mBio最新文献

{"title":"AntiviralDB: an expert-curated database of antiviral agents against human infectious diseases.","authors":"Jie Huang, Qixiang Song, Pan Zhang, Lei Deng, Feng Gao, Yelin Deng, Ewelina Krol, Daniel Růžek, Ricardo Khouri, Erik De Clercq, Guangdi Li","doi":"10.1128/mbio.02013-25","DOIUrl":"10.1128/mbio.02013-25","url":null,"abstract":"<p><p>Viral infectious diseases have caused millions of deaths worldwide. Antiviral agents are critical for controlling these infections; however, an open-access database dedicated specifically to antiviral agents remains unavailable. Here, we present AntiviralDB (https://www.antiviraldb.com/), an expert-curated resource that compiles both approved and experimental antiviral agents with laboratory-confirmed <i>in vitro</i> activity against a broad spectrum of human viruses. These include the human immunodeficiency virus, coronaviruses, hepatitis viruses, influenza virus, respiratory syncytial virus, herpes simplex virus, varicella-zoster virus, human cytomegalovirus, human papillomavirus, dengue virus, Zika virus, Ebola virus, mpox virus, norovirus, chikungunya virus, and 16 other common or life-threatening pathogens. Each antiviral agent in the database is annotated with key information, including its molecular target, <i>in vitro</i> antiviral activity (IC₅₀, EC₅₀, and CC₅₀ across specific viral strains and cell lines), mechanism of action, and relevant pharmacokinetic and pharmacodynamic parameters. AntiviralDB also provides clinical efficacy and safety data derived from randomized clinical trials. Unlike existing drug databases, AntiviralDB offers two distinctive features: (i) standardized laboratory protocols for antiviral drug screening under appropriate biosafety conditions and (ii) clinical guidelines for the therapeutic use of antiviral agents against viral infections. By serving as a comprehensive repository of antiviral agents and their clinical applications, AntiviralDB aims to advance antiviral drug discovery and support the effective clinical management of viral infectious diseases.</p><p><strong>Importance: </strong>Over the past decade, viral infectious diseases have caused significant morbidity and mortality worldwide, underscoring the urgent need for effective antiviral therapies. However, there is a lack of an open-access database that consolidates detailed information on antiviral agents, clinical guidelines, and laboratory protocols. To address this need, AntiviralDB was developed to integrate extensive data on antiviral agents-including clinical efficacy, safety profiles, pharmacokinetic parameters, and <i>in vitro</i> and <i>in vivo</i> activities-together with standardized experimental protocols and clinical treatment guidelines. This resource empowers researchers and clinicians to (i) identify promising antiviral candidates for controlling infectious diseases, (ii) accelerate the discovery and development of novel therapeutics, (iii) optimize the clinical use of existing antiviral drugs, and (iv) enhance a quick response to emerging viral outbreaks.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0201325"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033751","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":"Humoral immunity to current variants of SARS-CoV-2 in exposed adults, September 2023 to September 2024.","authors":"Lara M Jeworowski, Barbara Mühlemann, Felix Walper, Marie L Schmidt, Jenny Jansen, Andi Krumbholz, Terry C Jones, Victor M Corman, Christian Drosten","doi":"10.1128/mbio.01618-25","DOIUrl":"10.1128/mbio.01618-25","url":null,"abstract":"<p><p>SARS-CoV-2 evolves variants that evade population immunity. Monitoring group-level immunity is critical for assessing population susceptibility to newly circulating variants and updateability of imprinted immunity after exposure. We established a closely monitored cohort of 58 fully vaccinated adults in Berlin, Germany. Of these, 49 had at least one previous Omicron infection. In September 2023 and again in September 2024, we analyzed neutralizing antibody responses using full-virus plaque reduction neutralization tests against seven SARS-CoV-2 variants: B.1, BA.2, BA.5, EG.5.1, JN.1, KP.3.1.1, and XEC. Vaccination and exposure histories were traced using medical records, RT-PCR testing of any episode of respiratory tract infection, and serological testing for subclinical infections. Infecting variants were determined by sequencing or from unequivocal variant circulation at the time of positive testing. Titers from September 2023 included responses to both then-current and future variants. Over the study period, 13 subjects received monovalent XBB.1.5 vaccine. Thirty-four had one, and five more than one SARS-CoV-2 infection. None of the subjects was exposed to the most recent