PLoS Pathogens最新文献

{"title":"Listeria monocytogenes requires phosphotransferase systems to facilitate intracellular growth and virulence.","authors":"Matthew J Freeman, Noah J Eral, John-Demian Sauer","doi":"10.1371/journal.ppat.1012492","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012492","url":null,"abstract":"<p><p>The metabolism of bacterial pathogens is exquisitely evolved to support virulence in the nutrient-limiting host. Many bacterial pathogens utilize bipartite metabolism to support intracellular growth by splitting carbon utilization between two carbon sources and dividing flux to distinct metabolic needs. For example, previous studies suggest that the professional cytosolic pathogen Listeria monocytogenes (L. monocytogenes) utilizes glycerol and hexose phosphates (e.g., Glucose-6-Phosphate) as catabolic and anabolic carbon sources in the host cytosol, respectively. However, the role of this putative bipartite metabolism in L. monocytogenes virulence has not been fully assessed. Here, we demonstrate that when L. monocytogenes is unable to consume either glycerol (ΔglpD/ΔgolD), hexose phosphates (ΔuhpT), or both (ΔglpD/ΔgolD/ΔuhpT), it is still able to grow in the host cytosol and is 10- to 100-fold attenuated in vivo suggesting that L. monocytogenes consumes alternative carbon source(s) in the host. An in vitro metabolic screen using BioLog's phenotypic microarrays unexpectedly demonstrated that WT and PrfA* (G145S) L. monocytogenes, a strain with constitutive virulence gene expression, use phosphotransferase system (PTS) mediated carbon sources. These findings contrast with the existing metabolic model that cytosolic L. monocytogenes expressing PrfA does not use PTS mediated carbon sources. We next demonstrate that two independent and universal phosphocarrier proteins (PtsI [EI] and PtsH [HPr]), essential for the function of all PTS, are critical for intracellular growth and virulence in vivo. Constitutive virulence gene expression using a PrfA* (G145S) allele in ΔglpD/ΔgolD/ΔuhpT and ΔptsI failed to rescue in vivo virulence defects suggesting phenotypes are due to metabolic disruption and not virulence gene regulation. Finally, in vivo attenuation of ΔptsI and ΔptsH was additive to ΔglpD/ΔgolD/ΔuhpT, suggesting that hexose phosphates and glycerol and PTS mediated carbon source are relevant metabolites. Taken together, these studies indicate that PTS are critical virulence factors for the cytosolic growth and virulence of L. monocytogenes.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1012492"},"PeriodicalIF":5.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An anticipatory mechanism enhances the cooperative behaviors of quorum sensing mutants in Pseudomonas aeruginosa.","authors":"Min Yuan, Huifang Qiu, Xiaoqing Zhou, Weijun Dai","doi":"10.1371/journal.ppat.1013046","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013046","url":null,"abstract":"<p><p>Social interactions substantially influence the dynamics and functions of microbial communities. Cooperative behaviors serve to benefit populations, yet they are often exploited by cheating cells, thus creating a conflict between individuals in the microbial population. However, the underlying mechanisms by which cooperative behaviors are stabilized are incompletely elucidated. Here, we used quorum sensing (QS) as a model of cooperation, and functionally studied QS regulator LasR variant strains in the context of cooperative behaviors. We found that a LasR228 variant strain, bearing a non-conserved substitution in LasR, exhibited minimal LasR-dependent phenotypes. However, the function of this LasR228 variant strain was restored by inactivation of the transcriptional repressor PsdR, and the phenotypes of this variant strain were similar to the parental strain. Furthermore, we illustrate a post-transcriptional regulatory mechanism responsible for the activation of the LasR228 variant. Unlike LasR228, the PsdR-null-LasR228 strain demonstrated cooperative behaviors in competition with the LasR-null strain. Since psdR mutations precede the emergence of LasR variants in the evolution of P. aeruginosa using casein broth, this PsdR-mediated cooperative mechanism serves as an anticipatory control against potential cheating LasR variant strains. Additionally, our cell-killing assay showed that the cooperative PsdR-null-LasR228 strain was associated with increased bacterial pathogenicity to eukaryotic host cells. In conclusion, our study reveals the functional plasticity of LasR variants, which can be modulated by secondary mutations, affecting cooperation and conflict within populations. Our identification of a novel cooperative molecular mechanism offers insight into the maintenance of cooperation within microbial communities.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013046"},"PeriodicalIF":5.