, Isidor Happacher, Hubertus Haas, Yongjun Zhang, Zhibing Luo","doi":"10.1128/mbio.01981-25","DOIUrl":"10.1128/mbio.01981-25","url":null,"abstract":"<p><p>Nutritional immunity plays a vital role in limiting the proliferation of microbial pathogens in vertebrates and invertebrates. During coevolution with their hosts, pathogens have developed tactics to counteract the host nutritional immunity by acquiring iron via <u>s</u>iderophore-<u>i</u>ron <u>t</u>ransporter (SIT)-mediated uptake of siderophore-iron chelates. However, little is known about the role of SITs of insect fungal pathogens in combating host immune defense. Here, we demonstrate that <i>Beauveria bassiana</i>, an important insect pathogenic fungus, modulates dominant extracellular siderophores and co-expresses the SITs <i>BbMirA</i> and <i>BbMirB</i> for adaptation to the host <i>in vivo</i>. BbMirB, but not BbMirA, is crucial for <i>B. bassiana</i> full virulence. Disruption of <i>BbMirB</i> significantly reduces the virulence against <i>Galleria mellonella</i> larvae, delays immune evasion and <i>in vivo</i> hyphal body proliferation, and alters the host immune responses, including host nutritional immunity and immune-related gene expression. Loss of BbMirA or BbMirB leads to increased extracellular coprogen-type siderophores, including coprogen B, dimerumic acid, and their derivatives, suggesting these metabolites as their potential substrates. BbMirA and BbMirB co-localized to the plasma membrane, early/late endosomes, and vacuoles, implicating their roles in vesicular trafficking and siderophore-iron uptake. These findings highlight the importance of siderophore-iron transporters, particularly BbMirB, in fungal vesicular trafficking and host-pathogen interactions.IMPORTANCESiderophores are essential for iron uptake under iron-limiting conditions and are involved in fungal niche competition and pathogenicity via siderophore-iron transporters (SITs)-mediated uptake of specific substrates. However, the details of many SIT-mediated substrates in fungal colonization of hosts remain limited. Here, we identify two SITs, BbMirA and BbMirB, in the entomopathogenic fungus <i>Beauveria bassiana</i>, which are highly expressed during colonization of insect hemocoel. The two SITs have complementary functions in siderophore-iron uptake <i>in vitro</i>, but only BbMirB dominantly mediates the uptake of a derivative of dimerumic acid <i>in vivo</i> and plays a critical role in the pathogenic process via disturbing insect immune defense responses. These findings provide insights into the mechanisms of SITs mediating the interaction of fungal pathogens with their hosts.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0198125"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959524","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":"Targeting deubiquitinating enzymes and ubiquitin pathway modulators to enhance host defense against bacterial infections.","authors":"John Santelices, Alexander Schultz, Alyssa Walker, Nicole Adams, Deyaneira Tirado, Hailey Barker, Aria Eshraghi, Daniel M Czyż, Mariola J Ferraro","doi":"10.1128/mbio.00312-25","DOIUrl":"10.1128/mbio.00312-25","url":null,"abstract":"<p><p>The rise of antibiotic-resistant bacterial pathogens poses a critical global health challenge, necessitating innovative therapeutic strategies. This study explores host-targeted therapies by focusing on deubiquitinating enzymes (DUBs), key regulators of the ubiquitin-proteasome system (UPS) that mediate host-pathogen interactions. Using <i>Salmonella</i>-infected macrophages, we screened a UPS-targeted compound library and identified several compounds that enhanced bacterial clearance without affecting host cell viability. Among these, the dual USP25/USP28 inhibitor AZ-1 emerged as one of the top candidates. Transcriptomic profiling revealed infection-induced upregulation of DUBs, particularly USP25, USP46, and OTUD7B. USP25 knockdown significantly reduced intracellular <i>Salmonella</i>, confirming its role as a critical host factor. AZ-1 also exhibited broad-spectrum intracellular activity against multidrug-resistant <i>Pseudomonas aeruginosa</i>, <i>Klebsiella pneumoniae</i>, and <i>Acinetobacter baumannii</i>. <i>In vivo</i>, AZ-1 reduced fecal bacterial loads, clinical scores, and infection-induced weight loss, though it did not extend survival. AZ-1 had no direct