mBio最新文献

{"title":"HPSE-mediated proinflammatory signaling contributes to neurobehavioral deficits following intranasal HSV-1 infection.","authors":"Hemant Borase, Chandrashekhar D Patil, Tibor Valyi-Nagy, Deepak Shukla","doi":"10.1128/mbio.03765-24","DOIUrl":"10.1128/mbio.03765-24","url":null,"abstract":"<p><p>Herpes simplex virus-1 (HSV-1) is a neurotropic virus that can infect the brain, and an uncontrolled infection can lead to a range of diseases, including chronic nerve pain, encephalitis, and neurobehavioral abnormalities. These outcomes are often severe and have lasting consequences, highlighting the need to identify host factors that contribute to disease severity. In this study, we report that intranasal HSV-1 infection in murine model, which promotes viral dissemination into the brain, implicates the host protein heparanase (HPSE) as a key mediator of neuroinflammation. Specifically, we observed that the HPSE activity during HSV-1 infection in naïve animals promotes the upregulation of proinflammatory cytokines, enhances microglial activity in the brain, and contributes to cognitive impairment, anxiety, and motor coordination deficits. Such effects are significantly less detectable in heparanase deficient (<i>Hpse-/</i>-) mice. Additionally, we found that moderate activation of toll-like receptors (TLRs), particularly in <i>Hpse+/+</i> mice, may contribute to the activation of the inflammasome pathway. This, in turn, leads to the activation of caspase-1 (<i>Casp1</i>) and caspase-3 (<i>Casp3</i>), which may play a role in nerve function loss. Our findings position HPSE as a potential therapeutic target for mitigating virus-induced neuroinflammation and neurobehavioral defects.</p><p><strong>Importance: </strong>Herpes simplex virus-1 (HSV-1) infection in the brain can lead to severe and often permanent neurological consequences. Host factors influence disease outcomes in response to infection, and understanding these factors is crucial for developing effective therapies. This study identifies the host protein HPSE as a key mediator of neuroinflammation in response to HSV-1 infection. We demonstrate that the HPSE activity drives proinflammatory cytokine expression and microglial activation and promotes a signaling cascade involving toll-like receptors and caspase activation, potentially intensifying neuroinflammatory responses. These findings implicate HPSE as an important player in HSV-1 pathogenesis in the central nervous system and suggest that targeting HPSE could provide a novel therapeutic strategy to mitigate virus-induced neuroinflammation and neurobehavioral disturbance.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0376524"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516101","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 proteomic and functional view of intrabacterial lipid inclusion biogenesis in mycobacteria.","authors":"Tonia Dargham, John Jairo Aguilera-Correa, Romain Avellan, Ivy Mallick, Léa Celik, Pierre Santucci, Gael Brasseur, Isabelle Poncin, Vanessa Point, Stéphane Audebert, Luc Camoin, Wassim Daher, Jean-François Cavalier, Laurent Kremer, Stéphane Canaan","doi":"10.1128/mbio.01475-24","DOIUrl":"10.1128/mbio.01475-24","url":null,"abstract":"<p><p>During infection and granuloma formation, pathogenic mycobacteria store triacylglycerol as intrabacterial lipid inclusions (ILIs). This accumulation of nutrients provides a carbon source for bacterial persistence and slows down intracellular metabolism. <i>Mycobacterium abscessus</i> (<i>Mab</i>), a rapidly growing non-tuberculous actinobacterium, produces ILI throughout its infection cycle. Here, <i>Mab</i> was used as a model organism to identify proteins associated with ILI accumulation on a global scale. By using the APEX2 proximity labeling method in an <i>in vitro</i> model for ILI accumulation, we identified 228 proteins possibly implicated in ILI biosynthesis. Fluorescence microscopy of strains overexpressing eight ILI-associated proteins (IAP) candidates fused to superfolder green fluorescent protein showed co-localization with ILI. Genetic inactivation of these potential IAP-encoding genes and subsequent lipid analysis emphasized the importance of MAB_3486 and MAB_4532c as key enzymes influencing triacylglycerol storage. This study underscores the dynamic process of ILI biogenesis and advances our understanding of lipid metabolism in pathogenic mycobacteria. Identifying major IAP in lipid accumulation offers new therapeutic perspectives to control the growth and persistence of pathogenic mycobacteria.