Pub Date : 2025-12-01Epub Date: 2025-02-15DOI: 10.1080/21505594.2025.2466482
Haixin Bi, Fei Wang, Lin Lin, Dajun Zhang, Menghan Chen, Yuyao Shang, Lin Hua, Huanchun Chen, Bin Wu, Zhong Peng
Pasteurella multocida toxin (PMT) is an exotoxin produced by several members of the zoonotic respiratory pathogen P. multocida. The role of PMT in disrupting the mammalian respiratory barrier remains to be elucidated. In this study, we showed that inoculation of recombinantly expressed PMT increased the permeability of the respiratory epithelial barrier in mouse and respiratory cell models. This was evidenced by a decreased expression of tight junctions (ZO-1, occludin) and adherens junctions (β-catenin, E-cadherin), as well as enhanced cytoskeletal rearrangement. In mechanism, we demonstrated that PMT inoculation induced cytoplasmic Ca2+ inflow, leading to an imbalance of cellular Ca2+ homoeostasis and endoplasmic reticulum stress. This process further stimulated the RhoA/ROCK signalling, promoting cytoskeletal rearrangement and reducing the expression of tight junctions and adherens junctions. Notably, the T-type voltage-gated Ca2+ channel CaV3.1 was found to participate in PMT-induced cytoplasmic Ca2+ inflow. Knocking out CaV3.1 significantly reduced the cytotoxicity induced by PMT on swine respiratory epithelial cells and mitigated cytoplasmic Ca2+ inflow stimulated by PMT. These findings suggest CaV3.1 contributes to PMT-induced respiratory epithelial barrier disruption.
{"title":"The T-type voltage-gated Ca<sup>2+</sup> channel Ca<sub>V</sub>3.1 involves in the disruption of respiratory epithelial barrier induced by <i>Pasteurella multocida</i> toxin.","authors":"Haixin Bi, Fei Wang, Lin Lin, Dajun Zhang, Menghan Chen, Yuyao Shang, Lin Hua, Huanchun Chen, Bin Wu, Zhong Peng","doi":"10.1080/21505594.2025.2466482","DOIUrl":"10.1080/21505594.2025.2466482","url":null,"abstract":"<p><p><i>Pasteurella multocida</i> toxin (PMT) is an exotoxin produced by several members of the zoonotic respiratory pathogen <i>P. multocida</i>. The role of PMT in disrupting the mammalian respiratory barrier remains to be elucidated. In this study, we showed that inoculation of recombinantly expressed PMT increased the permeability of the respiratory epithelial barrier in mouse and respiratory cell models. This was evidenced by a decreased expression of tight junctions (ZO-1, occludin) and adherens junctions (β-catenin, E-cadherin), as well as enhanced cytoskeletal rearrangement. In mechanism, we demonstrated that PMT inoculation induced cytoplasmic Ca<sup>2+</sup> inflow, leading to an imbalance of cellular Ca<sup>2+</sup> homoeostasis and endoplasmic reticulum stress. This process further stimulated the RhoA/ROCK signalling, promoting cytoskeletal rearrangement and reducing the expression of tight junctions and adherens junctions. Notably, the T-type voltage-gated Ca<sup>2+</sup> channel Ca<sub>V</sub>3.1 was found to participate in PMT-induced cytoplasmic Ca<sup>2+</sup> inflow. Knocking out Ca<sub>V</sub>3.1 significantly reduced the cytotoxicity induced by PMT on swine respiratory epithelial cells and mitigated cytoplasmic Ca<sup>2+</sup> inflow stimulated by PMT. These findings suggest Ca<sub>V</sub>3.1 contributes to PMT-induced respiratory epithelial barrier disruption.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":" ","pages":"2466482"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-02-20DOI: 10.1080/21505594.2025.2467156
Qingying Fan, Haikun Wang, Shuo Yuan, Yingying Quan, Rishun Li, Li Yi, Aiqing Jia, Yuxin Wang, Yang Wang
Streptococcus suis, a zoonotic pathogen, is commonly found as a commensal bacterium in the respiratory tracts of pigs. Under specific conditions, it becomes invasive and enters the blood, causing severe systemic infections. For S. suis, effective acquisition of carbon sources in different host niches is necessary for its survival. However, as of now, our understanding of the metabolism of S. suis within the host is highly restricted. Pyruvate formate lyase (PFL) plays a crucial role in bacterial survival of in glucose-limited and hypoxic host tissues. Here, we investigated the physiological and metabolic functions of PFL PflB in S. suis and elucidated its pivotal role in regulating virulence within the mucosal and blood niches. We demonstrate that PflB is a key enzyme for S. suis to support mixed-acid fermentation under glucose-limited and hypoxic conditions. Additionally, PflB is involved in regulating S. suis morphology and stress tolerance, and its regulation of capsular polysaccharide content depends on dynamic carbon availability. We also found that PflB is associated with the capacity of S. suis to cause bacteremia and persist in the upper respiratory tract to induce persistent infection. Our results provide highly persuasive evidence for the relationship between metabolic regulation and the virulence of S. suis.