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis and mode of action for two broadly neutralizing nanobodies targeting the highly conserved spike stem-helix of sarbecoviruses including SARS-CoV-2 and its variants.","authors":"Liyan Guo, Zimin Chen, Sheng Lin, Fanli Yang, Jing Yang, Lingling Wang, Xindan Zhang, Xin Yuan, Bin He, Yu Cao, Jian Li, Qi Zhao, Guangwen Lu","doi":"10.1371/journal.ppat.1013034","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013034","url":null,"abstract":"<p><p>The persistent emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlights the need for developing broad-spectrum antiviral agents. Here, we report the identification of two sarbecovirus S2-specific alpaca nanobodies, namely H17 and H145, that effectively neutralize known SARS-CoV-2 variants (including the Omicron subvariants) and other sarbecoviruses (such as SARS-CoV, PANG/GD, WIV1, and HKU3). The two nanobodies recognize a linear epitope (D1139PLQPELDSFKEEL1152) in the upper region of the S2 stem-helix (SH), which is highly conserved among SARS-CoV-2 variants and other sarbecoviruses. The complex structure of the nanobody bound to the epitope SH-peptide reveal that nanobody binding will impede the refolding of S2, effectively neutralizing the virus. Moreover, the nanobodies bind viral S2 in an acidification-insensitive manner, demonstrating their capacity for entry inhibition especially when viruses enter via the endosomal route. Finally, H17 and H145 possess a better taking-action window for virus neutralization, superior to the RBD-targeting nanobodies that exert neutralization by competing against ACE2 binding. Taken together, the results suggest that anti-SH nanobodies H17 and H145 are promising broad-spectrum drug candidates for preventing and treating the pandemic infections by SARS-CoV-2 variants and other sarbecoviruses.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013034"},"PeriodicalIF":5.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupting the OTUD4-USP7 deubiquitinase complex to suppress herpesvirus replication: a novel antiviral strategy.","authors":"Shaowei Wang, Xuezhang Tian, Yunhong Zhong, Xiaoyu Xie, Ming Gao, Chuchu Zhang, Xi Cheng, Yining Qi, Bo Zhong, Pinghui Feng, Ke Lan, Junjie Zhang","doi":"10.1371/journal.ppat.1013052","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013052","url":null,"abstract":"<p><p>The development of effective and broad-spectrum antiviral therapies remains an unmet need. Current virus-targeted antiviral strategies are often limited by narrow spectrum of activity and the rapid emergence of resistance. As a result, there is increasing interest in alternative approaches that target host cell factors critical for viral replication. One promising strategy is the targeting of deubiquitinases (DUBs), enzymes that regulate key host and viral proteins involved in viral reactivation and replication. In this study, we explore the potential of targeting a DUB complex for antiviral therapy based on our previous study. Our previous work revealed that the OTUD4-USP7 DUB complex plays a crucial role in KSHV lytic reactivation. Here, we developed a peptide, p8, which effectively disrupts the interaction between OTUD4 and USP7, leading to decreased abundance of the key viral transcription factor, RTA, and suppression of murine herpesvirus replication in vivo. These findings underscore the OTUD4-USP7 DUB complex as a promising host-targeting antiviral therapeutic target for the treatment of KSHV-associated malignancies. Moreover, our study highlights the potential of DUB-targeting therapies as a novel and effective strategy for the development of broad-spectrum antiviral agents.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013052"},"PeriodicalIF":5.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efflux pumps and membrane permeability contribute to intrinsic antibiotic resistance in Mycobacterium abscessus.","authors":"Kerry McGowen, Tobias Funck, Xin Wang, Samuel Zinga, Ian D Wolf, Chidiebere Akusobi, Claudia M Denkinger, Eric J Rubin, Mark R Sullivan","doi":"10.1371/journal.ppat.1013027","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013027","url":null,"abstract":"<p><p>Mycobacterium abscessus is a pulmonary pathogen that exhibits intrinsic resistance to antibiotics, but the factors driving this resistance are incompletely understood. Insufficient intracellular drug accumulation could explain broad-spectrum resistance, but whether antibiotics fail to accumulate in M. abscessus and the mechanisms required for drug exclusion remain poorly understood. We measured antibiotic accumulation in M. abscessus using mass spectrometry and found a wide range of drug accumulation across clinically relevant antibiotics. Of these compounds, linezolid accumulates the least, suggesting that inadequate uptake impacts its efficacy. We utilized transposon mutagenesis screening to identify genes that cause linezolid resistance and found multiple transporters that promote membrane permeability or efflux, including an uncharacterized protein that effluxes linezolid and several chemically related antibiotics. This demonstrates that membrane permeability and drug efflux are critical mechanisms of antibiotic resistance in M. abscessus and suggests that targeting membrane transporters could potentiate the efficacy of certain antibiotics.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013027"},"PeriodicalIF":5.