antibacterial activity in axenic culture, indicating a host-targeting mechanism. Transcriptomic and signaling analyses revealed AZ-1 suppressed key immune pathways, including nuclear factor-kappa B (NF-κB) signaling. These findings establish DUBs as promising targets for host-directed therapies and support further development of UPS-targeted agents to combat antimicrobial resistance.IMPORTANCEAntibiotic-resistant infections, particularly those caused by intracellular pathogens, represent an urgent public health threat due to their ability to evade immune responses and resist conventional antibiotics. This study identifies the ubiquitin-proteasome system, specifically deubiquitinating enzymes, as viable targets for host-directed therapy. We demonstrate that the USP25/USP28 inhibitor AZ-1 enhances intracellular bacterial clearance without compromising host cell viability and is effective against several multidrug-resistant gram-negative pathogens. Knockdown of USP25 alone also reduced intracellular <i>Salmonella</i>, stressing out its proposed role in bacterial persistence. AZ-1 improved early infection outcomes <i>in vivo</i> but was insufficient as monotherapy. These findings support a novel therapeutic approach that targets host pathways to enhance bacterial clearance, offering a promising adjunct to traditional antibiotics in the fight against antimicrobial resistance.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0031225"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959554","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 novel regulator of the fungal phosphate starvation response revealed by transcriptional profiling and DNA affinity purification sequencing.","authors":"Lori B Huberman, Vincent W Wu, David J Kowbel, Juna Lee, Chris Daum, Vasanth R Singan, Igor V Grigoriev, Ronan C O'Malley, N Louise Glass","doi":"10.1128/mbio.02023-25","DOIUrl":"10.1128/mbio.02023-25","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Cells must accurately sense and respond to nutrients to compete for resources and establish growth. Phosphate is a critical nutrient source necessary for signaling, energy metabolism, and synthesis of nucleic acids, phospholipids, and cellular metabolites. During phosphate limitation, fungi import phosphate from the environment and liberate phosphate from phosphate-containing molecules in the cell. In the model filamentous fungus &lt;i&gt;Neurospora crassa&lt;/i&gt;, the phosphate starvation response is regulated by the conserved transcription factor NUC-1. The activity of NUC-1 is repressed by a complex of the cyclin-dependent kinase MDK-1 and the cyclin PREG when phosphate is plentiful. When phosphate is limiting, NUC-1 repression by MDK-1/PREG is relieved by the cyclin-dependent kinase inhibitor NUC-2. We investigated the global response of &lt;i&gt;N. crassa&lt;/i&gt; to phosphate starvation. During phosphate starvation, NUC-1 directly activated the expression of genes encoding phosphatases, nucleases, and a phosphate transporter and directly repressed genes associated with the ribosome. Additionally, NUC-1 indirectly activated the expression of an uncharacterized transcription factor, which we named &lt;i&gt;nuc-3&lt;/i&gt;. NUC-3 directly repressed the expression of genes involved in phosphate acquisition and liberation after an extended period of phosphate starvation. Additionally, NUC-3 directly repressed the expression of the cyclin-dependent kinase inhibitor &lt;i&gt;nuc-2&lt;/i&gt;. Thus, through the combination of NUC-3 direct repression of genes in the phosphate starvation response and &lt;i&gt;nuc-2&lt;/i&gt;, an activator of the phosphate starvation response, NUC-3 serves to act as a brake on the phosphate starvation response after an extended period of phosphate starvation. This braking mechanism could reduce transcription, a phosphate-intensive process, under conditions of extended phosphate limitation.IMPORTANCEFungi have evolved regulatory networks to respond to available nutrients. Phosphate is often a limiting nutrient for fungi that is critical for many cellular functions, including nucleic acid and phospholipid biosynthesis, cell signaling, and energy metabolism. The fungal response to phosphate limitation is important in interactions with plants and animals. We investigated the global transcriptional response to phosphate starvation and the role of a major transcriptional