{"title":"ACE2 mitigates PEDV-induced endoplasmic reticulum stress and autophagy by inhibiting ROS production","authors":"Zhiqiang Li , Xueqing Chen , Chang Ma, Gongmin Wang, Yuanshu Zhang","doi":"10.1016/j.micpath.2025.108023","DOIUrl":"10.1016/j.micpath.2025.108023","url":null,"abstract":"<div><div>Role of ACE2 in regulating inflammatory damage has been recognized, its association with ER stress and autophagy under PEDV infection remains elusive. To clarify the above associations, this study first established a stress injury model through PEDV infection to determine whether it can induce ER stress or autophagy. Then, the relationships between ER stress, autophagy and ROS under PEDV infection were verified. Finally, the immune regulatory role and molecular mechanism of ACE2 in PEDV induced ER stress and autophagy were explored by regulating the expression of ACE2. The results showed that PEDV elicited ER stress and activates the UPR response. Autophagy was triggered by PEDV to facilitate its replication with the involvement of ER stress as a mediator. ER stress and autophagy were both consequences of PEDV replication within cells. PEDV caused accumulation of ROS. ROS plays a pivotal role as an upstream regulatory factor in ER stress and autophagy. However, ACE2 plays a pivotal regulatory role in the aforementioned cellular processes. ACE2 inhibited ER stress and autophagy by reducing intracellular ROS production. These results reveal that PEDV infection can induce ER stress and mediate the occurrence of autophagy, and this process is regulated by the upstream factor ROS. Overexpression of ACE2 inhibits ER stress and autophagy by reducing the production of intracellular ROS, thereby restoring the REDOX homeostasis of host cells, and mitigating cell damage caused by PEDV. The research results provide new ideas and theoretical basis for ACE2 in intestinal inflammatory injury induced by PEDV infection.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"208 ","pages":"Article 108023"},"PeriodicalIF":3.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kai Liu , Hong Sun , Hong Wang , Junbo Zheng , Xiuzhen Wang , Xin Wang , Yeting Hou , Qian Ye , Ji Li
{"title":"Ellagic acid alleviates sepsis-induced intestinal injury by modulating gut microbiota and NF-κB-mediated MLCK/MLC signaling pathway","authors":"Kai Liu , Hong Sun , Hong Wang , Junbo Zheng , Xiuzhen Wang , Xin Wang , Yeting Hou , Qian Ye , Ji Li","doi":"10.1016/j.micpath.2025.108026","DOIUrl":"10.1016/j.micpath.2025.108026","url":null,"abstract":"<div><div>Sepsis is a systemic inflammatory response syndrome triggered by infection. Severe sepsis is associated with dysbiosis of the intestinal flora and impaired intestinal function. Ellagic acid (EA) is a natural compound known for its ability to inhibit bacteria and viruses, thereby preventing infections. However, it remains unclear whether EA mitigates intestinal barrier dysfunction. In this work, BALB/c mice were administered doses of EA via gavage, followed by an injection of lipopolysaccharide (LPS) to induce sepsis. Fecal samples, serum, and ileum tissues were collected for molecular or pathological analysis. The intestinal contents underwent 16S rRNA sequencing and targeted metabolomics for short-chain fatty acids (SCFAs) detection. Additionally, an <em>in vitro</em> injury model was established using IEC6 cells treated with LPS; subsequent changes in inflammation and oxidative stress were assessed following EA treatment. The results indicated that EA reduced inflammation and oxidative stress as well as ameliorated intestinal lesions and enhanced intestinal barrier function in both mouse and cell models. Moreover, EA inhibited the signaling of nuclear factor kappa-light-chain-enhancer of activated B cells/myosin light chain kinase/myosin light chain (NF-κB/MLCK/MLC) pathway. Besides, EA also rectified genomic and metabolomic disturbances within the gut microbiota caused by sepsis. In conclusion, EA mitigates sepsis-induced intestinal injury through modulation of gut microbiota composition and inhibition of NF-κB-mediated MLCK/MLC signaling pathway. Thus, EA might represent a promising therapeutic agent for addressing intestinal injuries associated with sepsis.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"208 ","pages":"Article 108026"},"PeriodicalIF":3.