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12017575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mystique, a broad host range Acinetobacter phage, reveals the impact of culturing conditions on phage isolation and infectivity.","authors":"Ellinor O Alseth, Carli Roush, Iris Irby, Mykhailo Kopylov, Daija Bobe, Monneh W Diggs, Kristy Nguyen, Huaijin Xu, Ingeborg Schmidt-Krey, Anton V Bryksin, Philip N Rather","doi":"10.1371/journal.ppat.1012986","DOIUrl":"https://doi.org/10.1371/journal.ppat.1012986","url":null,"abstract":"<p><p>With the global rise of antimicrobial resistance, phage therapy is increasingly re-gaining traction as a strategy to treat bacterial infections. For phage therapy to be successful however, we first need to isolate appropriate candidate phages for both clinical and experimental research. Acinetobacter baumannii is an opportunistic pathogen known for its ability to rapidly evolve resistance to antibiotics, making it a prime target for phage therapy. Yet phage isolation may be hampered by A. baumannii's ability to rapidly switch between capsular states. Here, we report the discovery and structural characterisation of a novel lytic phage, Mystique. This phage was initially isolated against the wild-type AB5075: a commonly used clinical model strain. When screening Mystique on 103 highly diverse isolates of A. baumannii, we found that it has a broad host range, being able to infect 85.4% of all tested strains when tested on bacterial lawns - a host range that expanded to 91.3% when tested in liquid culture. This variation between solid and liquid culturing conditions on phage infectivity was also observed for several other phages in our collection that were assumed unable to infect AB5075, and some capsule negative mutants that seemed resistant to Mystique proved susceptible when assayed in liquid. This highlights how differences in culturing conditions can drastically impact phage infectivity, with important consequences for phage isolation and characterisation efforts. Finally, Mystique was found to be able to infect other species of Acinetobacter, making it a multi-species phage with broad applicability for further research.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1012986"},"PeriodicalIF":5.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Live-cell RNA imaging with the inactivated endonuclease Csy4 enables new insights into plant virus transport through plasmodesmata.","authors":"David Burnett, Mohamed Hussein, Zoe Kathleen Barr, Laura Newsha Näther, Kathryn M Wright, Jens Tilsner","doi":"10.1371/journal.ppat.1013049","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013049","url":null,"abstract":"<p><p>Plant-infecting viruses spread through their hosts by transporting their infectious genomes through intercellular nano-channels called plasmodesmata. This process is mediated by virus-encoded movement proteins. Whilst the sub-cellular localisations of movement proteins have been intensively studied, live-cell RNA imaging systems have so far not been able to detect viral genomes inside the plasmodesmata. Here, we describe a highly sensitive RNA live-cell reporter based on an enzymatically inactive form of the small bacterial endonuclease Csy4, which binds to its cognate stem-loop with picomolar affinity. This system allows imaging of plant viral RNA genomes inside plasmodesmata and shows that potato virus X RNA remains accessible within the channels and is therefore not fully encapsidated during movement. We also combine Csy4-based RNA-imaging with interspecies movement complementation to show that an unrelated movement protein from tobacco mosaic virus can recruit potato virus X replication complexes adjacent to plasmodesmata. Therefore, recruitment of potato virus X replicase is mediated non-specifically, likely by indirect coupling of movement proteins and viral replicase via the viral RNA or co-compartmentalisation, potentially contributing to transport specificity. Lastly, we show that a 'self-tracking' virus can express the Csy4-based reporter during the progress of infection. However, expression of the RNA-binding protein in cis interferes with viral movement by an unidentified mechanism when cognate stem-loops are present in the viral RNA.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013049"},"PeriodicalIF":5.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modularization of the type II secretion gene cluster from Xanthomonas euvesicatoria facilitates the identification of a structurally conserved XpsCLM assembly platform complex.","authors":"Samuel Goll, Patrick Martin, Sylvestre Marillonnet, Daniela Büttner","doi":"10.1371/journal.ppat.1013008","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013008","url":null,"abstract":"<p><p>Many bacterial pathogens depend on a type II secretion (T2S) system to secrete virulence factors from the periplasm into the extracellular milieu. T2S systems consist of an outer membrane secretin channel, a periplasmic pseudopilus and an inner membrane-associated assembly platform including a cytoplasmic ATPase. The components of T2S systems are often conserved in different bacterial species, however, the architecture of the assembly platform is largely unknown. Here, we analysed predicted assembly platform components of the Xps-T2S system from the plant-pathogenic bacterium Xanthomonas euvesicatoria. To facilitate these studies, we generated a modular xps-T2S gene cluster by Golden Gate assembly of single promoter and gene fragments. The modular design allowed the efficient deletion and replacement of T2S genes and the insertion of reporter fusions. Mutant approaches as well as interaction and crosslinking studies showed that the predicted assembly platform components XpsC, XpsL and XpsM form a trimeric complex which is essential for T2S and associates with the cytoplasmic ATPase XpsE and the secretin XpsD. Structural modeling revealed a similar trimeric architecture of XpsCLM homologs from Pseudomonas, Vibrio and Klebsiella species, despite overall low amino acid sequence similarities. In X. euvesicatoria, crosslinking and fluorescence microscopy studies showed that the formation of the XpsCLM complex is independent of the secretin and vice versa, suggesting that the assembly of the T2S system is a dynamic process which involves the association of preformed subcomplexes.