{"title":"Pyruvate formate lyase regulates fermentation metabolism and virulence of <i>Streptococcus suis</i>.","authors":"Qingying Fan, Haikun Wang, Shuo Yuan, Yingying Quan, Rishun Li, Li Yi, Aiqing Jia, Yuxin Wang, Yang Wang","doi":"10.1080/21505594.2025.2467156","DOIUrl":"10.1080/21505594.2025.2467156","url":null,"abstract":"<p><p><i>Streptococcus suis</i>, a zoonotic pathogen, is commonly found as a commensal bacterium in the respiratory tracts of pigs. Under specific conditions, it becomes invasive and enters the blood, causing severe systemic infections. For <i>S. suis</i>, effective acquisition of carbon sources in different host niches is necessary for its survival. However, as of now, our understanding of the metabolism of <i>S. suis</i> within the host is highly restricted. Pyruvate formate lyase (PFL) plays a crucial role in bacterial survival of in glucose-limited and hypoxic host tissues. Here, we investigated the physiological and metabolic functions of PFL PflB in <i>S. suis</i> and elucidated its pivotal role in regulating virulence within the mucosal and blood niches. We demonstrate that PflB is a key enzyme for <i>S. suis</i> to support mixed-acid fermentation under glucose-limited and hypoxic conditions. Additionally, PflB is involved in regulating <i>S. suis</i> morphology and stress tolerance, and its regulation of capsular polysaccharide content depends on dynamic carbon availability. We also found that PflB is associated with the capacity of <i>S. suis</i> to cause bacteremia and persist in the upper respiratory tract to induce persistent infection. Our results provide highly persuasive evidence for the relationship between metabolic regulation and the virulence of <i>S. suis</i>.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2467156"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-03-06DOI: 10.1080/21505594.2025.2474866
Wei Peng, Qinggen Jiang, Yuting Wu, Li He, Bei Li, Weicheng Bei, Xia Yang
Streptococcus suis is an important zoonotic pathogen that threatens human and pig health. During infection, the host can impose oxidative stress to resist pathogen invasion. Resistance to oxidative toxicity is an important factor for pathogens. Glutathione synthesis contributes to reactive oxygen species (ROS) detoxification in bacterial cells. Little is known about the roles of glutathione synthesis and transport in S. suis. In this study, we demonstrated that glutathione treatment increased oxidative stress tolerance in S. suis. GshAB and GshT were found in S. suis glutathione synthesis and import by bioinformatics. In vitro, inactivation of gshAB and gshT led to increased sensitivity to oxidative stress. Inactivation of gshT led to growth defects in the medium. The intracellular glutathione content of gshAB or gshT deletion mutants was lower than that of wild type (WT) strain. The phagocytic resistance of gshAB and gshT mutants was lower than that of the WT strain. Moreover, the virulence of gshAB and gshT deletion mutants was significantly lower than that of the WT strain in mouse survival and tissue loading experiments. In conclusion, these results revealed the functions of GshAB and GshT in the pathogenesis of S. suis. These findings enhance our understanding of bacterial virulence mechanisms and may provide a new avenue for therapeutic intervention aimed at curbing S. suis infections.
