mBio最新文献

{"title":"Enantiomer-dependent biodistribution and exposure determine the <i>in vivo</i> behavior of a pleurocidin-derived antimicrobial peptide.","authors":"Janis Romanopulos, Paul Cressey, Charlotte K Hind, Seong-Heun Kim, Zayed A Shalim, Nadiya Mohamed Akram, Hala Alnasif Alhadi, Amelia Claxton, Yuang You, Anna V Kelis, Bailey Ramsden, Siham Memdouh, Ana C Jacob, Tam T Bui, Simon J Cleary, Maya Thanou, Richard T Amison, Vincenzo Abbate, J Mark Sutton, A James Mason","doi":"10.1128/mbio.01718-26","DOIUrl":"https://doi.org/10.1128/mbio.01718-26","url":null,"abstract":"<p><p>Antimicrobial peptides (AMPs) display rapid bactericidal activity <i>in vitro</i>, but have largely failed as systemically administered therapeutics, indicating that intrinsic potency alone does not predict <i>in vivo</i> efficacy. Here, we examine how pharmacokinetics, stereochemistry, and host context shape early <i>in vivo</i> activity using pleurocidin-derived peptides. The D-amino-acid analog D-P-KR rapidly eradicates priority bacterial pathogens within minutes <i>in vitro</i>, achieving this at low multiples of the minimum inhibitory concentration (MIC) for <i>Staphylococcus aureus</i> but requiring higher multiples for Gram-negative species. Near-infrared imaging of fluorescently labeled enantiomers reveals that stereochemistry strongly influences systemic behavior, with D-enantiomers showing reduced renal and hepatobiliary clearance and increased exposure following intravenous administration. Despite these favorable properties, systemic D-P-KR does not reduce pulmonary bacterial burden within 2 h of treatment in mouse models of <i>S. aureus</i> or <i>Klebsiella pneumoniae</i> pneumonia. In contrast, increasing exposure through short intravenous infusion produces a rapid, exposure-dependent reduction in pulmonary neutrophil recruitment in <i>S. aureus</i> infection, without corresponding early changes in bacterial burden. This effect is not observed in the disseminating <i>K. pneumoniae</i> model. These findings demonstrate a dissociation between rapid <i>in vitro</i> killing, early bacterial clearance, and host-response modulation, and show that early <i>in vivo</i> AMP activity is governed primarily by systemic exposure and infection context. More broadly, this work highlights the need to integrate pharmacokinetics, dosing strategy, and host response when evaluating antimicrobial peptides for systemic use.IMPORTANCEAntimicrobial peptides can kill bacteria far more rapidly than most conventional antibiotics, yet very few have succeeded as systemically administered drugs. This study shows that differences in peptide stereochemistry profoundly influence how antimicrobial peptides distribute within the body and how long effective exposure can be maintained. Our findings demonstrate that strong antibacterial activity <i>in vitro</i> does not necessarily translate into early bacterial clearance <i>in vivo</i>, but that delivery strategies can still affect host responses during infection. By linking peptide stereochemistry, systemic exposure, and biological outcomes, this work highlights why many antimicrobial peptides struggle to translate clinically and underscores the need to prioritize pharmacokinetics, formulation, and dosing strategy alongside antibacterial potency during antimicrobial peptide development.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0171826"},"PeriodicalIF":5.4,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840475","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":"Pre-existing systemic and nasal antibodies against avian H5 influenza A viruses vary according to childhood imprinting.","authors":"Peta Edler, Kevin J Selva, Ellie Reilly, Malet Aban, Ian G Barr, Jennifer A Juno, Adam K Wheatley, Amy W Chung, Stephen J Kent, David J Price, Marios Koutsakos","doi":"10.1128/mbio.01892-26","DOIUrl":"https://doi.org/10.1128/mbio.01892-26","url":null,"abstract":"<p><p>Avian influenza A viruses (IAVs) pose a constant pandemic threat, with the recent 2.3.4.4b clade of the H5 subtype causing high pathogenicity and spreading across animal species and geographic locations. Understanding human pre-existing immunity to avian H5 IAV can inform on population susceptibility, a critical aspect of pandemic preparedness. To that end, we analyzed the IAV HA-specific antibodies across individuals born between 1928 and 1999 with different early life exposures to IAV subtypes. Individuals born prior to 1957 had the highest pre-existing serum antibodies to group 1 HA antigens, including the 2.3.4.4b H5 and a group 1 HA stem antigen. These birth year-specific