regulator, NUC-1, in the model filamentous fungus &lt;i&gt;Neurospora crassa&lt;/i&gt;. Our data show that NUC-1 is a bifunctional transcription factor that directly activates phosphate acquisition genes, while directly repressing genes associated with phosphate-intensive processes. NUC-1 indirectly regulates an uncharacterized transcription factor, which we named &lt;i&gt;nuc-3&lt;/i&gt;. NUC-3 directly represses phosphate acquisition genes and &lt;i&gt;nuc-2&lt;/i&gt;, an activator of the phosphate starvation response, during extended periods of phosphate starvation. Thus, NUC-3 acts as a brake on the phosphate starvation response to reduce ","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0202325"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959716","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":"Chemical stimuli override a temperature-dependent morphological program by reprogramming the transcriptome of a fungal pathogen.","authors":"Dror Assa, Mark Voorhies, Anita Sil","doi":"10.1128/mbio.02234-25","DOIUrl":"10.1128/mbio.02234-25","url":null,"abstract":"<p><p>The human fungal pathogen <i>Histoplasma</i> changes its morphology in response to temperature. At 37°C, it grows as a budding yeast, whereas at room temperature (RT), it transitions to hyphal growth. Prior work has demonstrated that 15-20% of transcripts are temperature-regulated, and that transcription factors (TFs) Ryp1-4 are necessary to establish yeast growth. However, little is known about transcriptional regulators of the hyphal program. To identify TFs that regulate filamentation, we utilize chemical inducers of hyphal growth. We show that the addition of cAMP analogs or an inhibitor of cAMP breakdown overrides yeast morphology, yielding inappropriate hyphal growth at 37°C. Additionally, butyrate supplementation triggers hyphal growth at 37°C. Transcriptional profiling of cultures filamenting in response to cAMP or butyrate reveals that a limited set of genes responds to cAMP, while butyrate dysregulates a larger set. Comparison of these profiles to previous temperature- or morphology-regulated gene sets identifies a small set of morphology-specific transcripts, including nine TFs. We characterized three TFs, <i>STU1</i>, <i>FBC1</i>, and <i>PAC2</i>, whose orthologs regulate development in other fungi. We found that while only <i>FBC1</i> is necessary for RT-induced filamentation, each of these TFs is required for other aspects of RT development. Additionally, <i>FBC1</i> and <i>PAC2</i>, but not <i>STU1</i>, are necessary for filamentation in response to cAMP at 37°C. Ectopic expression of each of these TFs is sufficient to induce filamentation at 37°C and <i>PAC2</i> induction of filamentation at 37°C is dependent on <i>STU1</i>. Taken together, this work identifies filamentation-promoting TFs that form regulatory circuits to promote the hyphal program.IMPORTANCEFungal illnesses pose a significant disease burden. However, the regulatory circuits that govern fungal development remain largely unknown. This study utilizes chemicals that can override the normal growth morphology of the human pathogen <i>Histoplasma</i>. Using transcriptomic approaches, we identify novel regulators of the hyphal morphology and refine our understanding of the transcriptional circuits governing morphology in <i>Histoplasma</i>.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0223425"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029689","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":"Inflammation and B cell activation define a plasma proteome signature predicting tuberculosis in people with HIV.","authors":"Katharina Kusejko, Mohammad Arefian, Diane Duroux, Marius Zeeb, Cédric Dollé, Matthias Hoffmann, Niklaus Labhardt, Gilles Wandeler, Matthias Cavassini, Sabine Haller, Enos Bernasconi, Doris Russenberger, Roger D Kouyos, Huldrych F Günthard, Ben C Collins, Johannes Nemeth","doi":"10.1128/mbio.01585-25","DOIUrl":"10.1128/mbio.01585-25","url":null,"abstract":"<p><p>Improved biomarkers for predicting progression to active tuberculosis (TB) are urgently needed, especially in people with HIV, who are at elevated risk. We used high-throughput plasma proteomics and machine learning to identify signatures associated with TB progression in this population. From the Swiss HIV Cohort Study, we analyzed plasma samples collected at least 6 months