variant, XEC. Neutralization titers against all tested variants increased over time. Highest fold increases were seen against KP.3.1.1 and XEC. Reactivity profiles differed by exposure histories reflecting the most recent variant contact. Exposure to new variants leads to relative updates in population-level neutralizing antibody activity. Despite these updates, absolute group-level neutralization activity was low in September 2024 due to low titer levels against currently circulating variants KP.3.1.1 and XEC. Ongoing monitoring is needed to assess the need for further vaccine updates.IMPORTANCEAs new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants continue to emerge, understanding how population immunity evolves is essential to guide vaccine updates and public health strategies. Our study follows a group of fully vaccinated adults for 1 year (September 2023 to September 2024) to track how infection and vaccination affect the ability to neutralize new viral variants. Despite the continued emergence of immune escape variants, the results show that infection with recent variants helps to \"update\" immunity at the group level, even against newer variants such as KP.3.1.1 and XEC, although titers to new variants were low, confirming the existence of immune imprinting. These findings suggest that exposure to new variants adapts the immune system over time. This provides valuable insight into how populations build resilience against SARS-CoV-2 and whether updated vaccines are needed.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0161825"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040562","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":"mGem: How many fungal secondary metabolites are produced by filamentous fungi? Conservatively, at least 1.4 million.","authors":"Olivia L Riedling, Antonis Rokas","doi":"10.1128/mbio.01381-25","DOIUrl":"10.1128/mbio.01381-25","url":null,"abstract":"<p><p>The ~30,000 known fungal secondary metabolites (SMs) are a vital component of the bioeconomy. SMs are biosynthesized by biosynthetic gene clusters (BGCs), i.e., sets of genes in close physical proximity in the genome. The bulk of these SMs are produced by filamentous fungi in the Pezizomycotina subphylum (phylum Ascomycota). To gauge the magnitude of chemodiversity in this subphylum, we utilized data from the well-characterized genus <i>Aspergillus</i> and a previous Pezizomycotina genomic survey. With 30-50 BGCs per genome, our rarefaction analyses show that the ~85,000 known species in Pezizomycotina likely contain 1.4-4.3 million SMs from an estimated 870 thousand to 2.7 million gene cluster families. Considering that only 5% of fungal species have been described and that the actual number of Pezizomycotina species is likely closer to a million, the projected number of SMs is likely between ~16 and 50 million. These estimates suggest that most fungal SMs remain undiscovered.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0138125"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069919","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":"Thermodynamics shapes the <i>in vivo</i> enzyme burden of glycolytic pathways.","authors":"Daven B Khana, Annie Jen, Evgenia Shishkova, Kirsten Fisher, Eashant Thusoo, Jonathan Williams, Alex Henkel, David M Stevenson, Joshua J Coon, Daniel Amador-Noguez","doi":"10.1128/mbio.01837-25","DOIUrl":"10.1128/mbio.01837-25","url":null,"abstract":"<p><p>Thermodynamically constrained reactions and pathways are hypothesized to impose greater protein demands on cells, requiring higher enzyme amounts to sustain a given flux compared to those with stronger thermodynamics. To test this, we quantified the absolute concentrations of glycolytic enzymes in three bacterial species-<i>Zymomonas mobilis</i>, <i>Escherichia coli</i>, and <i>Clostridium thermocellum</i>-which employ distinct glycolytic pathways with varying thermodynamic driving forces. By integrating enzyme concentration data with corresponding <i>in vivo</i> metabolic fluxes and Δ<i>G</i> measurements, we found that the highly favorable Entner-Doudoroff pathway in <i>Z. mobilis</i> requires only one-fourth the amount of enzymatic protein to sustain the same flux as the thermodynamically constrained pyrophosphate-dependent glycolytic pathway in <i>C. thermocellum</i>, with the Embden-Meyerhof-Parnas pathway in <i>E. coli</i> exhibiting intermediate thermodynamic favorability and enzyme demand. Across all three pathways, early reactions with stronger thermodynamic driving forces generally required lower enzyme investment than later, less favorable steps. Additionally, reflecting differences in glycolytic strategies, the highly reversible ethanol fermentation pathway in <i>C. thermocellum</i> requires 10-fold more protein to maintain