mBio最新文献

{"title":"Longitudinal dynamics and lineage cross-reactivity of the human antibody response to West Nile virus.","authors":"Austin G Leach, Lingling Xu, Shilu Malakar, Monia Pacenti, Stefania Vogiatzis, Sanjeev Kumar, Jacob Vander Velden, Meng Wang, Mitchell J Kendzel, Veronika I Zarnitsyna, Sean Hui, Michael N Nguyen, Christopher A Nelson, Tyshawn Ferrell, Christopher J Neufeldt, Daved H Fremont, Vineet D Menachery, Michael P Busch, Philip J Norris, Marion Lanteri, Luisa Barzon, Jens Wrammert, Mehul S Suthar","doi":"10.1128/mbio.01766-26","DOIUrl":"10.1128/mbio.01766-26","url":null,"abstract":"<p><p>West Nile virus (WNV) is an emerging/re-emerging flavivirus representing one of the major global causes of mosquito-borne encephalitis, yet no approved therapeutics or vaccines currently exist. To characterize the kinetics of WNV-specific immunity, we evaluated the humoral response in a longitudinal cohort of 55 WNV lineage 1-infected blood donors up to 1 year. We demonstrate that WNV infection elicits robust and durable binding and neutralizing antibodies. Using a biphasic decay model, we estimated the half-life of neutralizing antibodies to be 37 days during the rapid decay phase and 472 days during the extended slow decay phase. Notably, the magnitude and durability of these antibodies were largely independent of viral RNA persistence in the whole blood (WB) compartment. To assess the breadth of this response, we evaluated cross-reactivity against an emerging divergent WNV lineage 2 strain and observed that WNV lineage 1-immune sera exhibited reduced neutralizing activity with high variability between donors during both acute and convalescent phases. These deficits in heterologous neutralization were reciprocally confirmed using an independent WNV cohort from Italy. Together, our results establish that lineage-specific divergence results in antibodies with a highly variable reduction in neutralization, indicating that successful WNV vaccine candidates should overcome this variability to confer pan-lineage protection.IMPORTANCEWest Nile virus (WNV) is a growing global health threat spread by mosquitoes that can cause severe disease, yet there are currently no approved vaccines or treatments available. We followed 55 WNV lineage 1-infected blood donors up to 1 year to study their antibody response to infection. We found that natural infection generates a long-lasting antibody response. Interestingly, the magnitude and durability of these antibodies were maintained regardless of viral RNA persistence in the whole blood compartment. However, a potential gap in cross-protective immunity emerged when we examined WNV lineage 1-specific antibodies against WNV lineage 2, a genetically distinct and divergent viral strain with over 25 mutations in the envelope protein. Sera from WNV lineage 1-infected donors showed a highly variable reduction in neutralizing activity against lineage 2 WNV during both the acute and convalescent phases of infection. We corroborated this observation using an independent cohort of patients from Italy, again demonstrating reduced cross-neutralization between the two viral lineages. Together, our results establish that lineage-specific divergence results in reduced cross-neutralization of heterologous strains, indicating that successful WNV vaccine candidates should overcome this barrier to confer pan-lineage protection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0176626"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990517","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":"<i>Candida auris MNN1</i> contributes to human neutrophil evasion via mechanisms independent of β-glucan unmasking.","authors":"Ashley M Holt, Mark V Horton, Chad J Johnson, Robert Zarnowski, Por Choua Vang, Megan Dean, Arianna Kaas, Brody D Andes, Ryley Jones, Douglas Lowman, Michael D Kruppa, Zuchao Ma, David L Williams, Jeniel E Nett","doi":"10.1128/mbio.01701-26","DOIUrl":"10.1128/mbio.01701-26","url":null,"abstract":"<p><p>Systemic <i>Candida</i> (<i>Candidozyma</i>) <i>auris</i> infections can have mortality rates up to 60%, and little is known about immune responses to this fungal pathogen. Neutrophils play a major role in immunity to many fungal pathogens, including <i>Candida</i> species. However, neutrophils internalize <i>C. auris</i> at a lower rate than <i>C. albicans</i>. We previously found that the <i>C. auris</i> cell wall mannan blocks access to β-glucan, an immunostimulatory motif. Here, we analyzed the immune-evasion properties of <i>C. auris</i> mannan separate from glucan masking. We generated eight mannosylation mutants and identified two with increased rates of phagocytosis by human neutrophils. One of these mutants, <i>mnn1</i>Δ, did not exhibit increased exposure of β-glucan. Nuclear magnetic resonance analysis of <i>mnn1</i>Δ mannan showed decreased α-1,3-mannose linkages and acid-labile side chains. These structural changes increased the affinity of human Dectin-2 and Mincle for mannans <i>in vitro</i>, and Fab blocking of Dectin-2 decreased human neutrophil phagocytosis of <i>mnn1</i>Δ. Overall, our work provides insight