mBio最新文献

{"title":"An NLRP3-stimulatory adjuvant improves the immunogenicity of influenza virus vaccines in mice and non-human primates.","authors":"Kelsey Finn, Jonathan Chow, Dania Zhivaki, Debrup Sengupta, Holly Concepcion, Veronica Komoroski, Carolyn MacFarlane, Philip D Coblentz, Milap Chokshi, Stephan Matissek, Emily Gosselin, Dahlia Alkekhia, Anastasia Nikiforov, Nicolina Lamberti, Victory Iheanyichukwu, Colin Kelly, Chisom Arinze, Andrew Cornforth, Sivan Elloul, Jonathan C Kagan","doi":"10.1128/mbio.02343-25","DOIUrl":"10.1128/mbio.02343-25","url":null,"abstract":"<p><p>Dendritic cells (DCs) are the primary inducers of immunity induced by infection or vaccination. To stimulate durable T cell-mediated immunity, multiple DC activities are required. DCs must present antigen, express costimulatory molecules, and secrete inflammatory cytokines to direct T cell activation. These activities must be coordinated with DC migration to the lymph node and production of memory T cell-inducing cytokines, such as IL-1β. Common vaccination approaches use adjuvants that stimulate a subset of these activities, leading to diminished T cell activities and poor immune durability. We describe herein a lipid-based adjuvant, called a hyperactivator, which elicits all five of the aforementioned DC activities. Other adjuvants examined, including those used clinically, were defective for one or more of the key activities needed for robust T cell activation. Vaccines in mice and nonhuman primates targeting influenza virus antigens, including the quadrivalent commercial product Afluria, displayed enhanced adaptive immune responses when administered using hyperactivators as adjuvants. These data highlight the impact of hyperactivator adjuvants as a means to enhance antigen-specific immunity, with potential applications towards a universal influenza vaccine.</p><p><strong>Importance: </strong>The generation of vaccines that stimulate T cell activities is an unmet need for the scientific community, as T cells are the primary mediators of immune memory. In this study, we report a new vaccine adjuvant called a hyperactivator. This hyperactivator adjuvant diversifies the T cell and antibody responses to virus antigens, such that in nonhuman primates, all influenza strains in the clinical vaccine Afluria are targeted. Hyperactivator adjuvants may represent a means to achieve the long-sought-after goal of a universal influenza vaccine.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0234325"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015768","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":"Probing the mechanism of peptidoglycan amidase activation by FtsEX-EnvC.","authors":"Jonathan Cook, Allister Crow","doi":"10.1128/mbio.02114-25","DOIUrl":"10.1128/mbio.02114-25","url":null,"abstract":"<p><p>The FtsEX-EnvC-AmiA/B system is a key component of the <i>E. coli</i> cell division machinery that directs breakage of the peptidoglycan layer during separation of daughter cells. Structural and mechanistic studies have shown that ATP binding by FtsEX in the cytoplasm drives periplasmic conformational changes in EnvC, which lead to the binding and activation of peptidoglycan amidases such as AmiA and AmiB. The FtsEX-EnvC amidase system is highly regulated to prevent cell lysis with at least two separate layers of autoinhibition that must be relieved to initiate peptidoglycan hydrolysis during division. Here, we test the FtsEX-EnvC amidase activation mechanism through site-directed mutagenesis. We identify mutations that disrupt the autoinhibition mechanism of FtsEX-EnvC and an N-terminal deletion variant that prevents activation. Finally, we develop a cysteine locking residue pair that stabilizes the complex in its amidase activating conformation. The reported EnvC variants greatly enhance our understanding of the FtsEX-EnvC autoinhibition mechanism and the conformational changes underpinning amidase activation. Our observations are consistent with the proposed mechanism of amidase activation by large-scale conformational changes in FtsEX-EnvC, allowing recruitment and activation of peptidoglycan amidases.IMPORTANCEIn <i>E. coli</i>, the FtsEX-EnvC system regulates two of the three division-associated amidases that break the peptidoglycan layer during bacterial division. Structural and mechanistic studies have revealed a detailed molecular mechanism for amidase activation in which an ABC transporter and its periplasmic partner reversibly activate periplasmic amidases under direction of the cytoplasmic cell division machinery. This paper explores structural features of EnvC that underpin autoinhibition and the activation mechanism. The FtsEX-EnvC system serves as a powerful example of a Type VII ABC transporter that uses transmembrane conformational changes to drive work in the periplasmic space.