Pub Date : 2026-01-14DOI: 10.1016/j.micpath.2026.108291
He Yang, Yaqian Gu, Yingying Dong, Huan Sun, Shuangshuang Liufu, Haiyan Xu, Ke Du, Linxiu Peng, Weichen Xu, Lili Lin, Tong Xie, Jinjun Shan, Xia Zhao
Respiratory syncytial virus (RSV) infection triggers excessive inflammation, contributing to disease severity. Baicalin exerts therapeutic effects against RSV infection by inhibiting viral replication and alleviating inflammation. However, the mechanisms underlying its immunoregulatory during RSV infection remain unclear. Here we found that baicalin alleviated RSV induced inflammation by regulating the macrophage immunometabolism. To investigate metabolic modulation, metabolomic analysis was performed, revealing an obvious reversal in the metabolic profile by baicalin administration. Further metabolic flux analysis using isotope tracers demonstrated that baicalin suppressed the accumulation of lactate and succinate induced by RSV infection. Mechanistically, baicalin inhibited glycolytic metabolism and succinate driven hypoxia-inducible factor 1α (HIF-1α) signaling during RSV infection, thereby suppressing NLR family, pyrin domain containing protein 3 (NLRP3) activation and reducing IL-1β release. The effects were validated in vitro using a glycolysis activator to confirm the suppression of glycolytic metabolism, and through co-treatment with dimethylsuccinate and RSV to verify the involvement of HIF-1α-mediated hypoxia pathway. Final targeting for baicalin at pyruvate kinase M2 (PKM2) was confirmed via molecular docking and limited proteolysis-coupled mass spectrometry. Taken together, these data elucidate a mechanism of baicalin through regulatory immunometabolism of macrophage to alleviate RSV-induced inflammation, which have critical roles in the treatment of RSV infection.
{"title":"Baicalin inhibits macrophage glycolysis and succinate-driven HIF-1α signaling by targeting PKM2 to alleviate RSV-induced inflammation.","authors":"He Yang, Yaqian Gu, Yingying Dong, Huan Sun, Shuangshuang Liufu, Haiyan Xu, Ke Du, Linxiu Peng, Weichen Xu, Lili Lin, Tong Xie, Jinjun Shan, Xia Zhao","doi":"10.1016/j.micpath.2026.108291","DOIUrl":"10.1016/j.micpath.2026.108291","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) infection triggers excessive inflammation, contributing to disease severity. Baicalin exerts therapeutic effects against RSV infection by inhibiting viral replication and alleviating inflammation. However, the mechanisms underlying its immunoregulatory during RSV infection remain unclear. Here we found that baicalin alleviated RSV induced inflammation by regulating the macrophage immunometabolism. To investigate metabolic modulation, metabolomic analysis was performed, revealing an obvious reversal in the metabolic profile by baicalin administration. Further metabolic flux analysis using isotope tracers demonstrated that baicalin suppressed the accumulation of lactate and succinate induced by RSV infection. Mechanistically, baicalin inhibited glycolytic metabolism and succinate driven hypoxia-inducible factor 1α (HIF-1α) signaling during RSV infection, thereby suppressing NLR family, pyrin domain containing protein 3 (NLRP3) activation and reducing IL-1β release. The effects were validated in vitro using a glycolysis activator to confirm the suppression of glycolytic metabolism, and through co-treatment with dimethylsuccinate and RSV to verify the involvement of HIF-1α-mediated hypoxia pathway. Final targeting for baicalin at pyruvate kinase M2 (PKM2) was confirmed via molecular docking and limited proteolysis-coupled mass spectrometry. Taken together, these data elucidate a mechanism of baicalin through regulatory immunometabolism of macrophage to alleviate RSV-induced inflammation, which have critical roles in the treatment of RSV infection.</p>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":" ","pages":"108291"},"PeriodicalIF":3.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989970","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}
Pub Date : 2026-01-14DOI: 10.1016/j.micpath.2026.108295
Nahla Alsayd Bouqellah