patterns were not reflected in the limited pre-existing serum neutralizing antibodies detectable against a 2.3.4.4b H5 IAV or in H5-specific memory B cell populations. They were, however, evident in pre-existing nasal IgG and IgA titers to H5, which were greater in individuals born prior to 1957. Our findings demonstrate that the immunological biases afforded by early life exposure extend to antibodies detected in the nasal mucosa, the site of IAV replication.IMPORTANCEUnderstating pre-existing immunity to influenza A viruses (IAVs) of pandemic potential is an important aspect of pandemic preparedness. This includes an understanding of the heterogeneity of pre-existing immunity across the population. Here, we demonstrate that pre-existing antibodies to H5 IAV vary according to the year of birth and childhood imprinting. We demonstrate that this is the case for both systemic and nasal antibodies, highlighting the importance of understanding pre-existing mucosal immunity at the sites of influenza virus replication.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0189226"},"PeriodicalIF":5.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148829768","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":"Flagella are required to activate expression of aggregation factors necessary for T6SS-mediated competition in host-like conditions.","authors":"Lauren Speare, Liang Zhao, Morgan N Pavelsky, Aundre Jackson, Steph Smith, Bhavyaa Tyagi, Garrett C Sharpe, Madison Woo, Scott M Gifford, Alecia N Septer","doi":"10.1128/mbio.03970-24","DOIUrl":"https://doi.org/10.1128/mbio.03970-24","url":null,"abstract":"<p><p>Bacteria employ antagonistic strategies to eliminate competitors of an ecological niche. Contact-dependent mechanisms, such as the type VI secretion system (T6SS), are prevalent in host-associated bacteria, yet we know relatively little about how T6SS+ strains make contact with competitors in highly viscous environments, such as host mucus. To better understand how cells respond to and contact one another in such environments, we performed a genome-wide transposon mutant screen of the T6SS-wielding beneficial bacterial symbiont, <i>Vibrio fischeri</i> MJ11, and identified two sets of genes that are conditionally required for killing. We found that surface modification and flagellar-associated genes do not affect T6SS directly and are therefore not required for interbacterial killing when cell contact is forced, yet are necessary for killing in high-viscosity liquid (hydrogel), where cell-cell contact must be biologically mediated. Quantitative transcriptomics revealed that <i>V. fischeri</i> significantly increases expression of both T6SS genes and cell surface modification factors upon transition from low- to high-viscosity media. Consistent with coincubation and fluorescence microscopy data, flagella are not required for T6SS expression in hydrogel. However, flagella were necessary to enhance expression of ~50% of the genome in hydrogel, including the surface modification genes identified in our screen and functional pathways important for host colonization, such as uptake of host-relevant iron and carbon sources, and nitric oxide detoxification enzymes. Our findings suggest that flagella play a key role when <i>V. fischeri</i> cells coordinately activate competitive strategies and host colonization factors, underscoring the significance of the physical environment in directing complex bacterial behaviors.IMPORTANCEThe physical environment has dramatic effects on bacterial behavior, but little is known about how mechanical signals impact antagonistic interactions. Symbiotic bacteria use molecular weapons to eliminate competitors for limited space within highly viscous host tissue and mucus. Previously, we found that a putative lipoprotein adhesin, TasL, and an unknown ligand are required to bring competitor cells within range of the T6SS weapon. Here, we found that mutations in flagella or predicted surface modification genes prevent TasL-mediated adhesion and killing in high viscosity. Transcriptomics revealed the flagella are required to coordinate expression of host colonization factors with the T6SS interbacterial weapon when transitioning from lower to higher viscosity conditions. These findings suggest that flagella may play a role in sensing mechanical signals, such as environmental viscosity, to enhance a symbiont's ability to successfully colonize the host while efficiently eliminating potential competitors from the host niche.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0397024"},"PeriodicalIF":5.