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Integrative strategies against multidrug-resistant bacteria: Synthesizing novel antimicrobial frontiers for global health","authors":"Jaishriram Rathored, Tanushree Budhbaware","doi":"10.1016/j.micpath.2025.108018","DOIUrl":"10.1016/j.micpath.2025.108018","url":null,"abstract":"<div><div>Concerningly, multidrug-resistant bacteria have emerged as a prime worldwide trouble, obstructing the treatment of infectious diseases and causing doubts about the therapeutic accidentalness of presently existing drugs. Novel antimicrobial interventions deserve development as conventional antibiotics are incapable of keeping pace with bacteria evolution. Various promising approaches to combat MDR infections are discussed in this review. Antimicrobial peptides are examined for their broad-spectrum efficacy and reduced ability to develop resistance, while phage therapy may be used under extreme situations when antibiotics fail. In addition, the possibility of CRISPR-Cas systems for specifically targeting and eradicating resistance genes from bacterial populations will be explored. Nanotechnology has opened up the route to improve the delivery system of the drug itself, increasing the efficacy and specificity of antimicrobial action while protecting its host. Discovering potential antimicrobial agents is an exciting prospect through developments in synthetic biology and the rediscovery of natural product-based medicines. Moreover, host-directed therapies are now becoming popular as an adjunct to the main strategies of therapeutics without specifically targeting pathogens. Although these developments appear impressive, questions about production scaling, regulatory approvals, safety, and efficacy for clinical employment still loom large. Thus, tackling the MDR burden requires a multi-pronged plan, integrating newer treatment modalities with existing antibiotic regimens, enforcing robust stewardship initiatives, and effecting policy changes at the global level. The international health community can gird itself against the growing menace of antibiotic resistance if collaboration between interdisciplinary bodies and sustained research endeavours is encouraged. In this study, we evaluate the synergistic potential of combining various medicines in addition to summarizing recent advancements. To rethink antimicrobial stewardship in the future, we provide a multi-tiered paradigm that combines pathogen-focused and host-directed strategies.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"208 ","pages":"Article 108018"},"PeriodicalIF":3.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ziyin Lu , Xuan Liu , Yukun Zhang , Yufang Han , Muhammad Ishfaq , Bing Lu , Xiuli Lu
{"title":"Oral immunization with recombinant Saccharomyces cerevisiae expressing TM1 of Mycoplasma gallisepticum induces unique specific antibodies and protective immunity","authors":"Ziyin Lu , Xuan Liu , Yukun Zhang , Yufang Han , Muhammad Ishfaq , Bing Lu , Xiuli Lu","doi":"10.1016/j.micpath.2025.108012","DOIUrl":"10.1016/j.micpath.2025.108012","url":null,"abstract":"<div><div><em>Mycoplasma gallisepticum</em> (MG) is one of the main pathogens causing chronic respiratory diseases in chickens, which seriously affects the sustainable and healthy development of the poultry industry and leading to heavy economic losses. Therefore, we developed a safe, efficient, convenient, and low-cost MG oral vaccine. The vaccine is based on a recombinant yeast surface display system to compensate for the shortcomings of existing vaccines. TM1, a protective antigen protein, is located on the outer membrane of MG cells. In this study, the physical and chemical properties, structure and epitopes of MG protective antigen protein were systematically analyzed by bioinformatics method, and TM1 protein was predicted to be suitable for vaccine development as MG immunogenic protein. Subsequently, we constructed recombinant <em>S. cerevisiae</em> expressing MG-TM1 protein and evaluated its immunoprotective effects following oral administration. First, the recombinant <em>S. cerevisiae</em> strain EBY100/pYD1-TM1 efficiently expressed TM1, as confirmed by high-throughput screening, PCR, and Western blot analysis. After oral administration with EBY100/pYD1-TM1 stimulates the high level of IgG and sIgA in chicken. Notably, it prevents MG colonization and effectively protected the respiratory system such as air sacs and lungs from damage. The above results suggest that EBY100/pYD1-TM1 can induce humoral and mucosal immune responses in chicken. Collectively, the recombinant <em>S. cerevisiae</em> expressing TM1 is a potentially safer and more effective agent against MG infection.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"208 ","pages":"Article 108012"},"PeriodicalIF":3.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sajjadul Kadir Akand , Areeba Rahman , Mohammad Masood , Shams Tabrez , Junaid Jibran Jawed , Mohammad Z. Ahmed , Yusuf Akhter , Mohammad Mahfuzul Haque , Abdur Rub