before TB diagnosis from 91 participants who later developed TB. We selected 293 controls matched for demographic and clinical parameters who remained TB-free to achieve a risk score specific to active TB. In total, 583 samples were analyzed, with 613-1,283 proteins quantified per sample. A random forest classifier predicted a significantly higher median probability of TB progression for cases (33%) than for controls (16%; <i>P</i> < 0.001). In this matched population, the score achieved an area under the receiver-operating characteristic curve of 0.77, an area under the precision-recall curve (AUPRC) of 0.60 (as compared to an expected AUPRC of 0.29), as well as a specificity of 87.3% and a sensitivity of 58.6% using the optimal threshold of 0.311. The plasma proteome of individuals who progressed to active TB showed a distinct shift toward systemic inflammation, B cell activation, and immunoglobulin production. Independent of progression to active TB, the proteome score correlated with broader indicators of immune suppression, including lower CD4 counts and unsuppressed HIV RNA. This suggests that integrating proteomic and clinical data could enhance the overall predictive power of the score.IMPORTANCEWe still lack reliable tools to predict who will develop tuberculosis (TB) among people with HIV. Moreover, the underlying biological events driving progression remain poorly understood. Our study reveals early immune changes that include unexpected alterations in B cell activation and antibody responses. These findings suggest that humoral immunity may play a more important role in TB pathogenesis than previously recognized and offer promising new directions for biomarker discovery and targeted prevention.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0158525"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959826","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":"Phenotypic heterogeneity of capsule production across opportunistic pathogens.","authors":"Amandine Nucci, Julie Le Bris, Sara Diaz-Diaz, Lilibeth Torres-Elizalde, Eduardo P C Rocha, Olaya Rendueles","doi":"10.1128/mbio.01807-25","DOIUrl":"10.1128/mbio.01807-25","url":null,"abstract":"<p><p>Phenotypic heterogeneity allows bacteria to adapt fast to changing environments. Extracellular capsules are well-known virulence factors, but also increase the cell adaptability and prevalence under hostile conditions. To limit their cost, some species regulate capsule production by genetic phase variation. Here, we demonstrated that phenotypic heterogeneity is a major mechanism controlling capsule production in <i>Klebsiella</i> and <i>Acinetobacter</i> species. We designed a method to agnostically measure heterogeneity and show that 71% of <i>Klebsiella pneumoniae</i> strains can be heterogeneous. This is mostly associated with <i>K. pneumoniae</i> strains that do not encode <i>rmp</i>, a genetic determinant of hypervirulence. Capsule serotype exchanges across several genetic backgrounds revealed that heterogeneity depends on specific genome-capsule locus interactions. Importantly, we showed that heterogeneity provides a fitness advantage especially in conditions where the capsule is costly, as estimated by comparing non-heterogeneous and heterogeneous strains during competition with their non-capsulated variants. Finally, heterogeneity impacts phage adsorption patterns, and could thus alter the rate of horizontal gene transfer events. This unsuspected heterogeneity may help understand the transition from commensalism to pathogenesis and can have important implications in virulence, environmental survival and evolution of some ESKAPE pathogens.IMPORTANCEThe polysaccharidic capsule is present in ~50% of species across the bacterial phylogeny, including all ESKAPE microorganisms, the six most significant multidrug-resistant (MDR) nosocomial pathogens. It is also an important virulence factor and a major target for both phage therapy and the development of vaccines. Here, we reveal that in two major genera of ESKAPE pathogens, <i>Klebsiella</i> spp. and <i>Acinetobacter</i> spp., capsule production within clonal populations is heterogeneous, leading to mixed populations of hyper-, hypo-, and intermediate-capsulated cells. Such heterogeneity responds to different environmental cues, including changes in nutrient availability and spatial structure. We show that this plasticity, known to enable faster, more efficient adaptation to environmental changes, limits capsule costs and could explain <i>Klebsiella</i> and <i>Acinetobacter</i> resilience. Finally, capsule heterogeneity can play a major role in bacterial evolution, as a driver of horizontal gene transfer, and in treatment failure. Thus, it should be taken into account in the design of prophylactic strategies and antimicrobial therapy.