{"title":"The role of glutathione for oxidative stress and pathogenicity of <i>Streptococcus suis</i>.","authors":"Wei Peng, Qinggen Jiang, Yuting Wu, Li He, Bei Li, Weicheng Bei, Xia Yang","doi":"10.1080/21505594.2025.2474866","DOIUrl":"https://doi.org/10.1080/21505594.2025.2474866","url":null,"abstract":"<p><p><i>Streptococcus suis</i> is an important zoonotic pathogen that threatens human and pig health. During infection, the host can impose oxidative stress to resist pathogen invasion. Resistance to oxidative toxicity is an important factor for pathogens. Glutathione synthesis contributes to reactive oxygen species (ROS) detoxification in bacterial cells. Little is known about the roles of glutathione synthesis and transport in <i>S</i>. <i>suis</i>. In this study, we demonstrated that glutathione treatment increased oxidative stress tolerance in <i>S</i>. <i>suis</i>. GshAB and GshT were found in <i>S</i>. <i>suis</i> glutathione synthesis and import by bioinformatics. In vitro, inactivation of <i>gshAB</i> and <i>gshT</i> led to increased sensitivity to oxidative stress. Inactivation of <i>gshT</i> led to growth defects in the medium. The intracellular glutathione content of <i>gshAB</i> or <i>gshT</i> deletion mutants was lower than that of wild type (WT) strain. The phagocytic resistance of <i>gshAB</i> and <i>gshT</i> mutants was lower than that of the WT strain. Moreover, the virulence of <i>gshAB</i> and <i>gshT</i> deletion mutants was significantly lower than that of the WT strain in mouse survival and tissue loading experiments. In conclusion, these results revealed the functions of GshAB and GshT in the pathogenesis of <i>S. suis</i>. These findings enhance our understanding of bacterial virulence mechanisms and may provide a new avenue for therapeutic intervention aimed at curbing <i>S. suis</i> infections.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2474866"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2024-12-26DOI: 10.1080/21505594.2024.2439497
Carol Uphoff Meteyer, Justin G Boyles
{"title":"Fungal chimera: A lethal mammalian fungus with invasion strategies of plant pathogens.","authors":"Carol Uphoff Meteyer, Justin G Boyles","doi":"10.1080/21505594.2024.2439497","DOIUrl":"https://doi.org/10.1080/21505594.2024.2439497","url":null,"abstract":"","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2439497"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-02-15DOI: 10.1080/21505594.2025.2466503
Xidian Tang, Chenyibo Zhang, Qingru Geng, Dekun Chen, Wentao Ma
Orf virus (ORFV) has been demonstrated to infect both goat non-immune cells, specifically goat epithelial cells, and goat blood immune cells. Our previous studies have indicated that ORFV gains entry into goat epithelial cells via clathrin-mediated endocytosis and macropinocytosis pathways. However, the pathway by which ORFV enters goat blood immune cells has not yet been elucidated. Our findings revealed a differential viral internalization pathway in ORFV-infects goat immune cells contrasting the internalization pathways in goat epithelial cells, potentially involving an antibody-related mechanism. Therefore, our hypothesis posits that ORFV gains entry into goat immune cells via the antibody-dependent enhancement (ADE) pathway. Our experimental findings confirm the presence of the ADE effect in ORFV-infected goat immune cells, mediated by Fc receptors (FcRs) as demonstrated in antibody-blocking experiments. Furthermore, the ADE effect was also observed in goat epithelial cells. Nevertheless, the ADE effect observed in goat epithelial cells was not found to be dependent on the interaction between the virus-antibody complex and Fc receptors, as demonstrated by antibody-blocking experiments. Instead, it is suggested that an alternative mechanism involving the complement factor and complement receptors (CRs) may be responsible. Overall, this research offers insights into the unique ADE pathway of ORFV infection in different cell types, offering a novel perspective on the infection and pathogenic mechanisms of ORFV.