into human neutrophil recognition of <i>C. auris</i> mannans and further understanding of mechanisms of immune evasion for this fungal pathogen.IMPORTANCECell surface glycan recognition plays an important role in the innate immune response to fungal pathogens. Here, we use <i>Candida auris</i> mannosylation mutants to identify <i>C. auris</i> genes that contribute to its neutrophil evasion properties. We identify a mannosylation gene, <i>MNN1</i>, that contributes to human and murine peripheral blood neutrophil evasion without significantly impacting beta-glucan masking. We attribute <i>MNN1</i> to the alteration of cell surface mannans that leads to decreased Dectin-2-binding affinity. While mannan has been associated with masking β-glucan in the <i>C. auris</i> cell wall, the impact of specific mannan structures on receptor binding presents an additional mechanism of neutrophil evasion for <i>C. auris</i>.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0170126"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039570","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":"Temperature during conidiophore development primes <i>Aspergillus fumigatus</i> spore transcriptome for asexual or sexual reproduction.","authors":"Justina M Stanislaw, Michelle Momany","doi":"10.1128/mbio.01831-26","DOIUrl":"10.1128/mbio.01831-26","url":null,"abstract":"<p><p><i>Aspergillus fumigatus</i> is a thermotolerant saprobe found in soils and plant debris worldwide and an important pathogen of humans, causing two million deaths annually. <i>A. fumigatus</i> makes abundant asexual spores (conidia), which are widely distributed by wind and can be inhaled from the environment. In susceptible individuals, inhaled conidia break dormancy, germinate, and grow in the lung, leading to serious disease. Recent work has shown that conidia made at 37°C and 50°C have different morphologies and germination kinetics. While the asexual cycle is well-characterized at 37°C, much less is known about the asexual cycle at 50°C. Here, we combine flow cytometry and transcriptomics to track morphology and gene expression in the hyphae, conidiophores, and conidia of <i>A. fumigatus</i> during asexual development at 37°C or 50°C. We show that the temperature during a narrow time window in late-stage conidiophore development dictates resulting conidial morphology, transcriptional program, and germination kinetics. As expected, conidiation at 37°C resulted in upregulation of <i>brlA</i>, encoding the master regulator of asexual development, and its downstream targets in conidiophores and conidia. Surprisingly, conidiation at 50°C resulted in upregulation of <i>MAT1-1-1</i>, encoding the master regulator of sexual development, and its downstream targets in conidiophores and conidia. Our findings suggest that temperature during late conidiophore development transcriptionally primes conidia for asexual, parasexual, or sexual development, enhancing chances of survival for progeny. Our findings are especially relevant for agricultural compost, where a wide gradient of temperatures exists, abundant <i>A. fumigatus</i> has been isolated, and resistance to antifungals is thought to evolve.IMPORTANCEThe human pathogen <i>Aspergillus fumigatus</i> has been found in natural and agricultural environments around the world. Disease is acquired when susceptible individuals inhale airborne asexual spores from the environment, which in agriculture generally includes proximity to compost and plant debris piles. This work shows that the environmental temperature when <i>A. fumigatus</i> spores are made determines the transcriptomes of those spores, priming them for future asexual or sexual development. The survival of asexual and sexual spores is very different at different temperatures, so these results are important for understanding how this pathogen survives in varied hostile environments. In addition, there are very few antifungal drugs with which to treat <i>A. fumigatus</i> infections, and resistance is increasing, driven in part by agricultural use of fungicides. These results suggest that higher temperatures during asexual spore formation can lead to increased sexual reproduction and greater chances to evolve antifungal resistance.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0183126"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865618","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":"Unique amino acid substitution within the spike glycoprotein S1 subunit promotes infectious bronchitis virus infection via enhancing viral attachment.","authors":"Tianyi Liu, Yujuan Zhang, Zongxi Han, Huixin Li, Yuhao Shao, Junfeng Sun, Shengwang Liu","doi":"10.1128/mbio.00884-26","DOIUrl":"10.1128/mbio.00884-26","url":null,"abstract":"<p><p>Due to the scarcity of cell-adapted strains and limitations of current reverse genetics techniques, the factors determining cell tropism of infectious bronchitis virus (IBV), a prototype <i>gammacoronavirus</i>, remain unclear. Here, we demonstrated that the expanded cell tropism of CEA, a chicken embryo fibroblast-adapted strain derived from tl/CH/LDT3/03, was related to