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0180725"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993071","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":"FABP4-dependent fatty acid oxidation-fueled mitochondrial ROS induces the mobilization of cellular iron and facilitates <i>Trypanosoma cruzi</i> proliferation in murine adipocytes.","authors":"Kazunari Ishii, Yusuke Kurihara, Michinobu Yoshimura, Nirwana Fitriani Walenna, Akinori Shimizu, Ryo Ozuru, Kenji Hiromatsu","doi":"10.1128/mbio.02180-25","DOIUrl":"10.1128/mbio.02180-25","url":null,"abstract":"<p><p>Fatty acid-binding protein 4 (FABP4) is a cytosolic lipid chaperone predominantly expressed in adipocytes. It has been shown that <i>Trypanosoma cruzi</i> targets adipose tissues and resides in adipocytes. However, how <i>T. cruzi</i> manipulates adipocytes to redirect nutrients for its benefit remains unknown. Here, we uncover the role of FABP4 in facilitating <i>T. cruzi</i> infection in murine 3T3-L1 adipocytes. We demonstrate that pharmacological or genetic inhibition of FABP4, carnitine palmitoyltransferase I (CPT-1), or fatty acid oxidation (FAO) abrogates the intracellular growth of <i>T. cruzi</i> in adipocytes. We also found that inhibiting FABP4, CPT-1, or FAO eliminates the infection-induced elevation of mitochondrial and cellular reactive oxygen species (ROS) in adipocytes. Furthermore, <i>T. cruzi</i> infection-induced elevation of ROS in adipocytes increased the cytosolic Fe²⁺, which fueled <i>T. cruzi</i> proliferation. The treatment with antioxidants such as ROS scavenger N-acetyl cysteine (NAC) or mitochondrial ROS inhibitors MitoQ increased the expression level of mRNA for Ferroportin and Ferritin, leading to the decrease in cytosolic Fe²⁺ and the intracellular growth inhibition of <i>T. cruzi</i> in adipocytes. The addition of ferrous sulfate reversed the FABP4 inhibitor or antioxidant-induced decrease in adipocyte parasite burden. Our results demonstrate that <i>T. cruzi</i> exploits host FABP4 to facilitate fatty acid oxidation and elevate cellular ROS, increasing the labile iron pool for the intracellular replication of <i>T. cruzi</i> in adipocytes. These results highlight the therapeutic possibility of host FABP4 as a drug target for <i>T. cruzi</i> infection.IMPORTANCEPersistent infection with a protozoan parasite<i>, Trypanosoma cruzi,</i> causes Chagas disease. While it has been appreciated that adipose tissues are one of the sites of persistent infection, the mechanism of how the parasite survives in adipocytes remains to be established. Our study highlights FABP4, a key regulator of metabolic dysfunction and inflammation, as a therapeutic host target controlling <i>T. cruzi</i> infection in adipocytes. We uncover the importance of FABP4 for <i>T. cruzi</i> replication in mouse adipocytes through engagement with lipid droplet degradation and trafficking of liberated free fatty acids to the host cell's mitochondria, which are utilized for fatty acid oxidation (FAO). <i>T. cruzi</i> infection-induced FAO fuels reactive oxygen species, and the subsequent iron mobilization accelerates parasite replication. These results shed light on the mechanisms of <i>T. cruzi</i> persistent infection in adipocytes, raising the possibility of host FABP4 as a drug target for <i>T. cruzi</i> infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0218025"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015743","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":"Incorporating microbiomes into the One Health Joint Plan of Action.","authors":"Estelle Couradeau, Jennifer B H Martiny, Fanette Fontaine, Christian Brechot, Marc Bonneville, Karel Callens","doi":"10.1128/mbio.01456-25","DOIUrl":"10.1128/mbio.01456-25","url":null,"abstract":"<p><p>The One Health Joint Plan of Action (2022-2026), developed by the United Nations Quadripartite (FAO, UNEP, WHO, and WOAH), provides a comprehensive framework to address global