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0211425"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015808","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":"Human antibody targeting <i>Vibrio cholerae</i> O1 O-specific polysaccharide induces an amotile hypovirulent bacterial phenotype: mechanism of protection against cholera.","authors":"Smriti Verma, Murat Cetinbas, Meagan Kelly, Stefania Senger, Christina S Faherty, Jeshina Janardhanan, Chanchal R Wagh, Taufiqur Rahman Bhuiyan, Fahima Chowdhury, Ashraful Islam Khan, Aklima Akter, Richelle C Charles, Jason B Harris, Stephen B Calderwood, Jens Wrammert, Matthew K Waldor, Merrill Asp, Jung-Shen Benny Tai, Jing Yan, Peng Xu, Pavol Kováč, Ruslan I Sadreyev, Firdausi Qadri, Edward T Ryan","doi":"10.1128/mbio.02235-25","DOIUrl":"10.1128/mbio.02235-25","url":null,"abstract":"<p><p>Antibodies targeting the O-specific polysaccharide (OSP) of <i>Vibrio cholerae</i> O1 are crucial determinants of protection against cholera. These antibodies agglutinate bacteria and, even in sub-agglutinating conditions, inhibit <i>V. cholerae</i> motility. To explore additional effects of OSP-specific antibodies, we examined the transcriptomic profiles of <i>V. cholerae</i> exposed to a human anti-OSP monoclonal antibody in the presence of mucin, the main component of intestinal mucus, and the substance in which <i>V. cholerae</i> and mucosal antibodies interact in infected humans. Beyond genes whose transcript levels were affected by either mucin alone or antibody alone, we identified a set of genes whose expression levels were specifically altered in the presence of both anti-OSP antibody and mucin. These genes are involved in diverse processes such as metabolism, transport, stress response, biofilm formation, motility, and second messenger signaling. Additional culture-based assays and a human small intestine enteroid model confirmed the broad impact of OSP-specific antibodies on <i>V. cholerae</i>, including the inhibition of motility, downregulation of virulence mechanisms, and a shift of bacterial metabolism toward decreased synthesis of intermediates and precursors in a sessile state secreting extracellular matrix component of a biofilm. Collectively, our findings reveal that antibodies targeting <i>V. cholerae</i> OSP markedly transform the pathogen's physiology and disrupt its virulence program. We propose that these effects explain how antibodies targeting <i>V. cholerae</i> OSP mediate protection against cholera at the intestinal surface of infected humans.IMPORTANCEImmunity to cholera is largely mediated by antibodies targeting the O-specific polysaccharide (OSP) of <i>Vibrio cholerae,</i> including through agglutination as well as inhibition of bacterial motility. Here, we used bacterial transcriptomic, biochemical, and cellular analyses to evaluate additional effects of OSP-specific antibodies on <i>V. cholerae</i> in complex media containing mucin and in a human enteroid-derived monolayer colonization model. We found that anti-OSP antibody in mucin impacts bacterial motility, growth, metabolic activity, extracellular matrix production, and levels of cyclic di-GMP. We did not observe a direct effect on bacterial viability, sodium motive force gradient, membrane integrity for large molecules, or virulence gene or regulon expression in bacterial cultures, although cholera toxin detection was significantly decreased in the enteroid model. Our results uncover the broad impact of anti-OSP antibodies in the presence of mucin on <i>V. cholerae</i> physiology and suggest several ways OSP-specific antibodies mediate protection against cholera in humans.