</p><p><strong>Importance: </strong>This study sheds light into the complex process of intracellular lipid accumulation and storage in the survival and persistence of pathogenic mycobacteria, which is of clinical relevance. By identifying the proteins involved in the formation of intrabacterial lipid inclusions and revealing their impact on lipid metabolism, our data may lead to the development of new therapeutic strategies to target and control pathogenic mycobacteria, potentially improving outcomes for patients with mycobacterial infections.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0147524"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492383","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":"Carbon source, cell density, and the microbial community control inhibition of <i>V. cholerae</i> surface colonization by environmental nitrate.","authors":"Jamaurie James, Renato E R S Santos, Paula I Watnick","doi":"10.1128/mbio.04066-24","DOIUrl":"10.1128/mbio.04066-24","url":null,"abstract":"<p><p>The intestinal diarrheal pathogen <i>Vibrio cholerae</i> colonizes the host terminal ileum, a microaerophilic, glucose-poor, nitrate-rich environment. In this environment, <i>V. cholerae</i> respires nitrate and increases transport and utilization of alternative carbon sources via the cAMP receptor protein (CRP), a transcription factor that is active during glucose scarcity. Here, we show that <i>V. cholerae</i> nitrate respiration in aerated cultures is under control of CRP and, therefore, glucose availability. <i>V. cholerae</i> nitrate respiration results in extracellular accumulation of nitrite because <i>V. cholerae</i> does not possess the machinery for nitrite reduction. This nitrite inhibits <i>V. cholerae</i> biofilm formation via an as-yet unelucidated mechanism that depends on the high cell density master regulator HapR. The genome of <i>Paracoccus aminovorans</i>, an intestinal microbe identified in the microbiome of cholera patients that has been shown to enhance <i>V. cholerae</i> biofilm accumulation in the neonatal mouse gut, encodes enzymes that reduce nitrite to nitrogen gas. We report that, in nitrate-supplemented co-cultures, <i>P. aminovorans</i> metabolizes the nitrite generated by <i>V. cholerae</i> and, thereby, enhances <i>V. cholerae</i> surface accumulation. We propose that <i>V. cholerae</i> biofilm formation in the host intestine is limited by nitrite production but can be rescued by intestinal microbes such as <i>P. aminovorans</i> that have the capacity to metabolize nitrite. Such microbes increase <i>V. cholerae</i> colonization of the host ileum and predispose to symptomatic infection.IMPORTANCE<i>Vibrio cholerae</i> colonizes the terminal ileum where both oxygen and nitrate are available as terminal electron acceptors. <i>V. cholerae</i> biofilm formation is inhibited by nitrate due to its conversion to nitrite during <i>V. cholerae</i> respiration. When co-cultured with a microbe that can further reduce nitrite, <i>V. cholerae</i> surface accumulation in the presence of nitrate is rescued. The contribution of biofilm formation to ileal colonization depends on the composition of the microbiota. We propose that the intestinal microbiota predisposes mammalian hosts to cholera by consuming the nitrite generated by <i>V. cholerae</i> in the terminal ileum. Differences in the intestinal abundance of nitrite-reducing microbes may partially explain the differential susceptibility of humans to cholera and the resistance of non-human mammalian models to intestinal colonization with <i>V. cholerae</i>.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0406624"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492443","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>Campylobacter jejuni</i> resistance to human milk involves the acyl carrier protein AcpP.","authors":"Bibi Zhou, Jolene M Garber, James Butcher, Artur Muszynski, Rebekah L Casey, Steven Huynh, Stephanie Archer-Hartmann, Sara Porfírio, Ashley M Rogers, Parastoo Azadi, Craig T Parker, Kenneth K S Ng, Kelly M Hines, Alain Stintzi, Christine M Szymanski","doi":"10.1128/mbio.03997-24","DOIUrl":"10.1128/mbio.03997-24","url":null,"abstract":"<p><p><i>Campylobacter jejuni</i> is a common foodborne pathogen worldwide that is associated with high rates of morbidity and mortality among infants in low- to middle-income countries (LMICs). Human milk provides infants with an important source of nutrients and contains antimicrobial components for protection against infection. However, recent studies, including our own, have found significantly higher levels of <i>Campylobacter</i> in diarrheal stool samples collected from breastfed infants compared to non-breastfed infants