health risks at the human-animal-plant-environment interface. However, it overlooks the critical role of microbiomes-complex microbial communities that underpin the health of all ecosystems and are central to the One Health paradigm. Microbiomes regulate key processes, such as nutrient cycling, pathogen suppression, antimicrobial resistance (AMR) dynamics, and environmental resilience, making their inclusion essential for achieving One Health goals. We argue that incorporating the central role of microbiomes will help us move from managing the symptoms of these challenges toward addressing their root causes and providing sustainable, long-term solutions. This perspective outlines how microbiome science can enhance the core action tracks of the One Health Plan, offering innovative solutions for zoonotic disease prevention, AMR mitigation, food safety, and environmental sustainability. Integrating microbiomes into the One Health agenda is imperative for fostering proactive, cross-sectoral, and sustainable approaches to global health challenges.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0145625"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015752","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":"Amplicon sequencing detects, identifies, and quantifies minority variants in mixed-species infections of <i>Cryptosporidium</i> parasites.","authors":"Randi Turner, Doaa Naguib, Elora Pierce, Alison Li, Matthew Valente, Travis C Glenn, Benjamin M Rosenthal, Jessica C Kissinger, Asis Khan","doi":"10.1128/mbio.01109-25","DOIUrl":"10.1128/mbio.01109-25","url":null,"abstract":"<p><p><i>Cryptosporidium</i> is a globally endemic parasite genus with over 40 recognized species. While <i>C. hominis</i> and <i>C. parvum</i> are responsible for most human infections, human cases involving other species have also been reported. Furthermore, there is increasing evidence of simultaneous infections with multiple species. Therefore, we devised a new means to identify various species of <i>Cryptosporidium</i> in mixed infections by sequencing a 431 bp amplicon of the 18S rRNA gene encompassing two variable regions. Using the DADA2 pipeline, amplicons were first identified to a genus using the SILVA 132 reference database; then <i>Cryptosporidium</i> amplicons to a species using a custom database. This approach demonstrated sensitivity, successfully detecting and accurately identifying as little as 0.001 ng of <i>C. parvum</i> DNA in a complex stool background. Notably, we differentiated mixed infections and demonstrated the ability to identify potentially novel species of <i>Cryptosporidium</i> both <i>in situ</i> and <i>in vitro</i>. Using this method, we identified <i>Cryptosporidium parvum</i> in Egyptian rabbits with three samples showing minor mixed infections. By contrast, no mixed infections were detected in Egyptian children, who were primarily infected with <i>C. hominis</i>. Thus, this pipeline provides a sensitive tool for <i>Cryptosporidium</i> species-level identification, allowing for the detection and accurate identification of minor variants and mixed infections.IMPORTANCE<i>Cryptosporidium</i> is a eukaryotic parasite and a leading global cause of waterborne diarrhea, with over 40 recognized species infecting livestock, wildlife, and people. While we have effective tools for detecting <i>Cryptosporidium</i> in clinical and agricultural water samples, there is still a need for a method that can efficiently identify known species as well as infections with multiple <i>Cryptosporidium</i> species, which are increasingly being reported. In this study, we utilized sequencing of a specific region to develop a sensitive and accurate identification workflow for <i>Cryptosporidium</i> species based on high-throughput sequencing. This method can distinguish between all 40 recognized species and accurately detect mixed infections. Our approach provides a sensitive and reliable means to identify <i>Cryptosporidium</i> species in complex clinical and agricultural samples. This has important implications for clinical diagnostics, biosurveillance, and understanding disease transmission, ultimately benefiting clinicians and produce growers.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":"16 10","pages":"e0110925"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251809","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}