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0223525"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040610","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":"Unculturable bacteria exploit a secretory protein to antagonize insect melanization for persistent infection.","authors":"You Li, Yu Du, Dongsheng Ren, Yu Bin, Qian Chen, Taiyun Wei","doi":"10.1128/mbio.01896-25","DOIUrl":"10.1128/mbio.01896-25","url":null,"abstract":"<p><p>Phloem-inhabiting unculturable bacterial pathogens are persistently transmitted by insect vectors. However, how they evade insect immune responses to ensure persistent transmission remains unknown. The important melanization immune response in insects is triggered by cleavage of prophenoloxidase (PPO) into active phenoloxidase (PO) via clip-domain serine proteases (CLIPs). Here, we demonstrate that infection of <i>Candidatus</i> Liberibacter asiaticus (<i>C</i>Las) in psyllid vectors activates the peptidoglycan recognition protein (PGRP)-CLIP1-CLIP4-PPO-PO signaling cascade to induce a mild melanization response, ensuring persistent <i>C</i>Las infection without causing significant insect fitness costs to the insect. A <i>C</i>Las-encoded secretory protein, SDE3230, directly interacts with PGRP and suppresses its activity in transducing this signaling cascade. CLIP4 cleaves PPO between arginine 125 and methionine 126 residues to active PO to induce melanization, and this cleavage pattern in psyllid is distinct from other insects. However, SDE3230 competitively binds to this cleavage site of PPO with CLIP4, thereby suppressing PPO effective cleavage. Collectively, these findings reveal the dual role of SDE3230 in facilitating the mild melanization response, benefitting persistent <i>C</i>Las infection and insect fitness.IMPORTANCEPsyllid-borne huanglongbing is the most destructive citrus disease worldwide, causing billions of dollars in annual production losses and threatening the entire citrus industry. Currently, the mechanism by which the causal agent <i>Candidatus</i> Liberibacter asiaticus (<i>C</i>Las) antagonizes psyllid innate immune responses to facilitate its coexistence with psyllid vectors is still unknown. Here, we report that <i>C</i>Las exploits the highly expressed secretory protein SDE3230 in psyllids to suppress the important melanization immune response in hemolymph via inhibiting the pattern recognition receptor PGRP activity and the cleavage of prophenoloxidase into active phenoloxidase by clip-domain serine proteases. The pattern of PPO cleavage is novel, and this process ultimately ensures persistent <i>C</i>Las infection and insect fitness. Our findings provide insights into how <i>C</i>Las has evolved novel strategies to evade the insect melanization response, thereby facilitating persistent <i>C</i>Las transmission.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0189625"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959703","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":"Nucleoid compaction influences carboxysome localization and dynamics in <i>Synechococcus elongatus</i> PCC 7942.","authors":"Claire E Dudley, Christopher A Azaldegui, Daniel J Foust, Olivia LaCommare, Julie S Biteen, Anthony G Vecchiarelli","doi":"10.1128/mbio.01919-25","DOIUrl":"10.1128/mbio.01919-25","url":null,"abstract":"<p><p>The bacterial nucleoid is not just a genetic repository-it serves as a dynamic scaffold for spatially organizing key cellular components. ParA-family ATPases exploit this nucleoid matrix to position a wide range of cargos, yet how nucleoid compaction influences these positioning reactions remains poorly understood. We previously characterized the maintenance of carboxysome distribution (Mcd) system in the cyanobacterium <i>Synechococcus elongatus</i> PCC 7942, where the ParA-like ATPase McdA binds the nucleoid and interacts with its partner protein, McdB, to generate dynamic gradients that distribute carboxysomes for optimal carbon fixation. Here, we investigate how nucleoid compaction impacts carboxysome positioning, particularly during metabolic dormancy when McdAB activity is downregulated. We demonstrate that a compacted nucleoid maintains carboxysome organization in the absence of active McdAB-driven positioning. This finding reveals that the nucleoid is not merely a passive matrix for positioning but a dynamic player in spatial organization. Given the widespread role of ParA-family ATPases in the positioning of diverse cellular cargos, our study suggests that the nucleoid compaction state is a fundamental, yet underappreciated, determinant of mesoscale organization across bacteria.