its enhanced attachment capacity. Then, a reverse genetics platform for IBV based on circular polymerase extension reaction (CPER) was established, enabling the successful recovery of rCEA and rLDT, which retained the biological properties of their respective parental viruses. Using this platform, we constructed a series of chimeric viruses based on the CEA strain by incorporating the entire S gene, the S1 and S2 subunits, and substitutions at differential sites derived from the tl/CH/LDT3/03 strain. Our findings indicated that subunit S1, rather than S2, was associated with viral adaptation in DF-1 cells, with the amino acid residue at position 413 in the C-terminal domain of the S1 protein as a key determinant. Evaluation with recombinant S1 proteins and chimeric viruses revealed that the histidine residue at position 413 (His413) promoted enhanced attachment of both S1 proteins and viruses to cells, while exerting no direct effect on viral entry. Mechanistically, His413 facilitated efficient viral binding to α-2,3-linked sialic acids presented on gangliosides rather than glycoproteins. This interaction activated Src kinase and triggered caveolae-mediated endocytosis, initiating viral entry and subsequent replication. Collectively, the CPER-based reverse genetics platform established in this study represents a significant technical advancement for IBV, and our findings provide novel insights into the cell adaptation and entry mechanisms of IBV.IMPORTANCEAlthough infectious bronchitis virus (IBV) was the first discovered coronavirus, the cellular receptors and cofactors that mediate successful infection, as well as the specific pathways and mechanisms of viral entry into host cells, remain to be elucidated. In this study, we established a reverse genetics platform for IBV using circular polymerase extension reaction for the first time. A series of chimeric viruses were subsequently recovered, and a specific amino acid substitution at position 413 in the C-terminal domain of the S1 subunit was identified as a key determinant for the expanded DF-1 cell tropism of IBV. The histidine residue at this site facilitated viral binding to α-2,3-linked sialic acids on gangliosides, thereby activating the caveola-mediated endocytosis and enabling viral entry into DF-1 cells. This study provides novel insights into the receptor-binding function of the IBV S protein and the strategies employed by the virus for cell adaptation. Additionally, our findings offer new perspectives for developing cell-culture-based vaccines.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0088426"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886939","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 canine gut microbiome as a translational model for human health and aging.","authors":"Zsolt Boldogkői, Dóra Tombácz","doi":"10.1128/mbio.01951-26","DOIUrl":"10.1128/mbio.01951-26","url":null,"abstract":"<p><p>The domestic dog is increasingly recognized as a complementary translational model for microbiome research relevant to human health while also offering direct benefits for veterinary medicine. Dogs share environments and dietary exposures with humans and show substantial taxonomic and gene-content similarity to the human gut microbiome, although the apparent degree of similarity depends strongly on whether read recruitment, gene-catalog overlap, or functional overlap is assessed. Dogs also develop spontaneous chronic enteropathies, obesity-associated metabolic dysfunction, cancers, cognitive dysfunction, and behavioral disorders in which gut microbial changes can be examined under clinically realistic conditions. Their shorter, breed- and body-size-dependent lifespan permits repeated sampling across development, aging, disease progression, and treatment within practical timeframes. Breed structure, full-sibling cohorts, controlled dietary interventions, and access to clinically indicated samples from multiple anatomical compartments can strengthen selected study designs, although they do not provide the tighter genetic, environmental, and microbial control achievable in rodents. Here, we evaluate the research questions for which canine cohorts are especially informative, synthesize evidence linking canine and human disease-associated microbiomes, and critically assess aging, causal inference, and One Health applications. Major limitations include the need for breed and body-size stratification, heterogeneous diet and husbandry, incomplete treatment histories, the lack of routinely available gnotobiotic canine systems, and gaps in canine-specific reference resources. The canine system is therefore most informative when study designs exploit its clinical realism while acknowledging the tighter experimental control offered by reductionist models, positioning the dog as a complementary rather than a universally superior model.