The main objective of the study was to attain improved effectiveness against various bacterial and fungal infections, tackling the widespread problem of multidrug resistance. The study presents the development and evaluation of a hybrid antimicrobial protein created by combining chitinase and sonorensin (HyChiSono). The hybrid protein HyChiSono, a 49.3 kDa chitinase–sonorensin fusion protein, was engineered, expressed in E. coli BL21(DE3), and purified to > 95 % homogeneity. Independent folding of each domain linked by a flexible (GGGGS) spacer was revealed by AlphaFold modelling; a highly ordered α/β structure was confirmed by far-UV CD. HyChiSono exhibited bactericidal activity, as assessed through well diffusion assays, membrane damage assays, and transmission electron microscopy (TEM). Quantitatively, HyChiSono demonstrated robust antibacterial activity, with recorded zones of inhibition (ZOIs) against Gram-positive Staphylococcus aureus (MIC 8 μg/mL; ZOI 17.0 ± 0.3 mm), Listeria monocytogenes (MIC 16 μg/mL; ZOI 19.3 ± 0.5 mm), and Gram-negative Escherichia coli (MIC 4 μg/mL; ZOI 18.5 ± 0.5 mm) and Salmonella enterica serovar Typhi (MIC 2 μg/mL; ZOI 18.0 ± 0.7 mm), outperforming native sonorensin by a factor of 2–4. SYTOX-green uptake and TEM demonstrated rapid membrane permeabilization and peptidoglycan thinning in both cell envelopes. Cell-wall targeting was rationalized by docking scores of −6.7 and −6.4 kcal/mol against N-acetyl-glucosamine and chitin. In addition to its antibacterial properties, the antifungal assays of hybrid protein exhibited 64.7 % growth inhibition of Fusarium oxysporum and 45.9 % against Alternaria solani, superior to standalone chitinase (41 % and 37 %, respectively). The bifunctional HyChiSono construct is offered as a single-molecule platform to combat multidrug-resistant bacteria and phytopathogenic fungi.
{"title":"Engineering a hybrid chitinase-sonorensin fusion protein for enhanced antibacterial and antifungal activity","authors":"Nahla Alsayd Bouqellah","doi":"10.1016/j.micpath.2026.108295","DOIUrl":"10.1016/j.micpath.2026.108295","url":null,"abstract":"<div><div>The main objective of the study was to attain improved effectiveness against various bacterial and fungal infections, tackling the widespread problem of multidrug resistance. The study presents the development and evaluation of a hybrid antimicrobial protein created by combining chitinase and sonorensin (HyChiSono). The hybrid protein HyChiSono, a 49.3 kDa chitinase–sonorensin fusion protein, was engineered, expressed in <em>E. coli</em> BL21(DE3), and purified to > 95 % homogeneity. Independent folding of each domain linked by a flexible (GGGGS) spacer was revealed by AlphaFold modelling; a highly ordered α/β structure was confirmed by far-UV CD. HyChiSono exhibited bactericidal activity, as assessed through well diffusion assays, membrane damage assays, and transmission electron microscopy (TEM). Quantitatively, HyChiSono demonstrated robust antibacterial activity<em>, with recorded zones of inhibition (ZOIs) against Gram-positive Staphylococcus aureus</em> (MIC 8 μg/mL; ZOI 17.0 ± 0.3 mm)<em>, Listeria monocytogenes</em> (MIC 16 μg/mL; ZOI 19.3 ± 0.5 mm)<em>, and Gram-negative Escherichia coli</em> (MIC 4 μg/mL; ZOI 18.5 ± 0.5 mm) <em>and Salmonella enterica serovar Typhi</em> (MIC 2 μg/mL; ZOI 18.0 ± 0.7 mm)<em>,</em> outperforming native sonorensin by a factor of 2–4. SYTOX-green uptake and TEM demonstrated rapid membrane permeabilization and peptidoglycan thinning in both cell envelopes. Cell-wall targeting was rationalized by docking scores of −6.7 and −6.4 kcal/mol against N-acetyl-glucosamine and chitin. In addition to its antibacterial properties, the antifungal assays of hybrid protein exhibited 64.7 % growth inhibition of <em>Fusarium oxysporum</em> and 45.9 % against <em>Alternaria solani</em>, superior to standalone chitinase (41 % and 37 %, respectively). The bifunctional HyChiSono construct is offered as a single-molecule platform to combat multidrug-resistant bacteria and phytopathogenic fungi.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"212 ","pages":"Article 108295"},"PeriodicalIF":3.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989995","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}
Pub Date : 2026-01-14DOI: 10.1016/j.micpath.2026.108299
Carmela Colica , Immacolata Vecchio , Elisabetta Aiello , Ludovico Abenavoli , Giuseppe Guido Maria Scarlata , Vincenzo Aiello
Chronic non-communicable diseases (CNCDs) extend beyond the metabolic domain, affecting neurological, cardiovascular, rheumatologic, respiratory, gastrointestinal, and renal systems. These conditions share underlying mechanisms involving low-grade inflammation, immune dysregulation, and metabolic imbalance, often influenced by gut microbiota alterations. The microbiota mediates systemic effects via microbial metabolites, immune modulation, and barrier integrity.