</p><p><strong>Importance: </strong>Bacteria can organize their internal components in specific patterns to ensure proper function and faithful inheritance after cell division. In the cyanobacterium <i>Synechococcus elongatus</i>, protein-based compartments called carboxysomes fix carbon dioxide and are distributed in the cell by a two-protein positioning system. Here, we discovered that when cells stop growing or face stress, these positioning proteins stop working, yet carboxysomes remain distributed in the cell. Our study shows that the bacterial chromosome, which holds genetic information, can also act as a flexible scaffold that holds carboxysomes in place when compacted. This insight reveals that the bacterial chromosome plays a key physical role in organizing the cell. Similar positioning systems are found across many types of bacteria; therefore, our findings suggest that nucleoid compaction may be a universal and underappreciated factor in maintaining spatial order in cells that are not actively growing.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0191925"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959833","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":"Inhibitory effect of capsule on natural transformation of <i>Streptococcus pneumoniae</i>.","authors":"Sheya Xiao Ma, Hannes Eichner, Michael Cammer, Jeffrey N Weiser","doi":"10.1128/mbio.01394-25","DOIUrl":"10.1128/mbio.01394-25","url":null,"abstract":"<p><p>The capsule of <i>Streptococcus pneumoniae</i> (<i>Spn</i>) is highly heterogeneous based on the expression of distinct polysaccharides. <i>Spn</i> transformation, controlled by the Com regulon, has been predominantly studied using unencapsulated laboratory strains. However, genomic studies revealed different rates of recombination events in clinical isolates of different serotypes. As these isolates were genetically distinct beyond capsule-encoding genes, the exact relationship between transformation and capsule remains unclear. Herein, we compared the transformability of a collection of isogenic capsule-switch strains. Strains with different capsule types and amounts significantly differed in their transformation frequency, with the unencapsulated strain having a higher frequency compared to encapsulated strains. A GFP-reporter of each strain monitoring the expression of a Com regulon-controlled gene showed similar kinetics, indicating differences in transformability were due to processes downstream of competence activation. The Com pilus, induced by competence, binds and takes in the donor DNA and is the central component of the transformation apparatus. The surface exposure of Com pilus significantly differed among serotypes with highly transformable strains having more cells binding ComGC antibody. Furthermore, electron microscopy demonstrated that transformability correlated with the proportion of cells bearing a Com pilus, which was affected by both the presence of capsule and serotype. Additionally, the unencapsulated strain displayed longer pili than encapsulated strains. Examination of capsule porosity revealed that serotypes with higher transformation frequencies had more porous capsules. Together, these results indicate that the capsule interferes with the assembly of Com pilus, thereby inhibiting the natural transformation of <i>Spn</i>.IMPORTANCEThe capsule is a major virulence factor of <i>Streptococcus pneumoniae</i> (<i>Spn</i>), providing a physical shield and exhibiting extensive diversity across at least 100 serotypes. Although natural transformation of <i>Spn</i> has predominantly been characterized in unencapsulated laboratory strains, clinical encapsulated isolates also exhibit transformability and demonstrate varied recombination rates during host carriage. We utilized otherwise genetically identical capsule-switch strains to isolate the effect of capsule on transformation. We demonstrate serotype- and quantity-dependent inhibition of transformation by the capsule, mediated through hindrance with the transformation pilus assembly and function. This study challenges the paradigm that unencapsulated laboratory strains fully recapitulate natural transformation dynamics. By redefining the capsule as a multifunctional modulator of <i>Spn</i> biology, balancing virulence and adaptability, our findings advance our understanding of pneumococcal evolution.