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0195126"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148969937","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 plasmid-encoded genetic switch orchestrates the bacterial virulence-fitness trade-off to drive antibiotic resistance dissemination.","authors":"Hongcheng Wei, Wenlan Yang, Tiejun Zhang, Wei Xu, Ke Wu, Linghan Kong, Hao Li, Kailu Wang, Wenjun Yan, Ming Yang, Changyu Zhou, Songhua Li, Zhonghan Li, Changwei Lei, Hongning Wang","doi":"10.1128/mbio.01899-26","DOIUrl":"10.1128/mbio.01899-26","url":null,"abstract":"<p><p>The global dissemination of multidrug-resistant plasmids poses a major threat to antimicrobial therapy. While these plasmids are known to carry antibiotic resistance genes, how they balance bacterial fitness and virulence to ensure their own persistence and dissemination remains unclear. Here, we identify a previously unannotated IncFII plasmid-encoded protein, which we name type 1 fimbrial repressor (T1FR). T1FR directly binds the <i>fimS</i> phase-variation switch, locking it in the \"off\" orientation to suppress type 1 fimbria (T1F) biogenesis, thereby attenuating bacterial adhesion, colonization, and pathogenicity. Concurrently, T1FR reprograms central carbon metabolism to offset the fitness cost of plasmid carriage, thereby enhancing plasmid transconjugative efficiency and host competitive fitness. This dual function is dynamically modulated by LtrA-mediated suppression of T1fr transcription, introducing plasticity into the virulence-fitness trade-off. Collectively, the LtrA-T1FR system orchestrates an evolutionary trade-off between plasmid fitness and host pathogenicity. Targeting the T1FR-T1F axis may offer a novel anti-adhesion therapeutic that avoids selection for antibiotic resistance.IMPORTANCEBacterial resistance has become one of the most serious public health issues worldwide. The evolution and spread of drug-resistant plasmids represent one of the significant approaches for bacteria to acquire resistance, and drug-resistant bacteria often have a high mortality rate. However, the association and regulatory mechanism between antibiotic-resistant plasmids and bacterial virulence are currently unclear. The IncFII plasmid is considered an epidemic-resistant plasmid and plays a critical role in the widespread spread of carbapenem antibiotic resistance genes. This study identified a novel protein, T1FR type 1 fimbrial repressor), in IncFII plasmids and explored its regulatory mechanism by inhibiting the generation of host bacterial type 1 fimbriae, thereby weakening bacterial virulence and facilitating stable plasmid transmission. This study provides the scientific basis for understanding the correlation between bacterial resistance and virulence and promotes the scientific prevention and comprehensive management of bacterial infections.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0189926"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977092","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":"Targeted, genome-scale overexpression in Proteobacteria.","authors":"Amy B Banta, Ashley N Hall, Kevin S Myers, Ryan D Ward, Bryce C Davis, Rodrigo A Cuellar, Michael Place, Claire C Freeh, Emily E Bacon, Jason M Peters","doi":"10.1128/mbio.02340-25","DOIUrl":"10.1128/mbio.02340-25","url":null,"abstract":"<p><p>Targeted, genome-scale gene perturbation screens using clustered regularly interspaced short palindromic repeats interference (CRISPRi) and activation (CRISPRa) have revolutionized eukaryotic genetics, advancing medical, industrial, and basic research. Although CRISPRi knockdowns have been broadly applied in bacteria, options for genome-scale gene overexpression face key limitations. Here, we develop a facile approach for genome-scale overexpression in bacteria we call CRISPR transposition and overexpression (CRISPRtOE). We first create a platform for comprehensive gene targeting using CRISPR-associated transposons (CASTs) and show that transposition occurs at a higher frequency in non-transcribed DNA. We then demonstrate that CRISPRtOE can upregulate gene expression in Proteobacteria with medical and industrial relevance by integrating synthetic promoters of varying strength upstream of target genes. Finally, we employ CRISPRtOE screening at the genome scale in the model bacterium <i>Escherichia coli</i> and the non-model biofuel producer <i>Zymomonas mobilis</i>, recovering known and novel antibiotic and engineering targets. We envision that CRISPRtOE will be a valuable overexpression tool for antibiotic mode of action, industrial strain optimization, and gene function discovery in bacteria.IMPORTANCESystematic alteration of bacterial gene expression enables identification of genes relevant to diverse fields of study and practical applications. Although many targeted, genome-scale genetic tools exist for reducing or eliminating gene expression, there are few facile approaches for systematic gene overexpression in bacteria. Here, we develop a targeted overexpression approach for Proteobacteria of medical and industrial importance that precisely inserts strong promoters upstream of genes using clustered regularly interspaced short palindromic repeats (CRISPR)-associated transposons. We demonstrate that this approach can be used to systematically overexpress genes in both model (<i>Escherichia coli</i> K-12) and non-model (<i>Zymomonas mobilis</i>) Proteobacteria for the purpose of understanding antibiotic resistance mechanisms and improving strain resilience in biofuel production conditions, respectively.