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013008"},"PeriodicalIF":5.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dual functions of the GTPase BipA in ribosome assembly and surface structure biogenesis in Salmonella enterica serovar Typhimurium.","authors":"Eunsil Choi, Eunwoo Ryu, Donghwee Kim, Ji-Won Byun, Kahyun Kim, Minho Lee, Jihwan Hwang","doi":"10.1371/journal.ppat.1013047","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013047","url":null,"abstract":"<p><p>The bactericidal/permeability-increasing protein (BPI)-inducible protein A (BipA) is a highly conserved protein in Gram-negative bacteria that is structurally similar to translational GTPases such as IF2, EF-Tu, and EF-G. Our previous research showed that deleting bipA in Escherichia coli at 20°C leads to a defect in 50S ribosomal assembly and impaired lipopolysaccharide (LPS) synthesis. This LPS defect activates the Regulator of Capsule Synthesis (Rcs) pathway, resulting in an overproduction of capsular polysaccharides, a reduction in biofilm formation, and decreased flagella-mediated motility. In this study, we aimed to elucidate the role of BipA in the pathogenicity of Salmonella enterica serovar Typhimurium. We constructed bipA deletion mutants in two pathogenic S. Typhimurium strains, SL1344 and 14028, as well as in the attenuated strain LT2. Our ribosome profiling experiments using the mutant S. Typhimurium strains revealed a defect in ribosome assembly at 20°C, with the accumulation of abnormal 50S ribosomal subunits. We further demonstrated that the absence of BipA in S. Typhimurium impaired LPS biosynthesis at 20°C, compromising membrane integrity and presumably activating the Rcs pathway. This activation altered virulence factors, including reduced biofilm formation, particularly in the 14028ΔbipA strain. Furthermore, the SL1344ΔbipA and 14028ΔbipA strains exhibited significantly decreased swimming motility at 20°C compared to 37°C, confirmed by microscopic observation showing fewer flagella at 20°C. Subsequently, both strains exhibited a significant reduction in invasion capability and cytotoxicity toward human intestinal epithelial cells (HCT116). This functional attenuation was corroborated by the decrease in virulence observed in the 14028ΔbipA strain in a mouse model. Our findings suggest that, in S. Typhimurium, BipA functions as a bacterial fitness factor, contributing to ribosome assembly, LPS synthesis, and virulence-related processes, particularly under stress conditions relevant to host environments.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013047"},"PeriodicalIF":5.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-6 trans-signaling mediates cytokine secretion and barrier dysfunction in hantavirus-infected cells and correlates to severity in HFRS.","authors":"Kimia T Maleki, Linda Niemetz, Wanda Christ, Julia Wigren Byström, Therese Thunberg, Clas Ahlm, Jonas Klingström","doi":"10.1371/journal.ppat.1013042","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013042","url":null,"abstract":"<p><strong>Background: </strong>Hantavirus causes hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Strong inflammatory responses and vascular leakage are important hallmarks of these often fatal diseases. The mechanism behind pathogenesis is unknown and no specific treatment is available. IL-6 was recently highlighted as a biomarker for HPS/HFRS severity. IL-6 signaling is complex and context dependent: while classical signaling generally provide protective responses, trans-signaling can cause severe pathogenic responses. Here, we investigated a potential role for IL-6 trans-signaling in hantavirus pathogenesis.</p><p><strong>Methods: </strong>Effects of IL-6 trans-signaling during in vitro hantavirus infection were assessed using primary human endothelial cells treated with recombinant soluble IL-6 receptor (sIL-6R). Plasma from Puumala orthohantavirus-infected HFRS patients (n=28) were analyzed for IL-6 trans-signaling potential and its associations to severity.</p><p><strong>Findings: </strong>In vitro, sIL-6R treatment of infected cells enhanced IL-6 and CCL2 secretion, upregulated ICAM-1, and affected VE-cadherin leading to a disrupted cell barrier integrity. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients receiving oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients that did not.</p><p><strong>Interpretation: </strong>IL-6 trans-signaling is linked to hantavirus pathogenesis. Targeting IL-6 trans-signaling might provide a therapeutic strategy for treatment of severe HFRS and perhaps also HPS.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 4","pages":"e1013042"},"PeriodicalIF":5.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}