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0139425"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959843","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":"Multiple long-range <i>cis</i> interactions generate CTCF insulator-dependent viral chromatin domains in quiescent HSV-1 genomes.","authors":"Alyssa Richman, Sophie Kogut, Terri Edwards, Joseph Boyd, Princess Rodriguez, Michael Mariani, Mason A Shipley, Kayley A Manuel, Ziyun A Ye, David C Bloom, Seth Frietze, Donna M Neumann","doi":"10.1128/mbio.01638-25","DOIUrl":"10.1128/mbio.01638-25","url":null,"abstract":"<p><p>In cellular genomes, CCCTC-binding factor (CTCF) insulators impact transcription over small distances in a one-dimensional manner and over much longer distances in a three-dimensional manner by maintaining chromatin loops. We have previously shown that the latent HSV-1 genome contains CTCF insulators that function to regulate lytic transcription of adjacent genes in a one-dimensional manner. Here, we test the hypothesis that HSV-1 CTCF insulators nucleate chromatin loops to regulate the expression of distance-separated gene regions through three-dimensional organization of viral genomes. We used 4C-seq methods to identify multiple long-range <i>cis</i> interactions in HSV-1 genomes that generate viral chromatin domains, including those nucleated by the viral CTCF insulator CTRL2. Deletion of the CTRL2 insulator disrupted these viral chromatin domains. Loop-nucleating interactions were quantitated with a novel approach (UMI-4C-seq) that utilizes unique molecular identifiers to label and count chromatin interactions associated with specific viewpoint primers. <i>Cis</i>-interaction peaks across four different viewpoints were quantified. Viral genomes lacking CTRL2 displayed more <i>cis</i>-interaction peaks and wider ranges of interaction lengths compared to wt virus, suggesting altered chromatin organization. Furthermore, differential looping analysis showed that viral genomes lacking CTRL2 displayed a more transcriptionally permissive chromatin environment. Thus, the CTRL2 insulator functions as a critical regulator of long-range chromatin interactions, and its deletion reshapes the viral chromatin landscape, leading to a more accessible and dynamic regulatory environment that may influence HSV-1 transcriptional programs and latency-associated chromatin states.IMPORTANCEHSV-1 is a significant lifelong human pathogen that infects 70% of adults worldwide. The latent HSV-1 genome is chromatinized and maintained in distinct chromatin structures that silence the virus, while reactivation is facilitated by transient reversal of host factors that maintain those chromatin domains. Understanding how this happens is critical for the development of novel therapeutics. It is becoming clear that CTCF insulators play a key role in the reversal that leads to reactivation. CTCF insulators are essential regulators of chromatin structure and gene expression in mammalian cells and play vital regulatory roles in transcriptional control of DNA viruses by organizing chromatin architecture during both latent and lytic stages of virus lifecycles. Here, we present the first report that latent HSV-1 genomes are organized into 3D structures to support latency yet allow the viral genome to reactivate, opening the door for future therapeutic targets.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0163825"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959848","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":"Lys-specific gingipain (Kgp) of <i>P. gingivalis</i> promotes viral infection by disabling the interferon pathway.","authors":"Ewelina Dobosz, Anna Golda, Michal Kanoza, Weronika Kowalczuk, Barbara Potempa, Jan Potempa, Anna Gasiorek, Natalia Madeja, Joanna Budziaszek, Danuta Mizgalska, Tulay Yucel-Lindberg, Joanna Koziel","doi":"10.1128/mbio.00298-25","DOIUrl":"10.1128/mbio.00298-25","url":null,"abstract":"<p><p>Periodontitis (PD) is a chronic inflammatory disease of the periodontium with a high prevalence and is considered a potential risk factor for the development of other diseases. These include viral infections of the upper and lower respiratory tracts, including those caused by the <i>Herpesviridae</i> family, human immunodeficiency virus, hepatitis C and B