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0234025"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012514","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 transcriptional response of <i>Yersinia pseudotuberculosis</i> to macrophage-released metabolites during growth within synthetic microcolonies.","authors":"Stacie A Clark, Alexander Palmer, Wenwen Huo, Alexander C Joyce, Kimberly M Davis, Juan Ortiz-Marquez, Tim van Opijnen, Ralph R Isberg","doi":"10.1128/mbio.00691-26","DOIUrl":"10.1128/mbio.00691-26","url":null,"abstract":"<p><p><i>Yersinia pseudotuberculosis</i> (<i>Yptb</i>) replicates in immune cell-encompassed microcolonies within tissues. Bacterial replication is controlled by protection against neutrophil attack and by macrophage-released antimicrobial factors, such as nitric oxide (NO). During these attacks, bacteria located on the microcolony periphery encounter extracellular signals that differ from those in the interior. To dissect individual microbial populations, γ interferon-activated macrophages were used to challenge microdroplet-grown <i>Yptb</i> harboring an NO-responsive mCherry reporter. Subsequently, bacterial subpopulations that hyperactivated the reporter were isolated from droplets composed of a reversible polymer matrix. RNA-seq analysis indicated that induction of nitrosative stress-associated genes was the primary determinant distinguishing peripheral bacteria from the remaining population. In addition, a secondary stress response that induced prophage-associated genes was detected, which could not be traced to either DNA damage or nitrosative stress responses. Activated macrophages also induced the expression of the <i>Yptb</i> itaconate degradation enzyme-encoding transcript throughout the entire colony. To determine if itaconate production by the interferon-activated Irg1 protein played a role in restricting <i>Yptb</i>, bacteria harboring an itaconate-responsive reporter and <i>Yptb</i> mutants defective for itaconate degradation were analyzed during bacterial colonization of the murine spleen. Only a subset of colonies appeared to be exposed to itaconate, which may explain the very small defects exhibited by mutants unable to degrade the interferon-induced macrophage product. These results indicate that the primary response of bacteria to macrophage-elicited factors is likely associated with protection against NO-derived metabolites.</p><p><strong>Importance: </strong>Bacterial microcolonies are often linked to invasive infectious diseases. Once established, organisms as diverse as <i>Staphylococcus aureus</i> and enteropathogenic <i>Yersinia</i> recruit activated macrophages that surround these sites. For <i>Yersinia pseudotuberculosis</i>, the layer of distant macrophages induces a nitric oxide (NO)-inactivating enzyme in the outermost bacteria, enabling bacteria in the core to survive. This study shows that the cellular states of bacteria in the periphery and the core can be examined by recreating tissue infection in an in vitro system, in which microcolonies form within droplets of a degradable solid matrix, surrounded by interferon-activated macrophages. Transcriptomic analysis revealed that the peripheral bacteria primarily differ from the core in their response to NO. Surprisingly, the entire colony is bathed in itaconate, an immune-modulating chemical produced by activated macrophages. The ability to respond to itaconate may help rare bacteria engulfed by macrophages to survive phagocytic attack.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0069126"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012581","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":"HCMV US30 induces TMED10-DRP1-mediated mitochondrial fission and apoptosis to promote viral multiplication.","authors":"Ya-Li Lei, Yu-Ting Cai, Ruo-Tong Chen, Peng Ren, Xue-Mei Yi, Yu-Zhi Fu, Yan-Yi Wang, Shu Li, Hong-Bing Shu","doi":"10.1128/mbio.01740-26","DOIUrl":"10.1128/mbio.01740-26","url":null,"abstract":"<p><p>Human cytomegalovirus (HCMV) hijacks host components to modulate cell death for its optimized replication and dissemination. We identified HCMV US30 as a viral factor that induces caspase-dependent apoptosis. US30 induces both DRP1-dependent mitochondrial fission and subsequent apoptosis, as well as IRE1α-mediated unfolded protein responses (UPR). Mechanistically, US30 interacts with NPL4 to impair ER-associated protein degradation and subsequently induce UPR. In parallel, US30 associates with the Endoplasmic reticulum-Golgi intermediate compartment (ERGIC) protein TMED10 and promotes its translocation to the cytoplasm, where it activates DRP1 to initiate mitochondrial fission and subsequent caspase-dependent apoptosis. US30 induces UPR and mitochondrial fission/apoptosis via distinct domains, and the two distinct effects are uncoupled. We also show that US30-induced mitochondrial fission and apoptosis, but not UPR, contribute