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148829813","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 bundled anti-parallel cytochrome nanowire structure suggests roles in cell-cell electron transfer and biofilm formation.","authors":"Holly A Petersen, Chi H Chan, Gilbert O Carpenter, Media Zakizadeh Tabari, Jessie Lynda Fields, Ayisha Zia, Shane T Rich-New, Allon I Hochbaum, Daniel R Bond, Fengbin Wang","doi":"10.1128/mbio.00906-26","DOIUrl":"10.1128/mbio.00906-26","url":null,"abstract":"<p><p>Long-range extracellular electron transfer enables respiring microbes to use minerals, organisms, or electrodes as electron acceptors by transporting electrons microns away from the cell surface. This process is primarily studied in <i>Geobacter sulfurreducens</i>, which produces at least three distinct, micrometer-long, multiheme cytochrome nanowires capable of electron transfer. However, the distribution and higher-order structure of such nanowires remains largely unknown. Here, we employed cryo-electron microscopy to determine the atomic structure of a unique cytochrome nanowire from <i>Desulfuromonas soudanensis</i> WTL, a halophilic, iron- and electrode-reducing bacterium from deep subsurface brine. These filaments are based on an OmcE tetraheme cytochrome homolog that assembles into highly ordered bundles of anti-parallel filaments. Electronic measurements of purified nanowire bundle films reveal that these bundles are conductive, with conductance increasing in a concentration-dependent manner. The apparent midpoint potential of these OmcE bundles was -145 mV vs SHE. They exhibit redox activity over a ~370 mV window attributable to five electrostatically coupled hemes, suggesting heme-heme interaction beyond the boundaries of individual OmcE repeat units. Observations of these bundles under diverse buffer conditions suggest that they represent stable supramolecular assemblies, although direct <i>in vivo</i> confirmation within intact biofilms remains a future goal. Furthermore, a similar cytochrome bundle structure was observed in <i>Geobacter metallireducens</i>, showing that this quaternary structure may be a common feature among nanowires secreted by electroactive microbes. Our findings demonstrate that cytochrome nanowires are widespread and can form specialized bundle interfaces. This novel state could facilitate conductive biofilm formation and form the basis for direct microbial electron exchange.<b>IMPORTANCE</b>All available structures of filaments containing a central core of closely spaced multiheme c-type cytochromes are derived from only a few organisms and are based on individual fibers easily imaged by cryo-electron microscopy. While imaging enriched preparations of extracellular appendages from a bacterium isolated from deep subsurface brine, we observed ordered bundles of anti-parallel cytochrome filaments. This quaternary arrangement contained specific contacts between adjacent nanowires, and a similar structure could be found in a relative from a related genus. This first report of bundling by nanowires suggests that such conductive structures may be missed in traditional surveys searching for novel filaments and provides an explanation for how nanowires could directly link adjacent cells in biofilms and granular communities.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0090626"},"PeriodicalIF":5.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148819089","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":"Building better microbial infection models: a call to do the \"field\" experiments.","authors":"Marvin Whiteley","doi":"10.1128/mbio.01768-26","DOIUrl":"https://doi.org/10.1128/mbio.01768-26","url":null,"abstract":"<p><p>Experimental model systems are essential in microbiology. However, models are often described as \"biologically relevant\" without a clear explanation of what that means or how relevance was established. Here, I argue that the missing piece in model development is benchmarking. New technologies and increasingly elaborate model systems can be powerful, but they do not guarantee that a model better represents the environment it is meant to reproduce. The guarantee that is implied cannot be made explicit until these models are evaluated against measurements of microbial behavior and function made directly in those environments. These \"field\" experiments are often messy, expensive, low throughput, and technically challenging, but provide the benchmarks needed to determine what a model captures, what it misses, and which questions it can tackle. While chemical measurements and quantification of physical features can guide model construction, the most important readout is the behavior of the microbes in the natural environment.