in LMICs. We hypothesized that <i>C. jejuni</i> has unique strategies to resist the antimicrobial properties of human milk. Transcriptional profiling found human milk exposure induces genes associated with ribosomal function, iron acquisition, and amino acid utilization in <i>C. jejuni</i> strains 81-176 and 11168. However, unidentified proteinaceous components of human milk prevent bacterial growth. Evolving both <i>C. jejuni</i> isolates to survive in human milk resulted in mutations in genes encoding the acyl carrier protein (AcpP) and the major outer membrane porin (PorA). Introduction of the PorA/AcpP amino acid changes into the parental backgrounds followed by electron microscopy showed distinct membrane architectures, and the AcpP changes not only significantly improved growth in human milk, but also yielded cells surrounded with outer membrane vesicles. Analyses of the phospholipid and lipooligosaccharide (LOS) compositions suggest an imbalance in acyl chain distributions. For strain 11168, these changes protect both evolved and 11168∆<i>acpP</i>^G33R strains from bacteriophage infection and polymyxin killing. Taken together, this study provides insights into how <i>C. jejuni</i> may evolve to resist the bactericidal activity of human milk and flourish in the hostile environment of the gastrointestinal tract.</p><p><strong>Importance: </strong>In this study, we evolved <i>C. jejuni</i> strains which can grow in the presence of human milk and found that cell membrane alterations may be involved in resistance to the antimicrobial properties of human milk. These bacterial membrane changes are predominantly linked to amino acid substitutions within the acyl carrier protein, AcpP, although other bacterial components, including PorA, are likely involved. This study provides some insights into possible strategies for <i>C. jejuni</i> survival and propagation in the gastrointestinal tract of breastfed infants.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0399724"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492634","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 <i>Ralstonia solanacearum</i> effector regulates plant cell death by disrupting the homeostasis of the BPA1-ACD11 complex.","authors":"Bingbing Xue, Yan Zhou, Yongxiao Xie, Xiaocheng Huang, Jinye Zhang, Yang Zhang, Wenyan Zhong, Jinjia Zhao, Dehong Zheng, Lifang Ruan","doi":"10.1128/mbio.03665-24","DOIUrl":"10.1128/mbio.03665-24","url":null,"abstract":"<p><p>Effectors secreted by phytopathogenic bacteria can suppress ETI responses induced by avirulence effectors, thereby overcoming crop resistance. However, the detailed mechanisms remain largely unknown. We report that the effector RipD from <i>Ralstonia solanacearum</i> regulates plant cell death in a protein abundance-dependent manner. RipD targets <i>Arabidopsis</i> BPA1, which directly interacts with the key cell death negative regulator ACD11. RipD competes with ACD11 for binding to BPA1, leading to the selective degradation of BPA1 via autophagy, sparing ACD11. A lower dose of RipD promotes BPA1 degradation but leads to ACD11 accumulation, thereby inhibiting RipAA-induced cell death. Conversely, higher levels of RipD degrade both BPA1 and ACD11, resulting in autophagy-dependent cell death. Visualization of RipD delivery by <i>R. solanacearum</i> indicated that it reaches levels sufficient to promote ACD11 accumulation and inhibit cell death. Our study reveals a novel mechanism by which an effector inhibits ETI and, for the first time, highlights the critical role of protein abundance in its function.IMPORTANCE<i>R. solanacearum</i> infects major economic crops, notably tomato, potato, and tobacco, leading to substantial yield reductions and economic losses. This pathogen utilizes various type III effectors to suppress host resistance, often resulting in weakened or lost resistance. However, the underlying mechanisms remain largely unknown. Here, we reveal a novel mechanism by which RipD targets the BPA1-ACD11 complex, which is involved in host immunity and cell death. RipD regulates ACD11 protein homeostasis in a dose-dependent manner by competitively binding and activating autophagy, thereby modulating plant cell death. Importantly, visualization analysis revealed that the amount of RipD secreted by <i>R. solanacearum</i> into host cells is sufficient to inhibit Avr effector-induced cell death. Our study highlights for the first time the critical role of effector dosage, deepening the understanding of how <i>R. solanacearum</i> suppresses host ETI-related cell death and providing guidance and resources for breeding bacterial wilt resistance.