the same flux as the irreversible, forward-driven ethanol fermentation pathway in <i>Z. mobilis</i>. Thus, protein investment across glycolytic pathways reflects differences in their thermodynamic favorability.IMPORTANCECells regulate metabolic fluxes to balance energy production, biosynthesis, and the efficient use of limited resources, including the finite capacity for synthesizing and maintaining metabolic enzymes. Here, we present <i>in vivo</i> evidence that strongly thermodynamically favorable metabolic pathways require significantly fewer enzyme resources to sustain a given flux compared to less thermodynamically favorable pathways. These findings underscore the connection between pathway thermodynamics, resource allocation, and enzyme burden, providing valuable insights for metabolic engineering strategies aimed at optimizing pathways for high flux with minimal protein cost.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0183725"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069951","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":"Rare but relevant: a comprehensive narrative review of rare HIV-1 group M subtypes.","authors":"Dana F Indihar, Rachael Oke, Rondel Hemerding, De'Travean Williams, Rupert England, Laricca Y London","doi":"10.1128/mbio.01264-25","DOIUrl":"10.1128/mbio.01264-25","url":null,"abstract":"<p><p>Human immunodeficiency virus type 1 (HIV-1) group M comprises 10 genetically diverse subtypes, with subtypes C and B being the most prevalent globally. However, rare subtypes F, H, J, K, and L, though individually responsible for less than 1% of HIV-1 infections worldwide, play relevant roles in viral evolution, global persistence, recombination, and drug resistance. This review provides a comprehensive synthesis of the available literature on these rare subtypes for the first time, emphasizing their distribution, recombination patterns, transmission dynamics, and drug resistance-associated mutations. A key observation is that many of these rare subtypes are more frequently found in recombinant forms than in non-recombinant forms, which may expand their geographic distribution and sustain their epidemiological presence. We further highlight drug resistance-associated mutations in the protease and reverse transcriptase regions of the rare subtypes, which may affect treatment outcomes. Advances in molecular tools, such as next-generation sequencing and Bayesian phylogeographic analyses, have improved the identification of the rare subtypes in both recombinant and non-recombinant forms. However, there remains a significant data gap in the clinical impact of these subtypes as they continue to be undersampled and understudied. This review thus underscores the need for augmenting subtype-specific surveillance strategies, especially in regions where the rare subtypes predominantly circulate. Expanding research on these rare subtypes will be essential for understanding HIV-1 recombination and evolutionary dynamics, identifying trends in drug resistance, and developing more globally inclusive anti-viral strategies that better reflect the diversity of HIV-1.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0126425"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959100","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":"PTP1B deficiency in myeloid cells increases susceptibility to <i>Candida albicans</i> systemic infection by modulating antifungal immunity.","authors":"Bethany Allen, Ivy M Dambuza, Susan H Berry, Delyth M Reid, Sam M McVey, Martina Mesiarikova, Larissa John, Moira Davie, Christa P Baker, J Simon C Arthur, Mirela Delibegovic, Gordon D Brown, Heather M Wilson","doi":"10.1128/mbio.01516-25","DOIUrl":"10.1128/mbio.01516-25","url":null,"abstract":"<p><p>Invasive candidiasis, primarily caused by <i>Candida albicans</i>, poses a significant threat to immunocompromised patients, with high mortality rates. Understanding how immune responses to <i>Candida albicans</i> are mounted and controlled is fundamental to developing new therapeutic strategies. Protein tyrosine phosphatase 1B (PTP1B) is a regulator of immunoreceptor signaling and downstream inflammatory and metabolic responses and a pharmaceutical target. Here, we reveal a critical role for myeloid cell-intrinsic PTP1B in antifungal immunity. Mice lacking PTP1B in myeloid cells (LysM PTP1B^-/-) were significantly more susceptible to systemic <i>C. albicans</i> infection, exhibiting lower survival, greater weight loss, and elevated fungal burdens in the kidney, liver, and brain. These mice also showed heightened proinflammatory mRNA expression in organs and increased kidney tubular inflammation, with increased leukocyte infiltration and chemokine production, contributing to immunopathology. Neutrophils from LysM PTP1B^-/- mice