{"title":"Antibody-dependent enhancement of ORFV uptake into host cells.","authors":"Xidian Tang, Chenyibo Zhang, Qingru Geng, Dekun Chen, Wentao Ma","doi":"10.1080/21505594.2025.2466503","DOIUrl":"10.1080/21505594.2025.2466503","url":null,"abstract":"<p><p>Orf virus (ORFV) has been demonstrated to infect both goat non-immune cells, specifically goat epithelial cells, and goat blood immune cells. Our previous studies have indicated that ORFV gains entry into goat epithelial cells via clathrin-mediated endocytosis and macropinocytosis pathways. However, the pathway by which ORFV enters goat blood immune cells has not yet been elucidated. Our findings revealed a differential viral internalization pathway in ORFV-infects goat immune cells contrasting the internalization pathways in goat epithelial cells, potentially involving an antibody-related mechanism. Therefore, our hypothesis posits that ORFV gains entry into goat immune cells via the antibody-dependent enhancement (ADE) pathway. Our experimental findings confirm the presence of the ADE effect in ORFV-infected goat immune cells, mediated by Fc receptors (FcRs) as demonstrated in antibody-blocking experiments. Furthermore, the ADE effect was also observed in goat epithelial cells. Nevertheless, the ADE effect observed in goat epithelial cells was not found to be dependent on the interaction between the virus-antibody complex and Fc receptors, as demonstrated by antibody-blocking experiments. Instead, it is suggested that an alternative mechanism involving the complement factor and complement receptors (CRs) may be responsible. Overall, this research offers insights into the unique ADE pathway of ORFV infection in different cell types, offering a novel perspective on the infection and pathogenic mechanisms of ORFV.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2466503"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-02-21DOI: 10.1080/21505594.2025.2467161
Xiangfu Wen, Jia Cheng, Mingchao Liu
Trueperella pyogenes is a prevalent opportunistic pathogen responsible for a wide range of infections in livestock and wildlife, such as in cattle, pigs, European bison and forest musk deer. Much of the successful infection of T. pyogenes relies on its virulence factors, including pyolysin as well as adhesion factors. The swift rise of bacterial resistance has highlighted the urgent need for developing new therapeutic strategies. Currently, virulence factor-mediated vaccine development and other therapeutic approaches are widely regarded as the primary interventions for addressing diseases associated with this pathogen. This review examines the broader virulence potential of T. pyogenes, focusing on haemolysin, host cell adhesion proteins, the prevalence of antibiotic resistance, and the development of vaccines mediated by virulence factors. Additionally, it discusses current and future approaches aimed at improving therapeutic interventions.
{"title":"Virulence factors and therapeutic methods of <i>Trueperella pyogenes</i>: A review.","authors":"Xiangfu Wen, Jia Cheng, Mingchao Liu","doi":"10.1080/21505594.2025.2467161","DOIUrl":"10.1080/21505594.2025.2467161","url":null,"abstract":"<p><p><i>Trueperella pyogenes</i> is a prevalent opportunistic pathogen responsible for a wide range of infections in livestock and wildlife, such as in cattle, pigs, European bison and forest musk deer. Much of the successful infection of <i>T. pyogenes</i> relies on its virulence factors, including pyolysin as well as adhesion factors. The swift rise of bacterial resistance has highlighted the urgent need for developing new therapeutic strategies. Currently, virulence factor-mediated vaccine development and other therapeutic approaches are widely regarded as the primary interventions for addressing diseases associated with this pathogen. This review examines the broader virulence potential of <i>T. pyogenes</i>, focusing on haemolysin, host cell adhesion proteins, the prevalence of antibiotic resistance, and the development of vaccines mediated by virulence factors. Additionally, it discusses current and future approaches aimed at improving therapeutic interventions.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2467161"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-03-06DOI: 10.1080/21505594.2025.2457949
Mei Li, Haixue Zheng
The African swine fever virus (ASFV) is the only giant double-stranded DNA virus known to be transmitted by insect vectors. It can infect pigs and cause clinical signs such as high fever, bleeding, and splenomegaly, which has been classified as a reportable disease by the WOAH. In 2018, African swine fever (ASF) was introduced into China and rapidly spread to several countries in the Asia-Pacific region, with morbidity and mortality rates reaching 100 percent, resulting in significant economic losses to the global pig industry. Because ASFV has large genomes and a complex escape host mechanism, there are currently no safe and effective drugs or vaccines against it. Therefore, it is necessary to optimize vaccination procedures and find effective treatments by studying the epidemiology of ASFV to reduce economic losses. This article reviews research progress on pathogenesis, genome, proteome and transcriptome, pathogenic mechanisms, and comprehensive control measures of ASFV infection.