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0366524"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492657","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":"HilD-regulated chemotaxis proteins contribute to <i>Salmonella</i> Typhimurium colonization in the gut.","authors":"Kendal G Cooper, Laszlo Kari, Audrey Chong, Naman Tandon, Kathleen Doran, Lidiane Gomes Da Silva, Diane C Cockrell, Arden Baylink, Olivia Steele-Mortimer","doi":"10.1128/mbio.00390-25","DOIUrl":"10.1128/mbio.00390-25","url":null,"abstract":"<p><p>In the enteric pathogen <i>Salmonella</i> Typhimurium, invasion and motility are coordinated by HilD, a master regulator that activates expression of genes encoding the type III secretion system 1 and some motility genes, including the chemotaxis gene <i>mcpC</i>. Previously, we have shown that McpC induces smooth swimming, which is important for type III secretion system 1-dependent invasion of epithelial cells. Here, we have studied another <i>Salmonella</i>-specific chemotaxis gene, <i>mcpA</i>, and demonstrate that it is also HilD regulated. Whereas HilD induction of <i>mcpC</i> occurs by direct derepression of H-NS, <i>mcpA</i> induction requires neither H-NS derepression nor the flagellar-specific sigma factor <i>fliA</i>; instead it occurs through a HilD-SprB regulatory cascade, providing experimental confirmation of previous transcriptional regulatory mapping. McpA and McpC contain methyl-accepting domains characteristic of bacterial chemoreceptors, and McpA also contains a chemoreceptor zinc-binding (CZB) protein domain found in a variety of bacterial proteins, many of which are involved in signaling or regulatory roles. Here, we show that, in a mouse model for acute <i>Salmonella</i> colitis, both <i>mcpA</i> and <i>mcpC</i> deletion mutants are outcompeted by wild-type <i>Salmonella</i> Typhimurium in the gut lumen. CZB domains bind Zn²⁺ through a conserved cysteine residue and are thought to perform redox-sensing through redox-initiated alterations in zinc homeostasis. We found that the conserved cysteine is required for McpA function in the mouse gut, thus demonstrating a virulence role for the CZB Zn²⁺-binding site during infection.</p><p><strong>Importance: </strong>The gut-adapted bacterium <i>Salmonella</i> Typhimurium causes inflammatory diarrhea via a process that involves active invasion of intestinal epithelial cells, secretion of inflammatory molecules, and recruitment of immune cells. Although bacterial motility and invasion of host cells are coordinated, how directed movement facilitates luminal survival and growth or invasion at the mucosal surface is not understood. Chemotaxis is the process by which bacteria control movement toward attractants and away from repellents. Previously, we identified a <i>Salmonella</i>-specific chemoreceptor, McpC, that is co-expressed with the invasion machinery and promotes smooth swimming for optimal host cell invasion. Here, we investigated another chemoreceptor, McpA, also regulated with invasion-associated genes and show it contributes to luminal expansion rather than invasion of epithelial cells. McpA activity requires a conserved Zn²⁺-binding domain, thought to be involved in sensing inflammation. This work demonstrates that coordination of invasion and chemotaxis plays a significant role in the gut.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0039025"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492661","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":"HIV-1 Gag-protease-driven replicative capacity influences T-cell metabolism, cytokine induction, and viral cell-to-cell spread.","authors":"Omolara O Baiyegunhi, Kensane Mthembu, Ann-Kathrin Reuschl, Doty Ojwach, Omotayo Farinre, Murunwa Maimela, Sheila Balinda, Matt Price, Madeleine J Bunders, Marcus Altfeld, Clare Jolly, Jaclyn Mann, Thumbi Ndung'u","doi":"10.1128/mbio.03565-24","DOIUrl":"10.1128/mbio.03565-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;High replicative capacity (RC) HIV-1 strains are associated with elevated viral loads and faster disease progression in the absence of antiretroviral therapy. Understanding the mechanisms by which high RC strains adversely affect the host is essential for developing novel anti-HIV interventions. This study investigates cellular metabolism, cytokine induction, and cell-to-cell spread as potential mechanisms differentiating clinical outcomes between low and high RC strains of HIV-1. We constructed chimeric viruses containing patient-derived &lt;i&gt;gag-proteases&lt;/i&gt; from HIV-1 subtypes B and C in the NL4-3 backbone. Viral RC was determined using a green fluorescent