displayed impaired maturation in infected kidneys and reduced reactive oxygen species production <i>in vitro</i>. Proteomic profiling of infected bone marrow-derived macrophages (BMDMs) revealed significant enrichment of type I interferon-regulated proteins in the absence of PTP1B. These BMDMs showed impaired phagocytosis, reduced killing capacity, and lower viability during infection, phenotypes recapitulated in human macrophages treated with a pharmacological PTP1B inhibitor. Collectively, our findings highlight PTP1B as a key modulator of innate immune responses to <i>C. albicans</i>, balancing antifungal activity and systemic toxicity with inflammation and metabolic fitness. Boosting specific PTP1B-dependent pathways may offer new strategies for enhancing host defense while minimizing fungal-induced immunopathology.IMPORTANCESystemic <i>Candida albicans</i> infections are a leading cause of hospital-acquired morbidity and mortality, particularly in immunocompromised individuals and patients receiving immunosuppressive treatments. Despite antifungal therapies, outcomes remain poor, underscoring the need to better understand host factors that control fungal clearance. Protein tyrosine phosphatase 1B (PTP1B) is a key intracellular regulator of immune and metabolic signaling. This study identifies a critical role for myeloid PTP1B in antifungal defense and susceptibility to systemic <i>C. albicans</i> infection. Loss of PTP1B impairs neutrophil and macrophage function, disrupts inflammatory balance, and compromises pathogen clearance. These findings reveal PTP1B as a central modulator of immune responses to <i>C. albicans</i> and highlight its potential as a target for host-directed therapies to improve outcomes in systemic fungal infections.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0151625"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959133","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":"Small pangenome of <i>Candida parapsilosis</i> reflects overall low intraspecific diversity.","authors":"Adam P Ryan, Sean Bergin, Jillian Scully, Evelyn Zuniga-Soto, Conor Hession, Amelia E Barber, Emilia Gómez-Molero, Oliver Bader, Florent Morio, Bing Zhai, Kenneth H Wolfe, Geraldine Butler","doi":"10.1128/mbio.01320-25","DOIUrl":"10.1128/mbio.01320-25","url":null,"abstract":"<p><p><i>Candida parapsilosis</i> is an opportunistic yeast pathogen that can cause life-threatening infections in immunocompromised humans. Whole-genome sequencing studies of the species have demonstrated remarkably low diversity, with strains typically differing by about 1.5 single nucleotide polymorphisms (SNPs) per 10 kb. However, SNP calling alone does not capture the full extent of genetic variation. Here, we define the pangenome of 372 <i>C</i>. <i>parapsilosis</i> isolates to determine variation in gene content. The pangenome consists of 5,859 genes, of which 48 are not found in the genome of the reference strain. This includes 5,791 core genes (present in ≥99.5% of isolates). Four genes, including the allantoin permease gene <i>DAL4</i>, were present in all isolates but were truncated in some strains. The truncated <i>DAL4</i> was classified as a pseudogene in the reference strain CDC317. CRISPR-Cas9 gene editing showed that removing the early stop codon (producing the full-length Dal4 protein) is associated with improved use of allantoin as a sole nitrogen source. We find that the accessory genome of <i>C. parapsilosis</i> consists of 68 homologous clusters. This includes 38 previously annotated genes, 27 novel paralogs of previously annotated genes, and 3 uncharacterized open reading frames. Approximately one-third of the accessory genome (24/68 genes) is associated with gene fusions between tandem genes in the major facilitator superfamily. Additionally, we identified two highly divergent <i>C. parapsilosis</i> strains and found that, despite their increased phylogenetic distance (~30 SNPs per 10 kb), both strains have similar gene content to the other 372.IMPORTANCE<i>Candida parapsilosis</i> is a human fungal pathogen listed in the high-priority group by the World Health Organization. It is an increasing cause of hospital-acquired and drug-resistant infections. Here, we studied the genetic diversity of 372 <i>C</i>. <i>parapsilosis</i> isolates, the largest genomic surveillance of this species to date. We show that there is relatively little genetic variation. However, we identified two more distantly related isolates from Germany, suggesting that even more sampling may yield more diversity. We find that the pangenome (the cumulative gene content of all isolates) is surprisingly small, compared to other fungal species. Many of the non-core genes are involved in transport. We also find that variations in gene content are associated with nitrogen metabolism, which may contribute to the virulence characteristics of this species.