{"title":"Leishmania donovani alters the host sphingolipid biosynthetic pathway regulatory microRNA hsa-miR-15a-5p for its survival","authors":"Sajjadul Kadir Akand , Areeba Rahman , Mohammad Masood , Shams Tabrez , Junaid Jibran Jawed , Mohammad Z. Ahmed , Yusuf Akhter , Mohammad Mahfuzul Haque , Abdur Rub","doi":"10.1016/j.micpath.2025.108019","DOIUrl":"10.1016/j.micpath.2025.108019","url":null,"abstract":"<div><div><em>Leishmania donovani</em> is an intracellular protozoan parasite that has successfully evolved to manipulate host macrophages. The exact mechanism by which <em>Leishmania</em> spp evades macrophage function is not fully understood. Recently, several studies have shown that pathogens target host-microRNA to alter cellular pathways for their persistence. Here, we explored the alterations in host sphingolipid biosynthetic pathway regulatory microRNAs during <em>Leishmania donovani</em> infection. Here, the sphingolipid biosynthetic pathway genes serine palmitoyltransferase long chain base subunit 1 (<em>SPTLC1</em>)<em>,</em> 3-ketodihydrosphingosine reductase (<em>KDSR</em>)<em>,</em> ceramide synthase 1(<em>CERS1</em>) and dihydroceramide desaturase 1 (<em>DEGS1</em>) were found to be upregulated while N-Acylsphingosine Amidohydrolase 1 (<em>ASAH1</em>) was downregulated but no significant changes were observed in sphingomyelin synthase 1 (<em>SGMS1</em>) and sphingosine kinase 1 (<em>SPHK1</em>) in <em>Leishmania donovani</em> infected THP-1 derived macrophages (TDM) at 24 h. Bioinformatic analysis using miRWalk 2.0 predicted SPTLC1 to be a target of hsa-miR-15a-5p and hsa-miR-330-5p, CERS1 to be targeted by hsa-miR-10396a-3p, and ASAH1 by hsa-miR-513a-5p; all of these miRNAs have been previously reported to be dysregulated during infection. Since hsa-miR-15a-5p was found common to target <em>SPTLC1</em> in all three databases, namely Targetscan, miRDB, and miRTarBase therefore the expression of hsa-miR-15a-5p was selected for further studies. We found a downregulated expression of hsa-miR-15a-5p during <em>Leishmania donovani</em> infection. <em>In silico</em> target prediction followed by in vitro target validation of hsa-miR-15a-5p showed SPTLC1 as one of the targets. Additionally, mimics of hsa-miR-15a-5p reduced the expression of <em>SPTLC1,</em> upregulated mainly the proinflammatory cytokines, and reduced the parasites in TDM as well as Peripheral Blood Mononuclear Cell (PBMC) derived human macrophages.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"208 ","pages":"Article 108019"},"PeriodicalIF":3.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zakirullah , Rashid Ahmad , Amna Shafqat , Mengzhe Li , Yigang Tong
{"title":"Novel Enterococcus phage BUCT630: Isolation and genomic insights targeting drug-resistant Enterococcus faecium in vitro and in vivo","authors":"Zakirullah , Rashid Ahmad , Amna Shafqat , Mengzhe Li , Yigang Tong","doi":"10.1016/j.micpath.2025.108017","DOIUrl":"10.1016/j.micpath.2025.108017","url":null,"abstract":"<div><div>The antibiotic-resistant <em>Enterococcus faecium (E. faecium)</em> is a significant health issue requiring alternative therapies. Phages could be an alternative to antibiotics and have promising activity in both <em>in vitro</em> and <em>in vivo</em> experiments. Here, we isolated and characterized a new lytic phage, BUCT630, from hospital sewage water targeting antibiotic-resistant <em>E. faecium</em>. Physiological characterization revealed that BUCT630 had a long adsorption time (50 min) and moderate burst size (130 PFU/cell), had relatively favourable stability in both acidic and alkaline environments, and withstand 50°C high temperature. Transmission electron microscopy (TEM) revealed that phage BUCT630 belongs to the unclassified <em>Caudoviricetes</em> through a phylogenetic tree based on a terminase large subunit and whole genome sequence. The host range was comparatively broad and can lyse 8 of 18 <em>Enterococcus</em> strains. Through BLASTn analysis, BUCT630 had 69% query coverage and 89% sequence identity with other phages in the database. The genomic analysis disclosed that phage BUCT630 is linear dsDNA with 41,942 bp having 35% GC content and comprises 61 open reading frames (ORF) free from antibiotic and virulence genes. Furthermore, BUCT630 <em>in vitro</em> could efficiently inhibit the <em>E. faecium</em> growth, and <em>in vivo</em>, it increased the survival rate to 90% in the <em>Galerria mellonela</em> model. Our findings revealed that BUCT630 is a promising therapeutic option for combating antibiotic resistant <em>E. faecium</em> infections.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"208 ","pages":"Article 108017"},"PeriodicalIF":3.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Microbial pathogenesisPub Date : 2025-09-01Epub Date: 2025-06-25DOI: 10.1016/j.micpath.2025.107841