{"title":"Insights and progress on epidemic characteristics, pathogenesis, and preventive measures of African swine fever virus: A review.","authors":"Mei Li, Haixue Zheng","doi":"10.1080/21505594.2025.2457949","DOIUrl":"10.1080/21505594.2025.2457949","url":null,"abstract":"<p><p>The African swine fever virus (ASFV) is the only giant double-stranded DNA virus known to be transmitted by insect vectors. It can infect pigs and cause clinical signs such as high fever, bleeding, and splenomegaly, which has been classified as a reportable disease by the WOAH. In 2018, African swine fever (ASF) was introduced into China and rapidly spread to several countries in the Asia-Pacific region, with morbidity and mortality rates reaching 100 percent, resulting in significant economic losses to the global pig industry. Because ASFV has large genomes and a complex escape host mechanism, there are currently no safe and effective drugs or vaccines against it. Therefore, it is necessary to optimize vaccination procedures and find effective treatments by studying the epidemiology of ASFV to reduce economic losses. This article reviews research progress on pathogenesis, genome, proteome and transcriptome, pathogenic mechanisms, and comprehensive control measures of ASFV infection.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":" ","pages":"2457949"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The emergence of antibiotic-resistant bacteria has attracted interest in the field of endolysins. Here, we analyzed the diversity of Streptococcus endolysins and identified a new endolysin, Ply2741, that exhibited broad-spectrum bactericidal activity. Our results demonstrated that Ply2741 could effectively eradicate multidrug-resistant gram-positive pathogens in vitro and in vivo. Structural analysis revealed that the bactericidal activity of Ply2741 depends on the classic "Cys-His-Asn" catalytic triad. Site-directed mutagenesis results further identified that the conserved residue Gln29, located near the catalytic triad, also contributes to the lytic activity of Ply2741. Furthermore, the key residues (R189 and W250) in the Ply2741 cell wall binding domain (CBD) responsible for binding to peptidoglycan were revealed by molecular docking and fluorescence-activated cell sorting (FACS) analysis. Ply2741 demonstrates a broad lytic spectrum, with significant bactericidal activity against Enterococcus, Staphylococcus, and Streptococcus and species. To the best of our knowledge, we found that residue Gln29 participated in the lytic activity of endolysin for the first time. Additionally, we systematically elucidate the binding mode and key residues of the Ply2741CBD. This study proposes Ply2741 as a potential antibiotic substitute and provides a structural basis for the modification and design of endolysins.