Recent research has highlighted that these microbiota-mediated interactions are not unidirectional but involve complex bidirectional signaling between the gut and distal organs. Microbial metabolites such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and tryptophan-derived indoles are messengers that influence neuroinflammation, endothelial function, immune responses, and even behavior. The gut microbiota is now viewed as an endocrine-like organ that can modulate systemic physiology.
Understanding these pathways has opened new avenues for treating systemic diseases by modulating the gut ecosystem, offering novel perspectives for therapeutic intervention in conditions that were traditionally managed without considering microbiota.
{"title":"Gut microbiota: origin or panacea for all ills? Gut microbiota and systemic diseases","authors":"Carmela Colica , Immacolata Vecchio , Elisabetta Aiello , Ludovico Abenavoli , Giuseppe Guido Maria Scarlata , Vincenzo Aiello","doi":"10.1016/j.micpath.2026.108299","DOIUrl":"10.1016/j.micpath.2026.108299","url":null,"abstract":"<div><div>Chronic non-communicable diseases (CNCDs) extend beyond the metabolic domain, affecting neurological, cardiovascular, rheumatologic, respiratory, gastrointestinal, and renal systems. These conditions share underlying mechanisms involving low-grade inflammation, immune dysregulation, and metabolic imbalance, often influenced by gut microbiota alterations. The microbiota mediates systemic effects via microbial metabolites, immune modulation, and barrier integrity.</div><div>Recent research has highlighted that these microbiota-mediated interactions are not unidirectional but involve complex bidirectional signaling between the gut and distal organs. Microbial metabolites such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and tryptophan-derived indoles are messengers that influence neuroinflammation, endothelial function, immune responses, and even behavior. The gut microbiota is now viewed as an endocrine-like organ that can modulate systemic physiology.</div><div>Understanding these pathways has opened new avenues for treating systemic diseases by modulating the gut ecosystem, offering novel perspectives for therapeutic intervention in conditions that were traditionally managed without considering microbiota.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"212 ","pages":"Article 108299"},"PeriodicalIF":3.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989989","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}
Pub Date : 2026-01-13DOI: 10.1016/j.micpath.2026.108303
Eduarda Ribeiro Braga, Emanoelly Machado Sousa da Silva, Anderson Hentz Gris, Jennifer Groeltz-Thrush, Pablo E. Piñeyro
Senecavirus A (SVA) has emerged as a significant viral pathogen of swine, traditionally associated with idiopathic vesicular disease but more recently linked to epidemic transient neonatal losses (ETNL), a syndrome characterized by increased mortality in piglets without consistent vesicular lesions. The mechanisms underlying SVA-associated neonatal mortality remain unclear due to the lack of specific clinical signs, frequent co-infections, and limited tissue characterization. This retrospective study analyzed 186 neonatal submissions (<24 days old) that were tested for SVA by RT-qPCR at the Iowa State University Veterinary Diagnostic Laboratory to elucidate the pathological, molecular, and microbial features associated with SVA infection. Clinical, histopathological, and microbiological data were compared between SVA-positive (n = 71) and SVA-negative (n = 253) cases, and selected tissues were analyzed by RNAscope® in situ hybridization (ISH) and immunohistochemistry (IHC) to localize viral RNA and assess co-infections with Rotavirus A and C. SVA was detected in 21.9 % of cases, most frequently in feces, serum, and spleen with significantly lower Ct values on spleen (p < 0.05), indicating a higher viral load and suggesting preferential replication in lymphoid tissues. RNAscope® analysis confirmed SVA RNA localization in spleen, lymph node, and within lymphoid aggregates of the lamina propria of the small intestine and colon, supporting a lymphoid tropism and possible immune cell replication. Clinically, diarrhea and increased mortality were the most frequent findings and were strongly associated with SVA detection (p < 0.001). The occurrence of co-infections was common; 28.2 % of SVA-positive animals had co-infection with Rotavirus A, while Rotavirus C and bacterial agents, such as Clostridium perfringens, E. coli, and Salmonella spp., were detected across both groups. Notably, respiratory pathogens including Streptococcus suis, Actinobacillus suis, and Streptococcus equisimilis were significantly more frequent in SVA-positive animals (p < 0.01), suggesting immunosuppression. Despite SVA's short viremic phase, its persistence in lymphoid tissues and association with mortality indicate a potential immunomodulatory role. These findings highlight SVA as a contributor to multifactorial neonatal disease, emphasizing the need for integrated molecular, histopathological, and epidemiological approaches to improve diagnosis and understanding of SVA pathogenesis.