viruses, influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which have been identified with greater frequency in patients with PD. The underlying molecular mechanisms that underpin this comorbidity remain to be elucidated; however, the compromised capacity of the oral mucosa-associated antiviral response is a plausible explanation. Driven by clinical data that revealed the <i>Herpesviridae</i> family as the most commonly identified viruses in PD patients, this study was aimed to determine the effect of <i>Porphyromonas gingivalis</i>, the key etiological factor in periodontitis, on the development of herpes simplex virus-1 (HSV-1) infection. Using a model of the human gingiva, it was demonstrated that <i>P. gingivalis</i> significantly increases infection with HSV-1, promoting tissue distribution and propagation of the virus. This phenomenon can be attributed to the impairment of the interferon response, a consequence of proteolytic modifications of major signaling components catalyzed by Kgp gingipain. Furthermore, <i>P. gingivalis</i> infection has been observed to promote reactivation of HSV-1 in neuronal cells but via IFN-independent mechanism. These findings, demonstrating the attenuation of the host defense, expand our basic knowledge of the mechanisms underlying polymicrobial infections and clarify the observed comorbidity of PD with viral disorders.IMPORTANCEPeriodontitis (PD) is a chronic inflammatory disease of the gingiva, with a high prevalence. Clinical reports indicate the significant role of PD in the development of comorbidities, including <i>Herpesviridae</i> infections; however, the molecular basis of this phenomenon has not yet been described. In our work, we uncovered a novel molecular mechanism by which the interferon-dependent antiviral response is tailored by the cysteine protease of <i>P. gingivalis</i>-Kgp. Using gingival keratinocytes and a model of human gingiva, we have demonstrated that lysin-specific gingipain attenuates the antiviral response and promotes the propagation of herpes simplex virus-1, which is one of the most frequently identified viruses in patients suffering from PD. These findings expand our knowledge of the mechanisms underlying polymicrobial infections and may provide a basis for considering PD as a gateway to viral infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0029825"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Pseudomonas aeruginosa lasR</i>-deficient mutant contributes to bacterial virulence through enhancing the PhoB-mediated pathway in response to host environment.","authors":"Xiaolei Pan, Liwen Yin, Dandan Zhou, Yongxin Jin, Zhihui Cheng, Un-Hwan Ha, Shouguang Jin, Weihui Wu","doi":"10.1128/mbio.01788-25","DOIUrl":"10.1128/mbio.01788-25","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is a major opportunistic pathogen that causes lung infections in patients with cystic fibrosis and chronic obstructive pulmonary disease. Loss-of-function mutations in the quorum-sensing regulatory gene <i>lasR</i> commonly arise during chronic infections, which are associated with exaggerated inflammation and accelerated decline in lung function. Here, in a murine cutaneous abscess model, infection with a Δ<i>lasR</i> mutant or a wild-type-Δ<i>lasR</i> mutant-mixed population resulted in higher bacterial loads and more severe tissue damage than infection by the wild-type strain. The Rhl and PQS quorum-sensing system genes, as well as phospholipase genes, were upregulated in the Δ<i>lasR</i> mutant and the wild-type-Δ<i>lasR</i> mutant-mixed population, which is mediated by PhoB in response to the <i>in vitro</i> and <i>in vivo</i> low-phosphate environments. We further demonstrate an auto-regulatory mechanism of PhoB and identify two LasR-regulated small RNAs that directly repress the translation of <i>phoB</i>. Overall, our results reveal a novel regulatory mechanism whereby mutation of <i>lasR</i> increases the pathogenesis of <i>P. aeruginosa</i>, providing an explanation for the more severe course of infection with the appearance of <i>lasR</i>-defective mutants.