{"title":"Structural and functional analysis reveals the catalytic mechanism and substrate binding mode of the broad-spectrum endolysin Ply2741.","authors":"Shuang Wang, Xinxin Li, Jiahui Ma, Xiaochao Duan, Haiyan Wang, Linkang Wang, Dayue Hu, Wenwu Jiang, Xiangmin Li, Ping Qian","doi":"10.1080/21505594.2024.2449025","DOIUrl":"10.1080/21505594.2024.2449025","url":null,"abstract":"<p><p>The emergence of antibiotic-resistant bacteria has attracted interest in the field of endolysins. Here, we analyzed the diversity of <i>Streptococcus</i> endolysins and identified a new endolysin, Ply2741, that exhibited broad-spectrum bactericidal activity. Our results demonstrated that Ply2741 could effectively eradicate multidrug-resistant gram-positive pathogens <i>in vitro</i> and <i>in vivo</i>. Structural analysis revealed that the bactericidal activity of Ply2741 depends on the classic \"Cys-His-Asn\" catalytic triad. Site-directed mutagenesis results further identified that the conserved residue Gln29, located near the catalytic triad, also contributes to the lytic activity of Ply2741. Furthermore, the key residues (R189 and W250) in the Ply2741 cell wall binding domain (CBD) responsible for binding to peptidoglycan were revealed by molecular docking and fluorescence-activated cell sorting (FACS) analysis. Ply2741 demonstrates a broad lytic spectrum, with significant bactericidal activity against <i>Enterococcus</i>, <i>Staphylococcu</i>s, <i>and Streptococcus</i> and species. To the best of our knowledge, we found that residue Gln29 participated in the lytic activity of endolysin for the first time. Additionally, we systematically elucidate the binding mode and key residues of the Ply2741CBD. This study proposes Ply2741 as a potential antibiotic substitute and provides a structural basis for the modification and design of endolysins.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2449025"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-01-19DOI: 10.1080/21505594.2025.2454323
Ho Won Kim, Ji Won Lee, Hoe Sun Yoon, Hwan-Woo Park, Young Ik Lee, Sung Ki Lee, Jake Whang, Jong-Seok Kim
Mycobacterium abscessus (Mab), a nontuberculous mycobacterium, is increasing in prevalence worldwide and causes treatment-refractory pulmonary diseases. However, how Mab rewires macrophage energy metabolism to facilitate its survival is poorly understood. We compared the metabolic profiles of murine bone marrow-derived macrophages (BMDMs) infected with smooth (S)- and rough (R)-type Mab using extracellular flux technology. Mab infection shifted BMDMs towards a more energetic phenotype, marked by increased oxidative phosphorylation (OXPHOS) and glycolysis, with a significantly greater enhancement in OXPHOS. This metabolic adaptation was characterized by enhanced ATP production rates, particularly in cells infected with S-type Mab, highlighting OXPHOS as a key energy source. Notably, Mab infection also modulated mitochondrial substrate preferences, increasing fatty acid oxidation capabilities while revealing significant changes in glutamine dependency and flexibility. R-type Mab infections exhibited a marked decrease in glutamine reliance but enhanced metabolic flexibility and capacity. Furthermore, targeting metabolic pathways related to glutamine and fatty acid oxidation exacerbated Mab growth within macrophages, suggesting these pathways play a protective role against infection. These insights advance our understanding of Mab's impact on host cell metabolism and propose a novel avenue for therapeutic intervention. By manipulating host mitochondrial metabolism, we identify a potential host-directed therapeutic strategy against Mab, offering a promising alternative to conventional treatments beleaguered by drug resistance. This study underscores the importance of exploring metabolic interventions to combat Mab infection, paving the way for innovative approaches in the fight against this formidable pathogen.