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0176826"},"PeriodicalIF":5.4,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808760","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":"HMGB1-targeted anti-inflammatory rBox A gene therapy for viral airway infections and systemic inflammatory disease models.","authors":"Kari Ann Shirey, Daniel Prantner, Lynda Coughlan, Chanhee Park, Lin Zou, Wei Chao, John Joseph, Jorge C G Blanco, Stefanie N Vogel","doi":"10.1128/mbio.01819-26","DOIUrl":"10.1128/mbio.01819-26","url":null,"abstract":"<p><p>High mobility group box 1 (HMGB1) is a host-derived proinflammatory molecule released during cell injury. Elevated extracellular HMGB1 levels have been associated with disease severity. HMGB1 contributes to host influenza responses by stimulating TLR4/MD-2 signaling, amplifying lung inflammation, and tissue damage via cytokine production and leukocyte infiltration. HMGB1 also plays a central role in other inflammatory diseases, including sepsis and liver toxicity, making it both a biomarker of disease severity and a potential therapeutic target. We previously reported development of a non-replicating adenovirus (AdV) vector that carries an inflammation-inducible cassette that remains dormant in the absence of inflammation but produces recombinant HMGB1 Box A, a competitive antagonist of HMGB1, in response to inflammatory stimuli. Therapeutic treatment with AdV.C3-Tat/HIV-Box A mitigated lung and systemic inflammation in response to influenza in mice and cotton rats. Herein, we have optimized vector delivery and expanded its use in multiple models of infectious and non-infectious HMGB1-induced inflammation.</p><p><strong>Importance: </strong>Despite promising preclinical outcomes, clinical translation of high mobility group box 1 (HMGB1) or TLR4/MD-2 antagonists for inflammatory diseases has been limited by challenges of drug synthesis, dosing, delivery, and off-target effects. Recombinant Box A (rBox A) is a competitive inhibitor of HMGB1 that binds to TLR4 and disrupts HMGB1-mediated TLR4/MD-2 signaling. rBox A exhibits broad anti-inflammatory activity across multiple diseases (e.g., endotoxemia, sepsis, neuroimmune disorders, ischemia/reperfusion); however, its therapeutic utility is constrained by the need for high, repeated dosing. We have engineered a non-replicating adenoviral (AdV) vector (AdV.C3-Tat/HIV-Box A) that produces recombinant (r)Box A when \"sensed\" by an inflammation-responsive complement C3 (C3) promoter. Therapeutic administration of AdV.C3-Tat/HIV-Box A resulted in significant protection and reduced inflammation in multiple HMGB1-mediated disease models, advancing a first-in-class, broadly applicable, host-directed gene therapy that selectively disrupts HMGB1-TLR4 signaling and has potential as both a broad-spectrum therapeutic for HMGB1-driven inflammatory diseases and a rapid-response countermeasure against emerging respiratory pathogens.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0181926"},"PeriodicalIF":5.4,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808801","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":"Tunneling nanotubes contribute to Zika virus pathogenesis at the maternal-fetal interface <i>in vivo</i>.","authors":"Rafael Tomoya Michita, Long B Tran, Joyce Jose, Indira U Mysorekar","doi":"10.1128/mbio.01562-26","DOIUrl":"https://doi.org/10.1128/mbio.01562-26","url":null,"abstract":"<p><p>Zika virus (ZIKV) infection during pregnancy can result in severe fetal outcomes, yet the mechanisms of transplacental dissemination remain incompletely defined. We previously showed that ZIKV induces tunneling nanotubes (TNTs), actin-rich intercellular conduits that enable direct cell-to-cell transfer of viral components. Here, we investigated the <i>in vivo</i> role of TNTs in ZIKV maternal-fetal transmission using complementary pregnancy models. A TNT-deficient ZIKV mutant (ZIKV^ΔTNT), harboring a change between residues 40 and 52 of the nonstructural protein 1 (NS1), showed markedly reduced viral dissemination to maternal and fetal tissues across all models tested, whereas the TNT-competent ZIKV established a robust infection. ZIKV^ΔTNT infection was associated with reduced placental pathology, altered junctional-to-labyrinth architecture, improved placental efficiency, and protection from fetal growth restriction. Loss of TNT-forming capacity also limited viral persistence despite maternal type III interferon (IFN-λ) responses, suggesting