Qin-Rong Tan, Lin-Lin Yao, Min Yuan, Shaopeng Sun, Xiang-Dong Li
{"title":"Endocytosis in Fusarium graminearum requires coordination of the motor domain and two tail homology domains of myosin-1.","authors":"Qin-Rong Tan, Lin-Lin Yao, Min Yuan, Shaopeng Sun, Xiang-Dong Li","doi":"10.1016/j.micpath.2025.107841","DOIUrl":"10.1016/j.micpath.2025.107841","url":null,"abstract":"<p><p>Fusarium graminearum is a major pathogen for the outbreak of Fusarium head blight disease. Recently, it was found that phenamacril (a Fusarium-specific fungicide) specifically inhibits the motor function of F. graminearum myosin-1 (FgMyo1). By using the FgMyo1-specific inhibitor phenamacril and genetic manipulation of FgMyo1 gene, we investigated the roles of each FgMyo1 domains (motor domain, TH1 domain, TH2 domain, SH3 domain, and CA domains) in supporting F. graminearum growth, with a special focus on endocytosis and subapical localization of FgMyo1. We demonstrate that FgMyo1<sup>TH2</sup> (a truncated FgMyo1 containing the motor domain, IQ motifs, TH1 and TH2 domains) is sufficient to support endocytosis of F. graminearum and subapical localization of FgMyo1. Biochemical analysis and electron microscopy revealed that FgMyo1<sup>TH2</sup> contains two actin-binding sites (the motor domain and the TH2 domain) and is able to crosslink actin filaments to form bundles. Based on above results, we propose a positive-feedback model explaining FgMyo1-dependent actin polymerization at endocytic site in subapical hyphae of F. graminearum: FgMyo1 molecules anchor at bottom of endocytic pitch, driving inward movement of actin filaments and enhancing actin polymerization; with more actin filaments are formed, more FgMyo1 molecules are recruited to the endocytic site.</p>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":" ","pages":"107841"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Microbial pathogenesisPub Date : 2025-09-01Epub Date: 2025-06-25DOI: 10.1016/j.micpath.2025.107838
Khadija Akter, Young June Hong, Ihn Han, Eun Ha Choi
{"title":"Nonthermal plasma jet mitigates viral replication and inflammation in human coronavirus 229E-infected lung cells by targeting the NF-κB and MAPK pathways.","authors":"Khadija Akter, Young June Hong, Ihn Han, Eun Ha Choi","doi":"10.1016/j.micpath.2025.107838","DOIUrl":"10.1016/j.micpath.2025.107838","url":null,"abstract":"<p><p>SARS-CoV-2 is a pressing global health issue, largely driven by uncontrolled viral replication and severe proinflammatory responses. Despite significant technological progress made by humanity, medical science has frequently found itself incapable of effectively addressing pathogenic outbreaks. Nonthermal plasma is a promising technology for combating pathogenic microorganisms. Considering the pressing demand for new treatment options, we have investigated the prospects of plasma-treated medium (PTM) enriched with reactive oxygen and nitrogen species (ROS/RNS) as a promising approach to combat human corona virus (HCoV-229E). The PTM was prepared using nonthermal plasma jet (NTPJ) with air as a flowing gas. NTPJ treatment effectively reduced the viral infection in MRC-5 lung cells, as evidenced through the assessment of the cytopathogenic effects. The mRNA expression of the viral gene ACE-2, Spike (S) gene, Rd/Rp Helicase gene and the generation of inflammation markers, IL-6, TNF-α, IL-1β, IFN-γ,COX-2,NF-κB, CXCL-10, and CCl-5 were significantly reduced with NTPJ. Moreover, confocal microscopy analysis revealed a significant reduction in spike glycoprotein and nucleocapsid protein levels in the cytoplasm. This finding was further supported by flow cytometry analysis, which confirmed a significant decrease in spike glycoprotein levels. Furthermore, mechanism studies indicated that NTPJ may influence cellular processes in HCoV-229E infected lung cells by disrupting the NF-κB and MAPK pathways, particularly evidenced by changes in phosphorylation levels. The pretreatment of the virus with SP600125 inhibitor and NTPJ resulted in a significant reduction in the expression ratio of viral genes ACE-2, S gene and RdRP/Helicase. Therefore, these results suggest that NTPJ enhances both anti-viral and anti-inflammatory responses, making it a promising candidate for prevention and treatment of corona virus infections.</p>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":" ","pages":"107838"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}