{"title":"Diagnostic and pathological characterization of senecavirus A-associated epidemic transient neonatal losses in swine","authors":"Eduarda Ribeiro Braga, Emanoelly Machado Sousa da Silva, Anderson Hentz Gris, Jennifer Groeltz-Thrush, Pablo E. Piñeyro","doi":"10.1016/j.micpath.2026.108303","DOIUrl":"10.1016/j.micpath.2026.108303","url":null,"abstract":"<div><div>Senecavirus A (SVA) has emerged as a significant viral pathogen of swine, traditionally associated with idiopathic vesicular disease but more recently linked to epidemic transient neonatal losses (ETNL), a syndrome characterized by increased mortality in piglets without consistent vesicular lesions. The mechanisms underlying SVA-associated neonatal mortality remain unclear due to the lack of specific clinical signs, frequent co-infections, and limited tissue characterization. This retrospective study analyzed 186 neonatal submissions (<24 days old) that were tested for SVA by RT-qPCR at the Iowa State University Veterinary Diagnostic Laboratory to elucidate the pathological, molecular, and microbial features associated with SVA infection. Clinical, histopathological, and microbiological data were compared between SVA-positive (n = 71) and SVA-negative (n = 253) cases, and selected tissues were analyzed by RNAscope® <em>in situ</em> hybridization (ISH) and immunohistochemistry (IHC) to localize viral RNA and assess co-infections with Rotavirus A and C. SVA was detected in 21.9 % of cases, most frequently in feces, serum, and spleen with significantly lower Ct values on spleen (p < 0.05), indicating a higher viral load and suggesting preferential replication in lymphoid tissues. RNAscope® analysis confirmed SVA RNA localization in spleen, lymph node, and within lymphoid aggregates of the lamina propria of the small intestine and colon, supporting a lymphoid tropism and possible immune cell replication. Clinically, diarrhea and increased mortality were the most frequent findings and were strongly associated with SVA detection (p < 0.001). The occurrence of co-infections was common; 28.2 % of SVA-positive animals had co-infection with Rotavirus A, while Rotavirus C and bacterial agents, such as <em>Clostridium perfringens</em>, <em>E. coli</em>, and <em>Salmonella spp.,</em> were detected across both groups. Notably, respiratory pathogens including <em>Streptococcus suis</em>, <em>Actinobacillus suis</em>, and <em>Streptococcus equisimilis</em> were significantly more frequent in SVA-positive animals (p < 0.01), suggesting immunosuppression. Despite SVA's short viremic phase, its persistence in lymphoid tissues and association with mortality indicate a potential immunomodulatory role. These findings highlight SVA as a contributor to multifactorial neonatal disease, emphasizing the need for integrated molecular, histopathological, and epidemiological approaches to improve diagnosis and understanding of SVA pathogenesis.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"212 ","pages":"Article 108303"},"PeriodicalIF":3.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979369","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}
Exosomes are nanoscale extracellular vesicles secreted by a wide range of mammalian cells and serve as key mediators in the intercellular transfer of various biological materials such as proteins, nucleic acids, and lipids. However, it remains unclear whether microRNAs (miRNAs) present in exosomes derived from Seneca Valley virus (SVV)-infected IBRS-2 cells undergo substantial alterations. Moreover, the functions and regulatory pathways of differential miRNA target genes involved are unclear. In this study, Exosomes were isolated from SVV-infected IBRS-2 cells and examined for morphology, protein markers, and nucleic acid content using electron microscopy, western blotting, and PCR techniques. Then, the miRNAs present in the exosomes were sequenced, and Gene Ontology (GO) functional annotation along with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted on the target genes of differentially expressed miRNAs. Consequently, 1419 miRNAs were extracted from exosomes isolated from SVV-infected cells, and the GO functions of 281 differentially expressed miRNAs were related to RNA binding, nucleus, extracellular vesicular exosome, external side of the plasma membrane, cytoplasm, and nucleoplasm. In this study, we present the initial examination of the miRNA expression patterns and the functional roles of their related genes after SVV infects IBRS-2 cells. The results provide important information for investigating the pathogenesis of SVV and developing appropriate therapeutic strategies.