{"title":"Restriction of mitochondrial oxidation of glutamine or fatty acids enhances intracellular growth of <i>Mycobacterium abscessus</i> in macrophages.","authors":"Ho Won Kim, Ji Won Lee, Hoe Sun Yoon, Hwan-Woo Park, Young Ik Lee, Sung Ki Lee, Jake Whang, Jong-Seok Kim","doi":"10.1080/21505594.2025.2454323","DOIUrl":"10.1080/21505594.2025.2454323","url":null,"abstract":"<p><p><i>Mycobacterium abscessus</i> (Mab), a nontuberculous mycobacterium, is increasing in prevalence worldwide and causes treatment-refractory pulmonary diseases. However, how Mab rewires macrophage energy metabolism to facilitate its survival is poorly understood. We compared the metabolic profiles of murine bone marrow-derived macrophages (BMDMs) infected with smooth (S)- and rough (R)-type Mab using extracellular flux technology. Mab infection shifted BMDMs towards a more energetic phenotype, marked by increased oxidative phosphorylation (OXPHOS) and glycolysis, with a significantly greater enhancement in OXPHOS. This metabolic adaptation was characterized by enhanced ATP production rates, particularly in cells infected with S-type Mab, highlighting OXPHOS as a key energy source. Notably, Mab infection also modulated mitochondrial substrate preferences, increasing fatty acid oxidation capabilities while revealing significant changes in glutamine dependency and flexibility. R-type Mab infections exhibited a marked decrease in glutamine reliance but enhanced metabolic flexibility and capacity. Furthermore, targeting metabolic pathways related to glutamine and fatty acid oxidation exacerbated Mab growth within macrophages, suggesting these pathways play a protective role against infection. These insights advance our understanding of Mab's impact on host cell metabolism and propose a novel avenue for therapeutic intervention. By manipulating host mitochondrial metabolism, we identify a potential host-directed therapeutic strategy against Mab, offering a promising alternative to conventional treatments beleaguered by drug resistance. This study underscores the importance of exploring metabolic interventions to combat Mab infection, paving the way for innovative approaches in the fight against this formidable pathogen.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2454323"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amino acid metabolism provides significant insight into the development and prevention of many viral diseases. Therefore, the present study aimed to compare the amino acid profiles of hand, foot, and mouth disease (HFMD) patients with those of healthy individuals and to further reveal the molecular mechanisms of HFMD severity. Using UPLC-MS/MS, we determined the plasma amino acid expression profiles of pediatric patients with HFMD (mild, n = 42; severe, n = 43) and healthy controls (n = 25). Brain tissues from CVA6-infected mice were examined using untargeted metabolomics. Several amino acids were significantly different between the three groups. Pathway analysis revealed that arginine, proline, and tryptophan metabolism are implicated in the pathogenesis of HFMD. A similar arginine depletion was observed in the brain tissues of CVA6-infected mice. Importantly, L-arginine supplementation improved the survival rate of CVA6-infected mice, inhibited virus multiplication, and reduced pathological autophagy associated with mTOR-autophagy pathway in the brain. Collectively, arginine, as the hub amino acid metabolite of the mammalian target of rapamycin (mTOR) signaling pathway affecting autophagy, plays an important role in the pathogenesis of severe HFMD. L-arginine supplementation may serve as a potential therapeutic option for critical patients with HFMD.
{"title":"Arginine depletion-induced autophagy and metabolic dysregulation are involved in the disease severity of hand, foot, and mouth disease.","authors":"Yuefei Jin, Wangquan Ji, Liang Zhang, Dejian Dang, Bingqing Yu, Xiaolong Zhang, Yuxiang Zhang, Jiaqi Li, Yaodong Zhang, Rongxin Yang, Haiyan Yang, Shuaiyin Chen, Fang Wang, Guangcai Duan","doi":"10.1080/21505594.2024.2440541","DOIUrl":"https://doi.org/10.1080/21505594.2024.2440541","url":null,"abstract":"<p><p>Amino acid metabolism provides significant insight into the development and prevention of many viral diseases. Therefore, the present study aimed to compare the amino acid profiles of hand, foot, and mouth disease (HFMD) patients with those of healthy individuals and to further reveal the molecular mechanisms of HFMD severity. Using UPLC-MS/MS, we determined the plasma amino acid expression profiles of pediatric patients with HFMD (mild, <i>n</i> = 42; severe, <i>n</i> = 43) and healthy controls (<i>n</i> = 25). Brain tissues from CVA6-infected mice were examined using untargeted metabolomics. Several amino acids were significantly different between the three groups. Pathway analysis revealed that arginine, proline, and tryptophan metabolism are implicated in the pathogenesis of HFMD. A similar arginine depletion was observed in the brain tissues of CVA6-infected mice. Importantly, L-arginine supplementation improved the survival rate of CVA6-infected mice, inhibited virus multiplication, and reduced pathological autophagy associated with mTOR-autophagy pathway in the brain. Collectively, arginine, as the hub amino acid metabolite of the mammalian target of rapamycin (mTOR) signaling pathway affecting autophagy, plays an important role in the pathogenesis of severe HFMD. L-arginine supplementation may serve as a potential therapeutic option for critical patients with HFMD.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2440541"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}