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0132025"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959540","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":"Soluble MFGE8 mediates cell entry of Crimean-Congo hemorrhagic fever virus.","authors":"Xue Ma, Zhi-Sheng Xu, Yan Fu, Yanlong Ma, Wen-Tian Du, Qian Li, Ran Zhan, Sicheng Tian, Lulu Yang, Ziqiao Wang, Fei Feng, Zhichao Gao, Manli Wang, Sheng Cao, Yan-Yi Wang, Rong Zhang","doi":"10.1128/mbio.01617-25","DOIUrl":"10.1128/mbio.01617-25","url":null,"abstract":"<p><p>Crimean Congo hemorrhagic fever virus (CCHFV) causes fatal tick-borne disease in humans and is a priority pathogen of the World Health Organization. No licensed vaccines or specific antiviral drugs are available. To understand the cell entry of CCHFV and identify potential antiviral targets to combat the disease, here, we perform the CRISPR knockout screen in wild-type cells, followed by a complementary CRISPR activation screen in cells deficient in common attachment factors (heparan sulfate, AXL, TIM-1). We identify the soluble milk fat globule-EGF factor 8 protein (MFGE8), also known as lactadherin, as a proviral factor for CCHFV infection. Overexpression of MFGE8 enhances the pseudotyped, tecVLP, and authentic CCHFV infection, while knockout decreases the infection. MFGE8 is found to promote the virus binding and internalization. Expression of MFGE8 with D48E mutation of the RGD motif and the use of pharmacological inhibitor and gene-editing suggests that MFGE8 mediates virus entry through integrin receptors on the cell surface. Further study demonstrates that soluble MFGE8 protein acts as a bridge to support the entry by binding to not only the reported phosphatidylserine (PtdSer) but also Gc protein on viral envelope and to integrins on cells. The finding of MFGE8 that can bind directly to Gc protein and the entry mode of CCHFV that employs a soluble protein may expand the tissue tropism and increase the pathogenicity of CCHFV. Our study also provides new insight into the underlying mechanisms of cell entry and development of countermeasures for CCHFV.</p><p><strong>Importance: </strong>CCHFV causes severe hemorrhagic fever outbreaks, with a mortality rate of up to 40%. Countries generally list CCHFV as one of the pathogens that requires the highest biosafety level 4 (BSL-4) of containment, which hinders the study of its cell biology and pathogenesis. LDLR was recently identified as a receptor for CCHFV, but other receptors or co-factors remain to be explored. We perform genome-wide CRISPR screens using a safe replication-competent CCHFV pseudovirus and identify a secretory MFGE8 protein that functions as an entry mediator by binding to both the Gc protein and PtdSer on the viral envelope and to the integrins on the cells. Cell entry mediated by a soluble protein may greatly expand the tissue tropism, and the strategies developed to disturb the interaction of MFGE8 with virions or with integrins may help to mitigate the fatal disease induced by CCHFV.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0161725"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959581","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":"Mapping a <i>Toxoplasma gondii</i> interactome by crosslinking mass spectrometry and machine learning.","authors":"Tadakimi Tomita, Elizabeth Weyer, Rebekah B Guevara, Simone Sidoli, Jennifer T Aguilan, Louis M Weiss","doi":"10.1128/mbio.02159-25","DOIUrl":"10.1128/mbio.02159-25","url":null,"abstract":"<p><p><i>Toxoplasma gondii</i>, a widespread human parasite, persists in hosts through complex molecular interactions. Protein-protein interactions (PPIs) underpin essential biological processes, including parasite-host interactions and cellular invasion. Herein, we utilized advanced crosslinking mass spectrometry (XL-MS) techniques to map a <i>T. gondii</i> tachyzoite cytosolic extract interactome. By integrating MS-cleavable and non-cleavable analysis, we identified a total of 196 unique PPIs at medium confidence (false discovery rate [FDR] < 5%) and 171 at high confidence (FDR < 1%), revealing both known and novel interactions within critical cellular complexes such as the ribosome, proteasome, and dense granule proteins. Structural validation confirmed spatial proximity of crosslinked residues, while comparative analyzes against existing data sets (hyperLOPIT, ToxoNET, and STRING) corroborated the biological relevance of identified interactions. Furthermore, we introduced a machine learning approach leveraging biological annotations and experimental data to significantly enhance the detection and validation of PPIs. Our findings not only provide a refined