</p><p><strong>Importance: </strong><i>Pseudomonas aeruginosa</i> is an opportunistic pathogen that causes life-threatening infections. The bacterial quorum-sensing systems play important roles in coordinating gene expression during infection. Loss-of-function mutations in a quorum-sensing regulator gene <i>lasR</i> are commonly found in clinical isolates, which are associated with more rapid lung function decline. Here, in a murine cutaneous abscess model, we demonstrate that the presence of a <i>lasR</i>-defective mutant results in hyperproduction of virulence factors, increased antibiotic resistance, and more severe tissue damage, which resembles the human circumstance. We further identify the host environment signal and a novel regulatory pathway whereby mutation of <i>lasR</i> increases the bacterial pathogenesis. Our findings offer new insights into the LasR-mediated regulatory network in response to the host environment and provide clues to understand the lung disease progression driven by <i>lasR</i>-defective mutants.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0178825"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992992","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":"Bayesian estimation of HIV acquisition dates for prevention trials.","authors":"Raabya Rossenkhan, Elena E Giorgi, Danica Shao, James Ludwig, Phillip Labuschagne, Craig A Magaret, Thumbi Ndung'u, Daniel Muema, Kamini Gounder, Krista L Dong, Bruce D Walker, Morgane Rolland, Merlin L Robb, Leigh Anne Eller, Fredrick Sawe, Sorachai Nitayaphan, Eduard Grebe, Michael P Busch, Kevin P Delaney, Shelley Facente, Lindsay N Carpp, Allan C deCamp, Yunda Huang, Bette Korber, Michal Juraska, Erika Rudnicki, Ewelina Kosmider, Daniel B Reeves, Bryan T Mayer, John Hural, Wenjie Deng, Dylan H Westfall, Anna Yssel, David Matten, Tanmoy Bhattacharya, Lawrence Corey, Peter B Gilbert, Carolyn Williamson, James I Mullins, Paul T Edlefsen","doi":"10.1128/mbio.01881-25","DOIUrl":"10.1128/mbio.01881-25","url":null,"abstract":"<p><p>Accurate timing estimates of when participants acquire HIV in HIV prevention trials are necessary for determining antibody levels at acquisition. The Antibody-Mediated Prevention (AMP) Studies showed that a passively administered broadly neutralizing antibody can prevent the acquisition of HIV from a neutralization-sensitive virus. We developed a pipeline for estimating the date of detectable HIV acquisition (DDA) in AMP Study participants using diagnostic and viral sequence data. Using a Bayesian strategy that combines three streams of data (REN [rev/vpu/env/Δnef] sequence, GP [gag/Δpol] sequence, and diagnostic) where their 95% credible intervals overlap based on pre-specified criteria and decision rules. We evaluated the performance of our AMP pipeline using PacBio viral sequence data from 41 participants across two prospective acute HIV acquisition cohort studies, FRESH and RV217, with twice-weekly sampling. These cohort studies enrolled young women in South Africa and men and women in Kenya and Thailand, respectively, with a high likelihood of HIV acquisition. In evaluating performance, \"true DDA\" was the center of bounds between last-negative and first-positive RNA diagnostic tests (median time 4 days, range 2-7 days); bias was the mean difference between estimated and true DDA. Using diagnostic data alone yielded timing estimates with a bias of 2.4 days and root mean square error (RMSE) of 7.9 days. These results were improved using sequence + diagnostic data (bias 1.5 days, RMSE 6.9 days), as well as by restricting sequence-based estimation to samples from ≤5 weeks post-DDA (bias 0.2 days, RMSE 7.8 days).IMPORTANCEIn HIV prevention trials, accurate timing estimates of when individual participants acquire HIV can be used to estimate antibody levels at the time of acquisition, which is useful for projecting antibody levels needed for prevention. The results we report here suggest that if sequence-based estimation of acquisition timing is used in future clinical trials of combination broadly neutralizing antibody (bnAb) regimens or multispecific bnAbs for HIV prevention, a sampling frequency of at least monthly is needed. Moreover, in the samples analyzed here, we observed less bias in sequence-based timing estimation for samples taken <5 weeks post-DDA. This observation is consistent with the timing of immune-driven selective pressures that may negatively impact the power to detect acquisition sieve effects.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0188125"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023644","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}