{"title":"Differentially significant miRNA target gene analysis in exosomes extracted from Seneca Valley virus infected IBRS-2 cells","authors":"Dajun Zhang , Guowei Xu , Wenxia Jiang , Dengshuai Zhao , Shikai Cai , Yuanhang Zhang , Ping Li , Han Gao , Fuqiang Huang , Shengfeng Chen , Feng Wen , LiMei Qin , Keshan Zhang","doi":"10.1016/j.micpath.2026.108300","DOIUrl":"10.1016/j.micpath.2026.108300","url":null,"abstract":"<div><div>Exosomes are nanoscale extracellular vesicles secreted by a wide range of mammalian cells and serve as key mediators in the intercellular transfer of various biological materials such as proteins, nucleic acids, and lipids. However, it remains unclear whether microRNAs (miRNAs) present in exosomes derived from Seneca Valley virus (SVV)-infected IBRS-2 cells undergo substantial alterations. Moreover, the functions and regulatory pathways of differential miRNA target genes involved are unclear. In this study, Exosomes were isolated from SVV-infected IBRS-2 cells and examined for morphology, protein markers, and nucleic acid content using electron microscopy, western blotting, and PCR techniques. Then, the miRNAs present in the exosomes were sequenced, and Gene Ontology (GO) functional annotation along with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted on the target genes of differentially expressed miRNAs. Consequently, 1419 miRNAs were extracted from exosomes isolated from SVV-infected cells, and the GO functions of 281 differentially expressed miRNAs were related to RNA binding, nucleus, extracellular vesicular exosome, external side of the plasma membrane, cytoplasm, and nucleoplasm. In this study, we present the initial examination of the miRNA expression patterns and the functional roles of their related genes after SVV infects IBRS-2 cells. The results provide important information for investigating the pathogenesis of SVV and developing appropriate therapeutic strategies.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"212 ","pages":"Article 108300"},"PeriodicalIF":3.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990011","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}
Chlamydia trachomatis is a common sexually transmitted bacterial pathogen that often causes urogenital infection and may progress to chronic inflammation and fibrosis due to its clinically silent nature. Although azithromycin and doxycycline are widely used for treatment, therapeutic failure has been documented in clinical cases. In this study, we demonstrate that orlistat disrupts the chlamydial developmental cycle both in vitro and in vivo. Orlistat inhibits early stages of chlamydial infection, reticulate body replication, and reticulate body-to-elementary body differentiation. Transcriptomic analysis revealed significant downregulation of multiple genes associated with mid-to-late developmental stages, indicating disruption of the chlamydial developmental program. These findings suggest that orlistat interferes with chlamydial growth and development, although the underlying mechanisms have not been fully defined.
{"title":"Orlistat impairs Chlamydia trachomatis development by disrupting its developmental cycle.","authors":"Jingpin Gao, Mingxin Jiang, Jianlin Chen, Hongbo Zhang","doi":"10.1016/j.micpath.2026.108301","DOIUrl":"10.1016/j.micpath.2026.108301","url":null,"abstract":"<p><p>Chlamydia trachomatis is a common sexually transmitted bacterial pathogen that often causes urogenital infection and may progress to chronic inflammation and fibrosis due to its clinically silent nature. Although azithromycin and doxycycline are widely used for treatment, therapeutic failure has been documented in clinical cases. In this study, we demonstrate that orlistat disrupts the chlamydial developmental cycle both in vitro and in vivo. Orlistat inhibits early stages of chlamydial infection, reticulate body replication, and reticulate body-to-elementary body differentiation. Transcriptomic analysis revealed significant downregulation of multiple genes associated with mid-to-late developmental stages, indicating disruption of the chlamydial developmental program. These findings suggest that orlistat interferes with chlamydial growth and development, although the underlying mechanisms have not been fully defined.</p>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":" ","pages":"108301"},"PeriodicalIF":3.5,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966440","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}
Pub Date : 2026-01-10DOI: 10.1016/j.micpath.2026.108297