protein (GFP)-reporter T-cell line assay and cytokine production in T-cells was assessed using Luminex. Virus cell-to-cell spread efficiency was measured through flow cytometry-based detection of p24, while nutrient uptake assays and mitotracker dye detection served as surrogate markers for T-cell metabolism and mitochondrial function. Chimeric subtype C viruses exhibited significantly lower RC compared to subtype B viruses (&lt;i&gt;P&lt;/i&gt; = 0.0008). Cytokine profiling revealed distinct cytokine signatures associated with low RC subtype C viruses. Viral RC negatively correlated with tumor necrosis factor alpha (TNF-α), IL-8, and IL-13 induction, while it positively correlated with platelet-derived growth factor (PDGF-bb), IL-7, monocyte chemoattractant protein-1 (MCP-1), fibroblast growth factor (FGF)-basic levels, viral spread efficiency (&lt;i&gt;P&lt;/i&gt; = 0.008, &lt;i&gt;r&lt;/i&gt; = 0.5), and cellular glucose uptake (&lt;i&gt;P&lt;/i&gt; = 0.02, &lt;i&gt;r&lt;/i&gt; = 0.5). Conversely, RC was negatively correlated with glutamine levels (&lt;i&gt;P&lt;/i&gt; = 0.001, &lt;i&gt;r&lt;/i&gt; = -0.7), indicating a link between RC and nutrient utilization. Furthermore, mitochondrial depolarization was elevated in subtype B infections when compared to subtype C infections (&lt;i&gt;P&lt;/i&gt; = 0.0008). These findings indicate that high RC strains exert distinct cellular effects that may influence HIV-1 pathogenesis, highlighting the need to develop novel therapeutic strategies.IMPORTANCEVirus replicative capacity (RC) influences disease progression following HIV-1 transmission; however, the mechanisms underlying the differential clinical outcomes remain poorly understood. Our study reveals variations in cytokine induction and cellular metabolism in T-cells infected with HIV-1 subtype B and C viruses exhibiting high or low RC. T-cells infected with high RC strains showed increased induction of IL-7 and platelet-derived growth factor (PDGF-bb), along with heightened glucose uptake and elevated glutamine consumption compared to those infected with low RC strains. By contrast, low RC strains induced higher levels of IL-8, IL-13, and tumor necrosis factor alpha (TNF-α) and demonstrated reduced efficiency in modulating cellular metabolism and virus cell-to-cell spreadability. These findings highlight distinct biological differences between high and low RC viruses, providing val","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0356524"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492663","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":"Mono- and multidomain defense toxins of the RelE/ParE superfamily.","authors":"Kenn Gerdes","doi":"10.1128/mbio.00258-25","DOIUrl":"10.1128/mbio.00258-25","url":null,"abstract":"<p><p>Toxin-antitoxin (TA) modules are widely distributed across prokaryotes, often existing in large numbers despite their associated fitness costs. Most type II TA modules are bicistronic operons encoding a monodomain toxin and its cognate protein antitoxin. The RelE/ParE superfamily encompasses toxins with a conserved Barnase-EndoU-ColicinE5/D-RelE (BECR) fold. Yet, their cellular targets differ remarkably: RelE toxins function as ribosome-dependent RNases, while ParE toxins act as DNA gyrase inhibitors. Using a comprehensive bioinformatics approach, this study analyzed 13 BECR-fold toxin families as classified in the Pfam database. Intriguingly, the ParE family was found to include a subcluster of mRNA-cleaving toxins, challenging its conventional role as solely DNA-targeting. This study identified a novel tripartite operon encoding a PtuA-like defense ATPase, a homolog of type IV restriction endonucleases, and a RelE homolog, suggesting a coordinated role in defense mechanisms. Multidomain BECR-fold toxins, including transmembrane variants, were also discovered, extending the functional repertoire of type II TA modules to membrane-associated systems. These findings clarify the evolutionary relationships and functional diversity within the RelE/ParE superfamily and discover novel, putative defense systems that can now be investigated experimentally.IMPORTANCEToxin-antitoxin modules play critical roles in prokaryotic survival and adaptation, contributing to genome stabilization and defense against phages and invading plasmids. The RelE/ParE superfamily exemplifies the structural and functional diversity of these systems, with members targeting distinct cellular processes, such as translation and DNA supercoiling. By elucidating the relationships among the 13 BECR-fold toxin families, this study enhances our understanding of microbial resistance mechanisms and reveals potential new opportunities for research into prokaryotic defense and regulation. These insights may have significant implications for medical and biotechnological applications, particularly in understanding bacterial responses to genetic invaders.