to the multiplication and dissemination of HCMV. These findings reveal that HCMV US30 induces mitochondrial fission and apoptosis to promote viral replication and dissemination and provide potential targets for intervention of HCMV-induced diseases.IMPORTANCEHuman cytomegalovirus (HCMV) is a human pathogenic herpesvirus that causes global epidemics. HCMV hijacks cellular compartments to maintain its replication and dissemination, which is associated with host cell fate. Here, we identified HCMV US30 as a viral factor to induce caspase-dependent apoptosis. Proteomics analysis revealed that US30 disrupts both ER and mitochondrial homeostasis. We further found that US30-induced mitochondrial fission, but not UPR, mediates apoptosis. Mechanistically, our results indicate that US30 interacts with NPL4 to activate UPR and associates with TMED10 to trigger mitochondrial fission, which are dependent on distinct domains of US30. Most importantly, we found that US30 alters the localization of TMED10 from ERGIC to the cytosol to activate DRP1. Finally, our results showed that US30-induced mitochondrial fission and apoptosis, but not UPR, contribute to the multiplication and dissemination of HCMV. These findings enhance our understanding of HCMV-host interplay and provide potential targets for intervention of HCMV-induced diseases.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0174026"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017295","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 conserved partner-switching system controls terminal differentiation in multicellular cyanobacteria.","authors":"Stéphanie Champ, Eva Furet, Frédérique Pompeo, Xiaomei Xu, Sylvain Lemeille, Marine Novelli, Zorah Dermoun, Matthieu Bergé, Emmanuel Talla, Amel Latifi","doi":"10.1128/mbio.01685-26","DOIUrl":"10.1128/mbio.01685-26","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Canonical partner-switching systems (PSSs) regulate sigma factor activity through reversible phosphorylation, but their established roles have been largely limited to stress responses and sporulation in Firmicutes. Whether this regulatory mechanism also controls developmental cell fate decisions in other bacterial phyla has remained unknown. Here, we identify a canonical PSS that governs heterocyst differentiation in the multicellular cyanobacterium &lt;i&gt;Anabaena&lt;/i&gt; sp. PCC 7120. This system comprises the anti-sigma factor All2284 (NfsS) and the anti-anti-sigma factor All2283 (NfsR). Structural predictions and biochemical assays showed that NfsS phosphorylates NfsR on a conserved serine residue, whereas bacterial two-hybrid and co-purification assays demonstrated that NfsS binds the developmental sigma factors SigC and SigE. Deletion of &lt;i&gt;nfsR&lt;/i&gt; abolished heterocyst formation and diazotrophic growth, and transcriptomic analysis revealed broad failure to induce late heterocyst genes, including nitrogen fixation functions such as &lt;i&gt;nifHDK&lt;/i&gt; and &lt;i&gt;fdxH&lt;/i&gt;. Phylum-wide comparative genomics further showed that PSS genes and putative functional clusters are strongly enriched in filamentous and heterocyst-forming taxa, indicating an association between the expansion of these signaling modules and the emergence of multicellularity and developmental specialization. Together, these findings establish a PSS as a direct regulator of terminal cell differentiation in a gram-negative bacterium and reveal partner switching as a conserved regulatory principle linking environmental signaling to developmental fate in a major bacterial phylum.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;While partner-switching systems are classically associated with stress responses and sporulation control in Firmicutes, whether this regulatory logic governs developmental decisions in other bacterial phyla has remained unknown. Here, we establish that a related partner-switching mechanism operates in a distinct bacterial lineage, the cyanobacteria, where it controls a major developmental transition involving terminal cell differentiation. Specifically, we show that a phosphorylation-dependent checkpoint involving the anti-sigma factor NfsS and the anti-anti-sigma factor NfsR directly regulates heterocyst formation. Disruption of this switch abolishes cell differentiation and diazotrophic growth, revealing that this system is an obligate gatekeeper for terminal differentiation. Conceptually, these findings substantially extend the known functional repertoire of partner-switching circuits: rather than controlling stress adaptation or spore dormancy, this module has been co-opted to govern a complex, multicellular developmental program in an organism that underpins global carbon and nitrogen cycles. This work, therefore, establishes a new paradigm for phosphorylation-based control of developmental sigma factors and provides a tractable model for dissecting how conserved signaling m","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0168526"},"PeriodicalIF":5.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887857","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}