Salina Patel , Shivananda Behera , Lincoln Naik , Mousumi Das , Dev Kiran Nayak , Pramathesh Kumar Dandsena , Mustafeez Ali Quaderi , Amit Mishra , Ramandeep Singh , Surajit Das , Rohan Dhiman
Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), remains a major global health threat, highlighting the need for novel therapeutic strategies. Host-directed therapies (HDTs), particularly autophagy induction via natural or pharmacological agents, offer promising strategies for combating mycobacteria. This study assessed the anti-mycobacterial potential of marine-derived Streptomyces spp. Briefly, the isolated marine Streptomyces spp. underwent primary and secondary screenings to assess their inhibitory activity against M. smegmatis. Notably, the cell-free extract of Streptomyces fradiae DNS4 (S. fradiae DNS4) demonstrated the most vigorous anti-mycobacterial activity. Optimization of culture conditions revealed maximal secondary metabolite production in ISP-7 medium at 28°C and pH 7 by S. fradiae DNS4. Furthermore, extraction using ethyl acetate, followed by GC-MS analysis, identified seventeen compounds, including the potent anti-mycobacterial secondary metabolite 2,4-di-tert-butylphenol [2,4-(DTBP)]. Subsequent experiments evaluated the host-directed anti-mycobacterial mechanism of action for 2,4-(DTBP) using dTHP-1 cells. At a non-cytotoxic concentration (10 μM), 2,4-(DTBP) treatment markedly reduced intracellular mycobacterial survival compared to untreated controls. Multiparametric investigations into autophagy induction, including LC3-I to LC3-II conversion, protein expression profiling of key autophagy markers, and MDC staining, demonstrated enhanced autophagic responses in 2,4-(DTBP)-treated macrophages. Upon 2,4-(DTBP) treatment, enhanced autophagic flux was further confirmed by increased LC3-II accumulation under Baf-A1 pre-treatment conditions. Importantly, autophagy inhibition by pre-treatment with 3-MA abolished the observed anti-mycobacterial effects, confirming the specific autophagy-dependent mechanism of 2,4-(DTBP). Collectively, these findings highlight the potential of marine-derived 2,4-(DTBP) from S. fradiae DNS4 as a novel host-directed anti-mycobacterial agent, which is mediated primarily through the targeted augmentation of autophagy in human macrophages.
{"title":"Marine Streptomyces-derived 2,4-di-tert-butylphenol enhances autophagy to eliminate mycobacteria in human macrophages","authors":"Salina Patel , Shivananda Behera , Lincoln Naik , Mousumi Das , Dev Kiran Nayak , Pramathesh Kumar Dandsena , Mustafeez Ali Quaderi , Amit Mishra , Ramandeep Singh , Surajit Das , Rohan Dhiman","doi":"10.1016/j.micpath.2026.108297","DOIUrl":"10.1016/j.micpath.2026.108297","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (<em>M. tb</em>), the causative agent of tuberculosis (TB), remains a major global health threat, highlighting the need for novel therapeutic strategies. Host-directed therapies (HDTs), particularly autophagy induction via natural or pharmacological agents, offer promising strategies for combating mycobacteria. This study assessed the anti-mycobacterial potential of marine-derived <em>Streptomyces</em> spp. Briefly, the isolated marine <em>Streptomyces</em> spp. underwent primary and secondary screenings to assess their inhibitory activity against <em>M. smegmatis</em>. Notably, the cell-free extract of <em>Streptomyces fradiae</em> DNS4 (<em>S. fradiae</em> DNS4) demonstrated the most vigorous anti-mycobacterial activity. Optimization of culture conditions revealed maximal secondary metabolite production in ISP-7 medium at 28°C and pH 7 by <em>S. fradiae</em> DNS4. Furthermore, extraction using ethyl acetate, followed by GC-MS analysis, identified seventeen compounds, including the potent anti-mycobacterial secondary metabolite 2,4-di-tert-butylphenol [2,4-(DTBP)]. Subsequent experiments evaluated the host-directed anti-mycobacterial mechanism of action for 2,4-(DTBP) using dTHP-1 cells. At a non-cytotoxic concentration (10 μM), 2,4-(DTBP) treatment markedly reduced intracellular mycobacterial survival compared to untreated controls. Multiparametric investigations into autophagy induction, including LC3-I to LC3-II conversion, protein expression profiling of key autophagy markers, and MDC staining, demonstrated enhanced autophagic responses in 2,4-(DTBP)-treated macrophages. Upon 2,4-(DTBP) treatment, enhanced autophagic flux was further confirmed by increased LC3-II accumulation under Baf-A1 pre-treatment conditions. Importantly, autophagy inhibition by pre-treatment with 3-MA abolished the observed anti-mycobacterial effects, confirming the specific autophagy-dependent mechanism of 2,4-(DTBP). Collectively, these findings highlight the potential of marine-derived 2,4-(DTBP) from <em>S. fradiae</em> DNS4 as a novel host-directed anti-mycobacterial agent, which is mediated primarily through the targeted augmentation of autophagy in human macrophages.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"212 ","pages":"Article 108297"},"PeriodicalIF":3.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959636","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}