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0025825"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492671","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>Piscirickettsia salmonis</i> pathogenicity: using the damage-response framework to look beyond smoke and mirrors.","authors":"Felipe C Cabello, Ana Millanao, Henry P Godfrey","doi":"10.1128/mbio.03821-24","DOIUrl":"10.1128/mbio.03821-24","url":null,"abstract":"<p><p><i>Piscirickettsia salmonis</i> is a globally distributed aquatic bacterium and a component of the normal salmon microbiome. It has significant biological and economic impact on Chilean salmon aquaculture due to the highly fatal disease, piscirickettsiosis. Unsuccessful attempts to prevent and treat this disease have resulted in heavy use of antimicrobials with adverse effects on the aquatic environment and piscine and human health. Evidence suggests <i>P. salmonis</i> could be a bacterium with relative pathogenic potential on farmed salmonids and other fishes that triggers piscirickettsiosis under particular conditions in the salmon and its environment. Application of a damage-response framework analysis could define the steps from asymptomatic <i>P. salmonis</i> infection to symptomatic disease, help tailor improved approaches to disease prevention and management, and, in turn, help avoid heavy use of antimicrobials which have global effects on animal health, human health, and environmental biodiversity (the One Health concept).</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0382124"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649760","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":"Spatiotemporal binding of cyclophilin A and CPSF6 to capsid regulates HIV-1 nuclear entry and integration.","authors":"Zachary Ingram, Christopher Kline, Alexandra K Hughson, Parmit K Singh, Hannah L Fischer, Rajalingham Radhakrishnan, Gregory A Sowd, Nayara F B Dos Santos, Barbie K Ganser-Pornillos, Simon C Watkins, Melissa Kane, Alan N Engelman, Zandrea Ambrose","doi":"10.1128/mbio.00169-25","DOIUrl":"10.1128/mbio.00169-25","url":null,"abstract":"<p><p>Human immunodeficiency virus type 1 (HIV-1) capsid, which is the target of the antiviral lenacapavir, protects the viral genome and binds multiple host proteins to influence intracellular trafficking, nuclear import, and integration. Previously, we showed that capsid binding to cleavage and polyadenylation specificity factor 6 (CPSF6) in the cytoplasm is competitively inhibited by cyclophilin A (CypA) binding and regulates capsid trafficking, nuclear import, and infection. Here, we determined that a capsid mutant with increased CypA binding affinity had significantly reduced nuclear entry and mislocalized integration. However, disruption of CypA binding to the mutant capsid restored nuclear entry, integration, and infection in a CPSF6-dependent manner. Furthermore, relocalization of CypA expression from the cell cytoplasm to the nucleus failed to restore mutant HIV-1 infection. Our results clarify that sequential binding of CypA and CPSF6 to HIV-1 capsid is required for optimal nuclear entry and integration targeting, providing insights for the development of antiretroviral therapies, such as lenacapavir.</p><p><strong>Importance: </strong>Human immunodeficiency virus (HIV) encodes a protein that forms a conical shell, called a capsid, that surrounds its genome. The capsid has been shown to protect the viral genome from innate immune sensors in the cell, to help transport the genome toward and into the nucleus, to keep the components of reverse transcription together for conversion of the RNA genome into DNA, and to target viral DNA integration into specific regions of the host genome. In this study, we show that HIV hijacks two host proteins to bind to capsid sequentially in order to choreograph the precise order and timing of these virus replication steps. Disruption of binding of these proteins to capsid or their location in the cell leads to defective HIV nuclear import, integration, and infection. Mutations that exist in the capsid protein of HIV in infected individuals may reduce the efficacy of antiretroviral drugs that target capsid.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0016925"},"PeriodicalIF":5.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516102","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}