a role for TNTs in immune evasion. Together, these findings provide <i>in vivo</i> evidence that TNTs are a key mechanism by which ZIKV enhances dissemination, promotes placental dysfunction, and drives fetal pathogenesis.IMPORTANCEZika virus infection during pregnancy can cause severe fetal abnormalities, yet how the virus overcomes the placenta remains incompletely understood. Here, we show that ZIKV exploits direct intercellular connections called tunneling nanotubes (TNTs) to facilitate cell-to-cell transmission and impact placental infection and fetal outcomes. Using multiple pregnancy models, we demonstrate that viruses capable of forming these structures disseminate more efficiently, damage the placenta, and lead to fetal growth restriction, whereas TNT-deficient viruses show reduced infection and milder disease. Importantly, TNT-mediated dissemination is associated with viral persistence despite maternal interferon responses, suggesting a role in immune evasion. These findings identify TNTs as a previously underappreciated pathway of viral transmission during pregnancy and suggest new therapeutic targets. More broadly, TNTs may contribute to the pathogenesis of other vertically transmitted or emerging viral infections.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0156226"},"PeriodicalIF":5.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795096","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":"PRRSV N protein antagonizes host antiviral immune responses by upregulating HSPA1B to induce autophagic degradation of Fos-related antigen 1.","authors":"Xiao Liu, Jianwu Zhang, Xiaoyang Yan, Yinan Meng, Haozhe Wang, Fang Lv, Bo Peng, Zifang Zheng, Yang Li, Yingtong Feng, Lele Xu, Shuqi Xiao","doi":"10.1128/mbio.01091-26","DOIUrl":"https://doi.org/10.1128/mbio.01091-26","url":null,"abstract":"<p><p>Porcine reproductive and respiratory syndrome virus (PRRSV) infection often causes severe immunosuppression in pigs. However, the mechanisms by which PRRSV antagonizes host antiviral immune responses remain incompletely understood. We found that granulocyte-macrophage colony-stimulating factor (CSF2) was significantly upregulated in porcine alveolar macrophages (PAMs) upon PRRSV infection. CSF2 upregulation inhibits PRRSV replication by promoting IL15 expression, and Fos-related antigen 1 (FRA1) enhances the antiviral activity of the CSF2-IL15 axis via transcriptional regulation. Further investigation revealed that the PRRSV N protein directly interacts with HSPA1B and activates HSPA1B-mediated chaperone-mediated autophagy (CMA) to degrade FRA1, thereby antagonizing host antiviral immunity. Our study reveals that the PRRSV N protein promotes FRA1 autophagic degradation by upregulating heat shock protein HSPA1B, thereby suppressing the host CSF2-IL15 antiviral pathway. This study provides new insights into the arms race between PRRSV and the host, as well as novel perspectives for the development of anti-PRRSV infection strategies.</p><p><strong>Importance: </strong>Focusing on the core scientific issue of PRRSV immune evasion, this study identifies a novel pathway by which host FRA1 restricts viral infection through regulating the CSF2-IL15 cytokine axis. It reveals that the PRRSV N protein hijacks HSPA1B-mediated chaperone-mediated autophagy to target and degrade the transcription factor FRA1, thereby dismantling the host CSF2-IL15 antiviral defense and advancing the understanding of PRRSV-related immunosuppression. These findings elucidate a new paradigm in the host-pathogen tug-of-war, whereby viruses exploit autophagy machinery to eliminate critical immune regulators. This work also provides mechanistic insights for the development of intervention strategies targeting CMA and cytokine homeostasis.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0109126"},"PeriodicalIF":5.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794977","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":"Fc-engineered broadly neutralizing antibodies overcome cytokine-induced CD16 cleavage to drive potent ADCC against diverse HIV-1 strains.","authors":"Claudia Melo, Teresa Murphy, Carissa S Holmberg, Meagan Kelly, Elyse K McMahon, Jonathan S Lochner, Rebecca M Lynch, Alberto Bosque","doi":"10.1128/mbio.01724-26","DOIUrl":"https://doi.org/10.1128/mbio.01724-26","url":null,"abstract":"<p><p>The persistence of latent HIV-1 reservoirs remains the primary barrier to a cure. Shock and kill strategies aim to reactivate these reservoirs and eliminate them via effector cells, such as natural killer (NK) cells. However, chronic infection leaves NK cells