Pub Date : 2026-01-10DOI: 10.1016/j.micpath.2026.108292
Letícia Maria Soares Azevedo , Diego Lisboa Rios , Larissa Nadur Arantes Diniz , Samantha Neves de Oliveira , Cínthia Firmo Teixeira , Danielle Cunha Teixeira , Vidyleison Neves Camargos , Antônio Lucio Teixeira , Frederico Soriani , Mauro Martins Teixeira , Vivian Vasconcelos Costa , Daniele G. Souza
Zika virus (ZIKV) is an arbovirus associated with neurological complications such as neonatal microcephaly and fetal anomalies, collectively referred to as congenital Zika syndrome. In the context of co-circulation with other arboviruses, it remains unclear whether pre-infection with a virus could be a risk factor for increased severity of ZIKV-induced disease. Here, we aimed to investigate whether there is differential gene expression in offspring of ZIKV-infected mothers pretreated with panflavivirus (4G2) at subneutralizing concentrations. Twelve weeks after birth, the offspring of these mothers were euthanized and their cerebral cortex was sampled for transcriptome analysis. Subsequently, the major differentially expressed genes (DEGs) were validated by RT-qPCR. Our results show that ZIKV infection induced fewer DEGs compared to the uninfected group, with the main findings being a suppression of genes related to cell cycle and morphogenesis. However, genes related to activation of the immune response and production of inflammatory mediators were preferentially expressed in the offspring of 4G2-treated mice compared to infected mice. Suppression of cellular and morphological processes was also observed, supporting ZIKV pathogenesis, particularly in the developing nervous system. The genetic and metabolic changes observed by transcriptomic analysis are therefore consistent with the more severe phenotypic observations in adult mice in previous studies. Our results contribute to the understanding of the severity of congenital ZIKV infection in the context of cross-reactivity of antibodies against other flaviviruses.
{"title":"Effect of antibody-dependent enhancement on the development of the offspring of mice infected by Zika virus: Analysis of the brain transcriptome","authors":"Letícia Maria Soares Azevedo , Diego Lisboa Rios , Larissa Nadur Arantes Diniz , Samantha Neves de Oliveira , Cínthia Firmo Teixeira , Danielle Cunha Teixeira , Vidyleison Neves Camargos , Antônio Lucio Teixeira , Frederico Soriani , Mauro Martins Teixeira , Vivian Vasconcelos Costa , Daniele G. Souza","doi":"10.1016/j.micpath.2026.108292","DOIUrl":"10.1016/j.micpath.2026.108292","url":null,"abstract":"<div><div>Zika virus (ZIKV) is an arbovirus associated with neurological complications such as neonatal microcephaly and fetal anomalies, collectively referred to as congenital Zika syndrome. In the context of co-circulation with other arboviruses, it remains unclear whether pre-infection with a virus could be a risk factor for increased severity of ZIKV-induced disease. Here, we aimed to investigate whether there is differential gene expression in offspring of ZIKV-infected mothers pretreated with panflavivirus (4G2) at subneutralizing concentrations. Twelve weeks after birth, the offspring of these mothers were euthanized and their cerebral cortex was sampled for transcriptome analysis. Subsequently, the major differentially expressed genes (DEGs) were validated by RT-qPCR. Our results show that ZIKV infection induced fewer DEGs compared to the uninfected group, with the main findings being a suppression of genes related to cell cycle and morphogenesis. However, genes related to activation of the immune response and production of inflammatory mediators were preferentially expressed in the offspring of 4G2-treated mice compared to infected mice. Suppression of cellular and morphological processes was also observed, supporting ZIKV pathogenesis, particularly in the developing nervous system. The genetic and metabolic changes observed by transcriptomic analysis are therefore consistent with the more severe phenotypic observations in adult mice in previous studies. Our results contribute to the understanding of the severity of congenital ZIKV infection in the context of cross-reactivity of antibodies against other flaviviruses.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"212 ","pages":"Article 108292"},"PeriodicalIF":3.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959651","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}