view of <i>T. gondii</i>'s molecular architecture but also highlight the utility of XL-MS coupled with computational tools in dissecting complex parasite proteomes. The XL-MS interactome map provides a new valuable resource for understanding parasite biology and developing targeted therapeutic strategies.IMPORTANCEOur work presents a novel application of crosslinking mass spectrometry (XL-MS) integrated with machine learning to systematically characterize the cytosolic protein-protein interactions in <i>Toxoplasma gondii</i>-a pathogen of significant clinical and epidemiological interest. This study addresses an important gap in microbial proteomics by leveraging advanced XL-MS techniques to capture transient and novel interactions, which are often challenging to detect with conventional methods. By combining both MS-cleavable and non-cleavable strategies with a robust machine learning approach, we were able to significantly enhance the identification of genuine protein interactions. The methodology described not only improves the depth and accuracy of interactome analysis but also offers a framework that can be applied to other complex microbial systems. We believe that the insights gained from our study will be of great interest to the microbiology community, particularly researchers focusing on host-pathogen interactions and the molecular mechanisms underlying parasitic infections.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0215925"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959845","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":"Proteomic profile at the time of surgery correlates with disease stage and surgical outcome in periprosthetic joint infection.","authors":"Kathleen O'Connor, Christina Koscianski, Nicholas Larson, Kiran K Mangalaparthi, Cody Hoffmann, Nicholas A Bedard, Khaled Elmenawi, Merrick T Ducharme, Jessica D Hohenstein, Daniel O'Brien, Akhilesh Pandey, Robin Patel","doi":"10.1128/mbio.01700-25","DOIUrl":"10.1128/mbio.01700-25","url":null,"abstract":"<p><p>Periprosthetic joint infection (PJI) is the most common and difficult to treat form of arthroplasty failure. While treatment with debridement, antibiotics, and implant retention (DAIR) is preferable to one- or two-stage implant exchange based on morbidity and cost, outcomes are not successful in all cases selected for this management strategy. DAIR is currently recommended when infection is perceived to be in an \"acute\" phase, based on symptom duration; despite this selection strategy, DAIR failure rates are high. A more objective means of predicting DAIR success could improve patient outcomes by limiting DAIR failures. To explore this possibility, advanced proteomic analysis of sonicate fluid samples from 95 subjects with PJI was performed using proximity extension assay (PEA), with 77 samples additionally undergoing complementary proteomics analysis with liquid chromatography with tandem mass spectrometry (LC-MS/MS). Sparse partial least squares differentiation analysis (sPLS-DA) separated samples from patients who underwent DAIR with known outcomes (<i>n</i> = 19) into successful or unsuccessful groups, predicting DAIR surgical outcome (area under the curve [AUC]: 1; mean \"leave one out\" AUC: 0.6). Proteins predictive of DAIR surgical outcome were significantly enriched for the \"protein repair\" Gene Ontology (GO) pathway (<i>P</i>-adj = 0.02). Additionally, proteomic signatures associated with symptom duration in PJI categorized samples into short and long symptom duration PJI. In summary, an investigation of 7,261 unique human proteins separated PJI-associated samples based on symptom duration and identified a proteomic profile predictive of DAIR success.IMPORTANCEChronic infections are generally understood to last months to years, with acute infections lasting days to weeks. The transition from acute to chronic infection is, however, poorly understood. Periprosthetic joint infection (PJI) has been considered more challenging to treat when \"chronic\" than when \"acute.\" A surgery preferred for its recovery time and cost-debridement, antibiotics, and implant retention (DAIR)-is recommended for PJI management when symptom duration is short; yet, even in this select patient group, DAIR is associated with a high treatment failure rate. A means to better identify those predicted to have a successful outcome if they undergo DAIR is needed. Here, over 7,000 proteins from human clinical PJI samples were measured and shown to be able to separate samples based on symptom duration. Importantly, a proteomic profile predictive of DAIR success was identified.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0170025"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959851","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}