exhausted. In this study, we investigated the interplay between cytokine-mediated NK cell activation and antibody-dependent cellular cytotoxicity (ADCC) across diverse HIV-1 subtypes. We demonstrated that while cytokine stimulation enhanced natural cytotoxicity, it simultaneously induces shedding of the Fc receptor CD16 via the metalloproteinase enzyme ADAM17. However, restoring CD16 expression through ADAM17 inhibition (TAPI-1) did not improve ADCC, suggesting that CD16 surface levels in NK cells are not the only limiting factor. On the other hand, Fc-engineered broadly neutralizing antibodies (bNAbs) with increased CD16 affinity, in particular LPLIL and GASDALIE, significantly enhance ADCC across different HIV-1 subtypes, regardless of NK cell activation or CD16 downregulation. These findings suggest that enhancing receptor affinity of bNAbs can bypass viral immune evasion and NK cell exhaustion, supporting their potential incorporation into HIV cure strategies.IMPORTANCEEradicating latent HIV reservoirs remains a global health priority as it would liberate millions of people living with HIV (PLWH) from the economic and physiological burdens of lifelong antiretroviral therapy (ART). By utilizing a primary human cell model that resembles <i>in vivo</i> conditions across diverse viral strains, we identified that simply preventing CD16 receptor shedding from natural killer (NK) cells is insufficient to improve HIV-1 clearance. Instead, we demonstrated that enhancing the binding of antibodies to the CD16 receptor enables NK cells to overcome viral immune evasion and the loss of CD16 expression. This allows for potent elimination of infected cells through antibody-dependent cellular cytotoxicity (ADCC). These findings provide a clear strategy for designing more effective \"kill\" components in future therapeutic strategies.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0172426"},"PeriodicalIF":5.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795024","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":"Why are archaea not pathogenic? A hypothesis based on metabolism-habitat covariation.","authors":"Daniel J Harrison, Matthew S Fullmer, Nobuto Takeuchi","doi":"10.1128/mbio.01185-26","DOIUrl":"https://doi.org/10.1128/mbio.01185-26","url":null,"abstract":"<p><p>Pathogenicity, the ability to cause infectious diseases in multicellular eukaryotes, is widespread among bacteria and eukaryotes but has not been reliably identified in archaea. To explore possible reasons for this disparity, we perform comparative analyses of thousands of bacterial and archaeal isolates. Our results show that isolated bacterial pathogens possess the ability to use organic compounds as sources of energy, electrons, and carbon (chemo-organo-heterotrophy or COH), suggesting that COH is a metabolic prerequisite for pathogenicity. Moreover, we find that isolated archaea capable of COH do not inhabit multicellular eukaryotes and instead predominantly inhabit extreme environments that preclude such eukaryotes. In contrast, all isolated archaea that inhabit multicellular eukaryotes are incapable of COH metabolism. This metabolism-habitat covariation in isolated archaea, together with COH as a potential prerequisite for pathogenicity in bacteria, suggests that the absence of archaeal pathogens may be due to a combination of the two factors: COH-capable archaea lack the environmental opportunity to inhabit multicellular eukaryotes, while non-COH archaea lack the metabolic prerequisite for pathogenicity.IMPORTANCEPathogenicity-the ability to cause infectious disease-is widespread among bacteria and eukaryotes but conspicuously absent from archaea, the third domain of life. To understand why archaea are non-pathogenic, we performed comparative analyses of thousands of bacterial and archaeal isolates. We found that the absence of pathogenic archaea can be explained by a combination of metabolic and environmental factors. Specifically, archaea living within eukaryotic, multicellular hosts lack a metabolic capability correlated with pathogenicity-chemo-organo-heterotrophy-whereas those possessing this metabolism typically live under extreme conditions, such as high temperature, and therefore lack the environmental opportunity to interact with eukaryotic hosts. These findings advance our understanding of microbes by revealing important links between their metabolism, habitats, and pathogenicity.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0118526"},"PeriodicalIF":5.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795105","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}