Pub Date : 2026-01-09DOI: 10.1016/j.micpath.2026.108296
Yan Wang, Shanshan Luo, Xinping Guo, Mengli Jin, Xingye Wang, Mingran Li, Shuang Jiang, Lin Wei, Mingjun Liu, Wu Song
Targeting bacterial virulence factors is considered a promising strategy because it poses a lower risk of promoting antibiotic resistance. This study investigated the therapeutic potential and underlying mechanism of prim-O-glucosylcimifugin (POG) against Staphylococcus aureus (S. aureus). In a diabetic mouse model, POG significantly reduced bacterial burden and accelerated wound healing, which was accompanied by enhanced tissue regeneration and collagen deposition, but no detectable toxicity. It also improved survival in a Galleria mellonella model infected with methicillin-resistant S. aureus. In vitro, POG did not inhibit bacterial growth, indicating an antivirulence rather than bactericidal mode of action. Transcriptomic analysis revealed that POG downregulated multiple virulence-associated genes, including α-hemolysin (hla), and disrupted quorum sensing, stress response, and metabolic pathways. Consistently, POG treatment suppressed hemolytic activity and the production of Hla. Molecular docking, molecular dynamics simulations, and cellular thermal shift assays confirmed the direct binding of POG to S. aureus caseinolytic protease P (SaClpP). Furthermore, fluorescence resonance energy transfer assays demonstrated that POG inhibited SaClpP activity in a dose-dependent manner, with an IC50 of 14.27 μg/mL. In a clpP knockout strain, the suppressive effects of POG on Hla production and hemolytic activity were abolished, confirming SaClpP as the key target responsible for its antivirulence effects. Collectively, these results demonstrate that POG is a promising antivirulence agent that attenuates S. aureus pathogenicity by targeting SaClpP.
{"title":"Prim-O-glucosylcimifugin targets Staphylococcus aureus caseinolytic protease P to inhibit α-hemolysin expression and promote healing of MRSA-induced diabetic skin infections","authors":"Yan Wang, Shanshan Luo, Xinping Guo, Mengli Jin, Xingye Wang, Mingran Li, Shuang Jiang, Lin Wei, Mingjun Liu, Wu Song","doi":"10.1016/j.micpath.2026.108296","DOIUrl":"10.1016/j.micpath.2026.108296","url":null,"abstract":"<div><div>Targeting bacterial virulence factors is considered a promising strategy because it poses a lower risk of promoting antibiotic resistance. This study investigated the therapeutic potential and underlying mechanism of prim-O-glucosylcimifugin (POG) against <em>Staphylococcus aureus</em> (<em>S. aureus</em>). In a diabetic mouse model, POG significantly reduced bacterial burden and accelerated wound healing, which was accompanied by enhanced tissue regeneration and collagen deposition, but no detectable toxicity. It also improved survival in a <em>Galleria mellonella</em> model infected with methicillin-resistant <em>S. aureus</em>. <em>In vitro</em>, POG did not inhibit bacterial growth, indicating an antivirulence rather than bactericidal mode of action. Transcriptomic analysis revealed that POG downregulated multiple virulence-associated genes, including α-hemolysin (<em>hla</em>), and disrupted quorum sensing, stress response, and metabolic pathways. Consistently, POG treatment suppressed hemolytic activity and the production of Hla. Molecular docking, molecular dynamics simulations, and cellular thermal shift assays confirmed the direct binding of POG to <em>S. aureus</em> caseinolytic protease P (SaClpP). Furthermore, fluorescence resonance energy transfer assays demonstrated that POG inhibited SaClpP activity in a dose-dependent manner, with an IC<sub>50</sub> of 14.27 μg/mL. In a clpP knockout strain, the suppressive effects of POG on Hla production and hemolytic activity were abolished, confirming SaClpP as the key target responsible for its antivirulence effects. Collectively, these results demonstrate that POG is a promising antivirulence agent that attenuates <em>S. aureus</em> pathogenicity by targeting SaClpP.</div></div>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":"212 ","pages":"Article 108296"},"PeriodicalIF":3.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952442","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}
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