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The T-type voltage-gated Ca2+ channel CaV3.1 involves in the disruption of respiratory epithelial barrier induced by Pasteurella multocida toxin.
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2025-02-15 DOI: 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}
引用次数: 0
Pyruvate formate lyase regulates fermentation metabolism and virulence of Streptococcus suis.
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2025-02-20 DOI: 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}
引用次数: 0
The role of glutathione for oxidative stress and pathogenicity of Streptococcus suis.
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2025-03-06 DOI: 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}
引用次数: 0
Fungal chimera: A lethal mammalian fungus with invasion strategies of plant pathogens. 真菌嵌合体:一种具有植物病原体入侵策略的致命哺乳动物真菌。
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-26 DOI: 10.1080/21505594.2024.2439497
Carol Uphoff Meteyer, Justin G Boyles
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引用次数: 0
Antibody-dependent enhancement of ORFV uptake into host cells.
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2025-02-15 DOI: 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}
引用次数: 0
Virulence factors and therapeutic methods of Trueperella pyogenes: A review.
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2025-02-21 DOI: 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.

化脓性真菌是一种流行的机会性病原体,可引起牲畜和野生动物的多种感染,如牛、猪、欧洲野牛和森林麝香鹿。化脓性链球菌的成功感染在很大程度上依赖于其毒力因子,包括溶菌酶和粘附因子。细菌抗药性的迅速增加凸显了开发新治疗策略的迫切需要。目前,毒力因子介导的疫苗开发和其他治疗方法被广泛认为是应对该病原体相关疾病的主要干预措施。本综述探讨了化脓性肺结核更广泛的毒力潜力,重点关注溶血素、宿主细胞粘附蛋白、抗生素耐药性的流行以及毒力因子介导的疫苗开发。此外,它还讨论了当前和未来旨在改进治疗干预的方法。
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引用次数: 0
Insights and progress on epidemic characteristics, pathogenesis, and preventive measures of African swine fever virus: A review.
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2025-03-06 DOI: 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.

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引用次数: 0
Structural and functional analysis reveals the catalytic mechanism and substrate binding mode of the broad-spectrum endolysin Ply2741. 结构和功能分析揭示了广谱内溶菌酶 Ply2741 的催化机理和底物结合模式。
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2025-01-14 DOI: 10.1080/21505594.2024.2449025
Shuang Wang, Xinxin Li, Jiahui Ma, Xiaochao Duan, Haiyan Wang, Linkang Wang, Dayue Hu, Wenwu Jiang, Xiangmin Li, Ping Qian

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.

耐药细菌的出现引起了人们对内毒素领域的兴趣。在此,我们分析了链球菌内溶素的多样性,并鉴定出一种新的内溶素Ply2741,它具有广谱杀菌活性。结果表明,Ply2741在体外和体内均能有效根除多重耐药革兰氏阳性病原菌。结构分析表明,Ply2741的杀菌活性取决于经典的“Cys-His-Asn”催化三元组。位点定向诱变结果进一步发现,位于催化三联体附近的保守残基Gln29也有助于Ply2741的裂解活性。此外,通过分子对接和荧光活化细胞分选(FACS)分析,揭示了Ply2741细胞壁结合域(CBD)中与肽聚糖结合的关键残基R189和W250。Ply2741具有较宽的裂解谱,对肠球菌、葡萄球菌、链球菌等具有显著的杀菌活性。据我们所知,我们首次发现残基Gln29参与了内溶素的裂解活性。此外,我们系统地阐明了Ply2741CBD的结合模式和关键残基。本研究提出了Ply2741作为一种潜在的抗生素替代品,并为内溶素修饰和设计提供了结构基础。
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引用次数: 0
Restriction of mitochondrial oxidation of glutamine or fatty acids enhances intracellular growth of Mycobacterium abscessus in macrophages. 限制线粒体氧化谷氨酰胺或脂肪酸可促进巨噬细胞内脓肿分枝杆菌的生长。
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2025-01-19 DOI: 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.

脓肿分枝杆菌(Mab)是一种非结核分枝杆菌,在世界范围内的患病率正在上升,并导致难治性肺部疾病。然而,Mab是如何重新连接巨噬细胞的能量代谢以促进其存活的,人们知之甚少。我们使用细胞外通量技术比较了小鼠骨髓源性巨噬细胞(bmdm)感染光滑型(S)和粗糙型(R)单抗后的代谢谱。单抗感染使BMDMs转向更有活力的表型,其特征是氧化磷酸化(OXPHOS)和糖酵解增加,其中OXPHOS的增强明显更大。这种代谢适应的特点是ATP产生率提高,特别是在被s型单抗感染的细胞中,这表明OXPHOS是关键的能量来源。值得注意的是,Mab感染还调节了线粒体底物偏好,增加了脂肪酸氧化能力,同时揭示了谷氨酰胺依赖性和灵活性的显著变化。r型单抗感染表现出谷氨酰胺依赖性显著降低,但代谢灵活性和能力增强。此外,靶向与谷氨酰胺和脂肪酸氧化相关的代谢途径可促进巨噬细胞内Mab的生长,表明这些途径对感染具有保护作用。这些见解促进了我们对Mab对宿主细胞代谢影响的理解,并为治疗干预提供了新的途径。通过操纵宿主线粒体代谢,我们确定了一种潜在的针对Mab的宿主定向治疗策略,为被耐药性困扰的传统治疗提供了一种有希望的替代方案。这项研究强调了探索代谢干预对抗单克隆抗体感染的重要性,为对抗这种强大病原体的创新方法铺平了道路。
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引用次数: 0
Arginine depletion-induced autophagy and metabolic dysregulation are involved in the disease severity of hand, foot, and mouth disease. 精氨酸耗竭诱导的自噬和代谢失调与手足口病的严重程度有关。
IF 5.5 1区 农林科学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-28 DOI: 10.1080/21505594.2024.2440541
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

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.

氨基酸代谢为许多病毒性疾病的发展和预防提供了重要的见解。因此,本研究旨在比较手足口病(手足口病)患者与健康个体的氨基酸谱,进一步揭示手足口病严重程度的分子机制。采用UPLC-MS/MS检测小儿手足口病患者血浆氨基酸表达谱(轻度,n = 42;重症患者(n = 43)和健康对照组(n = 25)。采用非靶向代谢组学方法检测cva6感染小鼠的脑组织。有几个氨基酸在三组之间存在显著差异。途径分析显示精氨酸、脯氨酸和色氨酸的代谢与手足口病的发病机制有关。在cva6感染小鼠的脑组织中观察到类似的精氨酸消耗。重要的是,补充l -精氨酸可提高cva6感染小鼠的存活率,抑制病毒增殖,并减少脑内与mtor自噬途径相关的病理性自噬。综上所述,精氨酸作为影响自噬的雷帕霉素(rapamycin, mTOR)信号通路的中枢氨基酸代谢物,在严重手足口病的发病过程中起着重要作用。补充l -精氨酸可作为手足口病危重患者的潜在治疗选择。
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引用次数: 0
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